Skeletal Structure and Function Schedule

Week/Day Date Morning 9 am-12 pm Teacher

Normal Processes; Organ structure and
W1D1 понедельник, 2 декабря 2024 function Dr.Alexandra
Abnormal Processes of Skin and
W1D2 вторник, 3 декабря 2024 subcutaneous tissue Dr.Philip
Bacterial Infectious disorders and
W1D3 среда, 4 декабря 2024 infestations Dr.Alexandra
W1D4 четверг, 5 декабря 2024 Viral Infectious disorders and infestations Dr.Julia
Fungal and parasitic skin disorders and
W1D5 пятница, 6 декабря 2024 infestations Dr.Elena

W2D1 понедельник, 9 декабря 2024 Immunologic and inflammatory disorders Dr.Alexandra

Adnexal disorders (hair and hair follicles,
nails, sweat glands, sebaceous glands, oral
W2D2 вторник, 10 декабря 2024 mucous membranes) Dr.Philip
W2D3 среда, 11 декабря 2024 Miscellaneous skin and mucosa disorders Dr.Alexandra
Bones, Joints, Tendons, Ligaments and
W2D4 четверг, 12 декабря 2024 Cartilage Dr.Philip
Muscle anatomy, physiology and the
W2D5 пятница, 13 декабря 2024 neuromuscular junction Dr.Julia

Immunological and Inflammatory Joint

W3D1 понедельник, 16 декабря 2024 Disorders Dr.Veronica
W3D2 вторник, 17 декабря 2024 Neoplasms of the Bone Dr.Veronica
Degenerative and Metabolic Disorders of
W3D3 среда, 18 декабря 2024 the Bone Dr.Veronica
Degenerative and Metabolic disorders of
W3D4 четверг, 19 декабря 2024 Joints and Connective Tissues Dr.Alexandra
Congenital Disorders and Adverse Effects of
W3D5 пятница, 20 декабря 2024 Medications Dr.Philip

W4D1 понедельник, 23 декабря 2024 Self-prep

W4D2 вторник, 24 декабря 2024 Self-prep
W4D3 среда, 25 декабря 2024 Self-prep
W4D4 четверг, 26 декабря 2024 Self-prep
Final exam Skeletal Structure and Function.
W4D5 пятница, 27 декабря 2024
 Skeletal Structure and Function

Week 1 Day 1

Normal Processes. Organ Structure and Function.

Learning Objectives:
1) Define different parts of integumentary system.
2) Outline the developmental process of the integumentary system.
3) Discuss the fetal maturation of the skin and neonatal changes and
outline the clinical relevance.
4) Define skin appendages and name the different types of skin
appendages.
A 4-month-old Caucasian boy presents to the pediatrician for a well-baby evaluation. He
has had normal measurements and developmental milestones since birth. Physical exam
reveals generalized hypopigmentation of skin, hair, and eyelashes. Ophthalmologic exam
demonstrates nystagmus, strabismus, and reduced pigmentation of the iris and retina. The
audiometric evaluation shows no abnormalities.

1) What is the most likely diagnosis?

2) Which pattern of inheritance is most likely responsible for this patient’s
condition?
3) Describe the pathophysiology of the patient’s condition.
1) This patient has oculocutaneous albinism (OCA). Albinism is characterized by the reduction or
absence of melanin resulting from defective melanocytes.
Albinism has a wide range of clinical manifestations based on the underlying genetic mutation. The
presence of ophthalmologic abnormalities confirms a suspected diagnosis of OCA
with hypopigmentation of the skin, hair, and eyelashes.
Generalized hypopigmentation with a normal ophthalmologic exam is not consistent with OCA.
Such patients must be further evaluated for metabolic disorders, such as phenylketonuria.

2) OCA is the most common form of albinism and is inherited in an autosomal recessive pattern.
Another less common form of albinism is ocular albinism (OA), in which the disease is isolated to
the eye, caused by gene mutations with X-linked inheritance pattern.

Syndromic forms of albinism include Chediak-Higashi syndrome, which has an autosomal recessive
pattern of inheritance.

Because there is no treatment for albinism, early diagnosis is essential to prevent complications,
the most significant of which include visual impairments and skin cancer.
3) Impaired melanin biosynthesis in melanocytes → absence or ↓ melanin → hypopigmentation of skin,
hair, and eyes.
Depending on the OCA type, there may be complete absence of pigmentation or a variable amount of
melanin production.
The number of melanocytes is not reduced.
Melanin is also important for the development of structures of the eye and the routing of nerve fibers
from the retina to the optic chiasm → ↓ vision in albinism.
A 33-year-old man presents to his primary care provider because of white spots on both
hands. The white spots have expanded in the last few months; they are not tender nor
ulcerated. His past medical history is relevant for hypothyroidism. Upon physical
examination, the patient shows depigmented macules on both hands, back, and
shoulders. Under a Wood lamp, the lesions emit a bright fluorescence and appear sharply
demarcated. There are no signs of inflammation in the skin lesions. His vital signs are
within normal limits.

1) What is the most likely diagnosis?

2) What diseases should be considered for
differential diagnosis?
1) Vitiligo is an acquired disorder of pigmentation characterized by depigmented macules with well-
defined borders, which develops secondarily to a loss of epidermal melanocytes. Although the
pathogenesis of vitiligo remains unknown (some studies suggest an autoimmune source/autoimmune
destruction of the melanocytes, and others suggest autophagy and oxidative stress as the root cause), the
formation of these hypopigmented skin lesions can be triggered by physical injury (e.g., trauma and sun
damage), illness, emotional stress, and even pregnancy.

Generalized vitiligo is the most common presentation. Vitiligo is characterized by the typically bilateral
distribution of depigmented patches and is usually not associated with other symptoms. Depigmented
patches can appear anywhere on the body but most commonly are seen on the hands, face, and genitals.
Woods lamp examination reveals depigmented patches, and it is the diagnostic test for vitiligo.

The diagnosis of vitiligo is clinical, with histological examination of skin biopsies reserved for
complicated cases in which the diagnosis is uncertain. The clinical manifestations and characteristics of
vitiligo include asymptomatic well-defined depigmented macules and patches that fluoresce under
Wood lamp examination. There is no inflammation in the vitiligo-affected skin areas, and depigmented
hairs are often seen within the skin lesions.

The treatment mostly consists of sun protection, topical steroids, or topical calcineurin inhibitors.
Corticosteroids act via various genomic and non-genomic pathways such as transactivation, transrepression, histone medication and Src kinase signaling.
2) Tinea versicolor (also known as pityriasis versicolor) is one of the most common superficial
cutaneous fungal infections. It is characterized by macules and patches that can be hypopigmented,
hyper-pigmentated, or erythematous. These macules are typically distributed around the trunk and
proximal upper extremities. Tinea versicolor is caused by saprophytic, lipid-dependent
yeast Malassezia. Tinea versicolor macules emit fluorescence under a Wood lamp examination and
show a characteristic fine scaling. Treatment is with topical antifungals.

Pityriasis alba is a benign dermatosis characterized by hypo-pigmentated macules and patches.

Although its cause is unknown, it has been associated with a residual post-inflammatory response
secondary to sun exposure. On examination with a Wood lamp, lesions are accentuated but
nonfluorescent.

Tinea corporis refers to a dermatophyte skin infection other than the face, feet, groin, scalp, or beard
hair. The causative organism includes the filamentous fungi from Trichophyton, Microsporum,
and Epidermophyton. Tinea corporis is characterized by pruritic, circular, erythematous, and scaling
plaques. These plaques spread centrifugally and present a central clearing and a clear raised border,
resulting in an annular plaque.
A 69-year-old man presents to his provider with an enlarging, ulcerative pink plaque on
his face. It has been present for 5 weeks and is shown in the image below. Physical
examination reveals a friable lesion that bleeds easily. Medical history is remarkable
for type 1 diabetes mellitus complicated by end-stage kidney disease, which required
kidney transplantation 5 years ago. The patient also reports a history of common viral
warts but has not had any in several years. A skin biopsy of the lesion reveals full-
thickness keratinocyte atypia with keratin pearls.

1) What is the most likely diagnosis of this

patient? ·

2) What risk factors for this patient’s

condition do you know?
1) Cutaneous squamous cell carcinoma (cSCC) is a malignant tumor of keratinocytes arising in the
skin's epidermis. It is the second most common skin cancer after basal cell carcinoma.
Cutaneous squamous cell carcinomas are locally invasive but grow slowly. Regional metastasis to lymph
nodes is more common than hematogenous spread.
The most common locations of cSCC are the face, neck, and lower lip. Their initial appearance may be
plaque-like, nodular, papillomatous, or verrucous. All forms eventually evolve into exophytic papules or
nodules with an indurated base. These skin cancers often bleed easily.

2) Risk factors for cSCC

Immunosuppression (e.g., human immunodeficiency virus (HIV), transplant patients who receive
immunosuppressive therapy): these patients are at an increased risk of cSCC and tend to exhibit more
aggressive tumors
Prolonged exposure to sunlight
Light skin
Hereditary skin disorders (e.g., xeroderma pigmentosum)
Chemical carcinogens (e.g., arsenic)
Premalignant lesions of the skin (e.g., actinic keratosis)
Skin damage (e.g., scars, burns, and ulcers)
A 73-year-old man presents to a dermatology clinic
after his family practitioner finds an ulcerated plaque
on the dorsal surface of his nose. This lesion has
changed in size and form and has bled on multiple
occasions even after the patient adopted sun-
protection measures. The patient’s medical history is
relevant for cigarette smoking and hypertension.
Physical examination reveals a poorly defined,
erythematous, ulcerated plaque on the surface of the
nose (see image). The lesion is diagnosed as
squamous cell carcinoma, and the patient undergoes
standard excision. However, the pathology report
indicates an incomplete excision.

1) What should be the next step in managing this

case?
2) Describe the staging of the disease. ·
1) Cutaneous squamous cell carcinoma is the second most common type of skin cancer in the
developed world. It results from the malignant proliferation of epidermal keratinocytes.
Cutaneous squamous cell carcinoma can arise on any cutaneous surface, with areas frequently
exposed to the sun being the most affected, especially in fair-skinned individuals.
Clinically, the condition is characterized by erythematous plaques with irregular borders that
·

typically ulcerate.
Actinic keratoses are premalignant lesions that can progress to cutaneous squamous cell carcinoma.

The first line of treatment involves standard excision; however, when this strategy fails to remove the
entire breadth of the tumor, the immediate indication is to proceed with a follow-up resection using
Mohs surgery. During this surgery, skin layers that contain cancerous tissue are progressively
removed and examined until it is confirmed that only cancer-free tissue is present. In cases where
further surgery is not possible, the indication is to proceed with radiation therapy.
 American Joint Commission on Cancer 2018 TNM system:
Only applicable to cSCC of the head and neck area (lip, ear, face, scalp, and neck).

Stage 0: cancer involves only the epidermis (in situ)

Stage I: Cancer is not large (≤ 2 cm)
No spread to the lymph nodes or other organs
Stage II: Cancer is large (>2 cm but ≤ 4 cm).
No spread to lymph nodes or other organs
Stage III: Cancer > 4 cm or cancer of any size with deep, perineural, or minor bone invasion and/or to
1 ipsilateral lymph node (no extranodal extension)
No spread to other organs
Stage IV: lesion of any size and has spread to other organs (distant metastasis)
A 52-year-old Caucasian man presents to the clinic for evaluation of a mole on his
back that he finds concerning. He states that his wife noticed the lesion and believes
that it has been getting larger. On inspection, the lesion is 10 mm in diameter with
irregular borders. A biopsy is performed. Pathology reveals abnormal melanocytes
forming nests at the dermo-epidermal junction and discohesive cell growth into the
epidermis.

1) What is the most likely diagnosis?

2) How it could be clinically suspected on examination?
3) Describe different subtypes of the patient’s disease.
4) What is the most important prognostic factor of this disease?
5) Discuss possible management options of the patient’s condition.
1) Superficial spreading melanoma is the most common form of melanoma in middle-aged
Caucasian people. It is commonly seen in sun-exposed areas. This type of melanoma has the best
prognosis because, it spreads superficially (horizontally in the upper layers) instead of vertically (into
the deeper layers), decreasing the risk of metastasis.

2) Melanoma is clinically suspected on examination using the ‘ABCDE’s.

A: asymmetry of the lesion
B: border irregularity
C: color that is not uniform
D: diameter > 6 mm (size of pencil eraser)
E: evolving size, shape, or color

The increase in size and irregular borders in this man’s lesion warrants a biopsy.

Histologic features of superficial spreading melanoma include

large, irregular melanocytes at the dermo-epidermal junction;
invasion of the upper dermis;
the absence of nevus cells.
3) Nodular melanoma has the highest likelihood of metastasis and the worst prognosis. This type of melanoma
grows vertically into the skin first: there is often no radial growth phase and lesions may be < 6 mm in
diameter. Lesions associated with this subtype often appear spontaneously and usually on sun-exposed skin.
ABCDE evaluation is not used in assessing nodular melanoma. Histologic features include dermal nodules of
irregular melanocytes that are growing deep into the dermis. Epidermal features will often be normal.
Lentigo maligna melanoma (LMM) evolves from a precursor lesion, lentigo maligna (LM) —that is,
melanoma in situ. This form of melanoma is found primarily in areas of the skin that have chronic skin
damage. This disease has a relatively slow progression since it begins with a precursor lesion that does not
initially invade the dermis. On exam, it presents with an annular, granular pattern with asymmetric
pigmented areas. Histology will show growth into the dermis. The depth of invasion is usually minimal.
LMM can be challenging to diagnose since lesions associated with it can often resemble normal skin changes
due to sun damage.
Desmoplastic melanoma is a rare and serious form of melanoma. It is seen most often in sun-exposed areas,
especially the head and neck. Many are not pigmented in appearance, and they also have unique histologic
features: vertically infiltrating irregular melanocytes in a fibrous matrix. This fibrous matrix gives the
associated lesion an appearance similar to a scar or fibroma and less like a classic melanoma. Although this type
of melanoma infiltrates early, it does not often metastasize.
Acral (hands and feet) lentiginous melanoma is the most common form of melanoma in African Americans.
This form of melanoma presents on the palms of the hands, soles of the feet, under the nail beds, and in the oral
mucosa—the hairless areas of the body, and is not caused by exposure to the sun. Most patients diagnosed
with this disease are elderly. Histologically, irregular melanocytes can be seen invading the dermis, usually
accompanied by desmoplasia. This type of melanoma has a poor prognosis and is usually diagnosed later in
the disease.
4) The most important prognostic factor of melanoma is the depth of invasion of the disease into
normal tissue. This determines the risk of metastasis and complications due to melanoma. This depth can
only be determined by biopsy, not by simply examining a lesion.

A lesion’s diameter can suggest the presence of a possible malignant lesion. A diameter > 6 mm is
suggestive of a possible malignancy. However, this is not a prognostic factor. In fact, many lesions that have
a radial growth phase, such as superficial spreading melanoma, have a better prognosis. Determining the
diameter of the lesion can aid in the diagnosis of the disease but has no effect on the outcome.

The S-100 protein is a tumor marker that is used to follow the treatment response and possible recurrence
of a number of cancers, including melanoma. This tumor marker is not specific for melanoma and should
not be used for diagnosis, however. Levels of S-100 do not correspond to prognosis; however, changes in
levels can suggest a response to treatment.

The evolution of a lesion over time (changes in its size or color) is another way to aid in the diagnosis of
melanoma. These changes can be considered normal and on their own are not indicative of disease or
prognosis. However, observing these kinds of changes can aid in the diagnosis of melanoma.

Melanoma is associated with mutations in the BRAF kinase gene. These mutations can be inherited or
spontaneous. Other genetic factors associated with melanoma play a lesser role. While a BRAF gene
mutation may increase a patient’s likelihood of developing melanoma, it is not indicative of the progress or
prognosis of the disease.
5) Wide local excision
Mohs micrographic surgery (used for in situ melanoma and lentigo maligna of the head and neck)
Regional lymph node dissection
Surgical metastasectomy (for isolated distant metastases)

For stage III disease (lymph node involvement) and stage IV (metastatic disease):
Immunotherapy (combination of):
Nivolumab or pembrolizumab (anti–programmed cell death antibody)
Ipilimumab (monoclonal antibody to cytotoxic T lymphocyte–associated antigen 4)
Targeted therapy:
For BRAF V600E/K mutation: combination vemurafenib (BRAF kinase inhibitors) with cobimetinib
(MEK inhibitor)
Other option for BRAF V600E/K mutation: dabrafenib + trametinib, encorafenib + binimetinib
For KIT mutation: imatinib (tyrosine kinase inhibitor)
Radiotherapy:
Mostly for palliation in locally advanced disease
 Skeletal Structure and Function

Week 1 Day 2

Abnormal Processes of Skin and subcutaneous tissue

Learning objectives:
1) List most frequent dermatologic symptoms and conditions in correlation with
pathology and pathophysiology aspects.
2) Summarize main manual diagnostic procedures in examination of the skin
 x
The Language of Skin Lesions
• Pustule
• A vesicle filled with pus
• Formed due to the collection of
inflammatory exudate that is rich in
leukocytes

May contain bacteria or may be sterile

Common in: Folliculitis, pustulxar
psoriasis, scabies, acne
• Nodule
• A large, firm lesion raised
above the surface of the
surrounding skin and
measuring 1–5 cm
• Usually extends into the
dermis and subcutaneous
tissue
• The surface may be smooth,
keratotic, ulcerated, or fungating.
• Examples: Neurofibromas, cyst,
lipomas
Macule
• A flat, non-palpable skin lesion measuring
≤ 1 cm in size
• Differs in color from surrounding skin
(hypopigmented/ hyperpigmented or
erythematous)
• Not raised or depressed compared to the
skin surface
• Examples: Freckles, Moles, Café-au-lait
macules, Macules in rubella, Macules in
measles
Papule
• A raised, palpable skin lesion
• measuring ≤ 1 cm in diameter
• The color can indicate the diagnosis:
• Brown or black papules are often
melanocytic lesions.
• Red papules are often vascular
lesions.

Examples:
• Nevi
• Warts
• Lichen planus
• Insect bites
• Seborrheic keratoses
• Molluscum contagiosum
• Angiomas
• Skin cancers
• Plaque
• Raised skin lesion measuring > 1 cm in
diameter
• Usually have palpable surface change as
lesion arises from the epidermis
• May have a flat-topped or rounded
appearance.

Examples: Psoriasis, Granuloma annulare,

Seborrheic dermatitis, Eczema.
• Vesicle
• A small, fluid-containing blister (collection of
fluid in the skin) measuring ≤ 1 cm in diameter
• Raised above the plane of the surrounding skin
• The fluid is visible as the lesions are translucent.
Observed in:
• Chickenpox
• Herpes zoster
• Impetigo
• Dermatitis herpetiformis
Bulla
• A large, clear fluid-containing
Blister measuring > 1 cm in diameter
May be caused by:
• Burns
• Bites
• Irritant/allergic contact dermatitis
• Drug reactions
• Classic autoimmune bullous diseases
include pemphigus vulgaris and
bullous pemphigoid.
Urticaria (Wheals or Hives)
Sharply demarcated and elevated lesions with irregular
borders:
• Usually erythematous and may have central pallor
• Formed due to sudden extravasation of fluid into the
dermis
• Wheals are pruritic and ALWAYS disappear within 24
hours.

Can be caused by:

• Medication hypersensitivity
• Insect stings
• orbites
• Autoimmune conditions
• Physical stimuli(e.g., temperature, pressure, sunlight)
Telangiectasia
Also known as "spiderveins” Appear as fine,
bright red line net-like pattern
Represent a dilation of capillaries that blanch
upon pressure Not elevated and are often found
on the face, trunk, and around the nailbed

Telangiectasias occur in:

• CREST syndrome (calcinosis, Raynaud's
phenomenon, esophageal dysmotility,
sclerodactyly, and telangiectasia)
• Dermatomyositis
• Systemic sclerosis
• Ataxia
• Skin cancers
Petechiae
• Punctate foci of hemorrhage
(seen as small red, purple, or brown spots)
measuring < 3 mm in size
• Petechiae are seen in the setting of:
• Thrombocytopenia
• Platelet dysfunction
• Vasculitis
• Infections
• (e.g.,meningococcemia, Rocky Mountain
spotted fever)
Purpura
• Extravasation of RBCs from cutaneous vessels
in the skin and mucous membranes:
• Usually palpable and non-blanching with
diascopy
• Usually red, purple, or even blue in color
•Purpura is seen in leukocytoclastic vasculitis
(e.g.,Henoch-Schöenlein purpura and polyarteritis
nodosa).
•A large area of purpura may be called an
ecchymosis
https://kazangmu.lecturio.com/#/article/3407 https://kazangmu.lecturio.com/#/article/3394
What is a skin lesion?
What is a primary skin lesion?
What do skin lesions look like?
What is a malignant skin lesion?
What do malignant skin lesions look like?
What is a benign skin lesion?
What do benign skin lesions look like?
What causes skin lesions?
Can cancer cause skin lesions?
Does AIDS cause skin lesions?
Does cirrhosis cause skin lesions?
How do you diagnose skin lesions?
How do you treat skin lesions?
What are the most important facts to know about skin lesions?
Skin lesions refer to any skin area that presents different characteristics—including color, shape, size, and texture—
from the surrounding skin. Skin lesions can be hereditary, such as moles or birthmarks, or acquired as a result of allergic
reactions, medications, sun exposure, and systemic diseases, such as autoimmune diseases, some infectious diseases,
and cancer, among others. Diagnosis of skin lesions begins with physical examination and medical history, and some
skin lesions may require further diagnostic tests, such as blood tests, imaging, or biopsy. Specific treatment depends on
the type of lesion and if malignancy is present. Some benign lesions may not need to be treated at all, while others may
need local treatment. If the skin lesion is caused by a systemic disease, treatment may also address the underlying cause.
On the other hand, malignant and premalignant lesions are generally treated with surgical removal to prevent their
progression. Finally, the use of protective sunscreen is recommended for all individuals.
A 29-year-old woman presents with skin lesions on her elbows and forearms. She notes that they first started appearing
2 months ago and have not improved. She describes the lesions as painless and rarely itchy. She denies any similar
symptoms in the past and has no other significant past medical history. A review of systems is significant for recent joint
pain, conjunctivitis, and corneal dryness. The patient is afebrile and vital signs are within normal limits. Physical
examination reveals well-demarcated salmon-colored plaques with white scale on her elbows and forearms.

What is the most likely diagnosis?

What is the pathophysiology of the present condition?
What are the most likely histopathologic findings in this patient's skin biopsy?
1. Most Likely Diagnosis: The most likely diagnosis is plaque psoriasis. The key clinical features include well-
demarcated salmon-colored plaques with white scale on extensor surfaces, such as the elbows and forearms. The
lesions are typically painless and may be associated with joint pain, known as psoriatic arthritis. The triad of skin
involvement, joint pain, and nail changes is common in psoriasis.
2. Pathophysiology: Psoriasis is a chronic immune-mediated inflammatory disorder that primarily affects the skin.
The exact cause is not fully understood, but it is thought to involve a combination of genetic, environmental, and
immunologic factors. In psoriasis, there is an abnormal activation of the immune system, leading to an increased
production of inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha) and interleukins. This
immune dysregulation causes hyperproliferation of keratinocytes in the epidermis, resulting in the characteristic
plaques and scaling seen in psoriasis.
3. Histopathologic Findings: Skin biopsy of a psoriatic lesion typically reveals the following histopathologic
findings:
1. Acanthosis: Thickening of the epidermis due to increased proliferation of keratinocytes.
2. Parakeratosis: Retention of nuclei in the stratum corneum, contributing to the characteristic scaling.
3. Munro microabscesses: Collections of neutrophils within the stratum corneum.
4. Dilated blood vessels: Enhanced blood flow in the dermis, contributing to the erythema.
5. Papillomatosis: Elongation of rete ridges, giving a characteristic appearance on histology.
https://ard.bmj.com/con
tent/64/suppl_2/ii30
A 3-year-old girl presents to the emergency department with skin desquamation over her hips, buttocks, and right arm.
She was previously seen by her pediatrician for symptoms of impetigo around the nasal folds and treated with topical
mupirocin. She was born at 39 weeks' gestation via spontaneous vaginal delivery, is up to date on all vaccines, and has
met all developmental milestones. Medical and family history are unremarkable. Her blood pressure is 100/60 mm Hg,
pulse is 140/min, respirations are 22/min, and temperature is 39.4°C (102.9°F). The total area of desquamation exceeds
20%, sparing the mucous membranes. She is transferred to the pediatric intensive care unit.

What is the most likely diagnosis and cause of her symptoms?

What is the pathophysiology of the process?
What are the possible ways of managing the condition?
Most Likely Diagnosis and Cause: This patient's presentation is consistent with Toxic Shock Syndrome (TSS), likely
triggered by Staphylococcus aureus or Streptococcus pyogenes infection. Given the recent history of impetigo and the
widespread desquamation, Staphylococcus aureus, specifically strains producing toxic shock syndrome toxin-1 (TSST-
1), is the most likely cause. TSS is a rare but potentially life-threatening condition associated with certain bacterial
toxins.
Pathophysiology: Toxic Shock Syndrome is mediated by superantigens produced by bacteria, particularly
Staphylococcus aureus and Streptococcus pyogenes. These superantigens cause a massive and uncontrolled release of
proinflammatory cytokines, leading to a systemic inflammatory response. In the case of TSST-1, which is associated
with Staphylococcus aureus, this triggers the release of cytokines such as interleukin-1 (IL-1), interleukin-2 (IL-2), and
tumor necrosis factor-alpha (TNF-alpha). The excessive cytokine release leads to the characteristic symptoms of TSS,
including fever, hypotension, and multiorgan dysfunction.
Management:
1.Fluid Resuscitation: Initial management involves aggressive fluid resuscitation to address hypotension and maintain
organ perfusion.
2.Antibiotics: Empiric broad-spectrum antibiotics such as vancomycin and clindamycin are typically initiated to cover
both Staphylococcus aureus and Streptococcus pyogenes until culture and sensitivity results are available.
3.Source Control: Identification and management of the primary infection source, such as wound care for impetigo, are
crucial.
4.Supportive Care: Supportive measures include monitoring and managing organ dysfunction, as well as addressing
complications such as renal failure or respiratory distress.
5.Intravenous Immunoglobulin (IVIG): IVIG may be considered in severe cases to neutralize superantigens and
modulate the immune response.
•SSSS: Primarily involves exfoliation of the skin, especially in areas with flexural folds (e.g., groin, axilla), and
typically spares mucous membranes.
•TSS: Involves systemic symptoms with potential multiorgan dysfunction, and the skin findings may not be as
prominent as in SSSS.
A 37-year-old man presents to the clinic because of multiple itching blisters on his buttocks for the past week. One year
ago, he noticed a similar outbreak on his inner thighs, but it receded spontaneously within a few days. Physical exam
reveals blisters that are tense and do not rupture with rubbing or pressure. A biopsy demonstrates epidermal detachment
from the basal lamina with subepidermal blisters containing extensive inflammatory infiltrates abundant with
eosinophils. Immunofluorescence shows a linear pattern of immune complex deposits at the basement membrane.

What is the most likely diagnosis?

What cellular structure is most likely involved in the formation of these blisters?
What would be the best treatment tacktics?
Most Likely Diagnosis: The most likely diagnosis is Bullous Pemphigoid. This autoimmune blistering disorder is
characterized by tense blisters that do not rupture easily, and it often presents with intense itching. The clinical history,
physical examination findings, and the histopathological and immunofluorescence findings described in the case are
consistent with Bullous Pemphigoid.
Cellular Structure Involved in Blisters Formation: The blisters in Bullous Pemphigoid are formed due to
autoantibodies targeting hemidesmosomal proteins within the basement membrane zone. Specifically, antibodies are
directed against BP180 (collagen XVII) and BP230, which are components of hemidesmosomes that anchor the
epidermis to the basement membrane.

Best Treatment Tactics:

1.Corticosteroids: Systemic corticosteroids, such as prednisone, are the mainstay of treatment for Bullous Pemphigoid.
They help suppress the autoimmune response and reduce inflammation.
2.Topical Steroids: High-potency topical corticosteroids can be used to manage localized lesions and reduce itching.
3.Immunosuppressive Agents: In cases of severe or refractory Bullous Pemphigoid, immunosuppressive agents like
azathioprine or mycophenolate mofetil may be considered as steroid-sparing agents.
4.Tetracycline and Nicotinamide: In milder cases or as adjunctive therapy, tetracycline and nicotinamide can be used.
5.Rituximab: In cases resistant to conventional therapy, rituximab, a monoclonal antibody targeting B cells, may be
considered.
6.Wound Care: Gentle wound care is important to prevent secondary infection of the blisters.
Tight Junctions:
Inflammatory Bowel Disease (IBD) such as Crohn's Disease or Ulcerative Colitis.
Tight junctions between epithelial cells in the intestinal mucosa maintain the integrity of the gut barrier. In IBD,
inflammation disrupts tight junctions, leading to increased intestinal permeability and translocation of luminal antigens,
contributing to chronic inflammation.

Adherens Junctions:
Cardiac Dysfunction in Dilated Cardiomyopathy.
Adherens junctions play a role in maintaining the structural integrity of cardiac myocytes. Disruption of adherens
junctions, often due to genetic factors or inflammation, can lead to dilated cardiomyopathy and impaired cardiac
function.

Desmosomes:
Pemphigus Vulgaris.
Pemphigus Vulgaris is an autoimmune blistering disorder where autoantibodies target desmogleins, which are
components of desmosomes in the skin. Disruption of desmosomes results in loss of cell adhesion, leading to the
formation of intraepidermal blisters.
Gap Junctions:
Arrhythmias in the Heart.
Gap junctions facilitate direct communication between adjacent cells by allowing the passage of ions and small
molecules. In the heart, disruption of gap junctions can lead to impaired electrical coupling between cardiac cells,
contributing to arrhythmias and conduction abnormalities.
·

Hemidesmosomes
Bullous Pemphigoid.
Bullous Pemphigoid is an autoimmune blistering disorder where autoantibodies target components of hemidesmosomes,
particularly BP180. Disruption of hemidesmosomes results in separation of the epidermis from the underlying basement
membrane, leading to the formation of tense blisters.
 Skeletal Structure and Function

Week 1 Day 3

Bacterial Infectious Disorders and Infestations

Learning Objectives:

1) Define and discuss the skin infectious disorders with bacterial nature.
2) Differentiate various dermatologic descriptors in infectious skin disorders.
3) Discuss pathology and pathophysiology aspects of infectious skin disorders.

&
A 74-year-old woman presents to the clinic for evaluation of an erythematous and
edematous skin rash on her right leg that has progressively worsened over the last 2
weeks. Her medical history is significant for hypertension and type 2 diabetes
mellitus. She takes lisinopril and metformin. Her vital signs are blood pressure
152/92 mm Hg, heart rate 76/min, respiratory rate 12/min, and temperature 37.8°C
(100.1°F). On physical exam, the patient appears alert and oriented. Observation of
the lesion reveals a -
Ipoorly demarcated region of erythema and edema along the
anterior aspect of the right tibia. Within the region of erythema is a 2- to 3-mm linear
break in the skin with no serous or purulent discharge. The lesion is tender and warm
when palpated. No vesicles, pustules, papules, or nodules are present. Ultrasound of
the lower extremity is negative for deep vein thrombosis and skin abscess. Blood
cultures are pending.

1) What is the most likely diagnosis based on history and physical examination?
2) What are the predisposing factors for this disease? What microorganisms could
be the cause?
3) What are the possible treatment options?
4) What diseases should be considered for differential diagnosis?
1) The clinical scenario describes an elderly diabetic woman presenting with an erythematous,
edematous, poorly demarcated skin lesion with pain and warmth on palpation. Middle-aged adults
and the elderly present with cellulitis (infection at the level of the deep dermis) more commonly than
younger individuals. The clinical manifestations of erythema, edema, pain, and warmth with a poorly
demarcated border aid to make the diagnosis.

2) Various factors predispose an individual to cellulitis, including disturbances in the skin barrier
secondary to trauma, skin inflammation (eczema, radiation), edema secondary to venous
insufficiency or lymphatic blockage, obesity, diabetes, HIV, skin breaks between toes, and
preexisting skin infections.
Streptococcus pyogenes (nonpurulent cellulitis) and Staphylococcus aureus (purulent cellulitis)
are frequent causes of soft tissue skin infections, but in a minority of cases, even gram-negative
bacilli may cause cellulitis.
·

3) Antibiotics such as cephalexin, dicloxacillin, and clindamycin are the options for treatment.
If methicillin-resistant S. aureus is suspected, amoxicillin plus trimethoprim-sulfamethoxazole is a
useful management regimen.
If treatment is unsuccessful, consider admitting the patient to the hospital for parenteral therapy.
4) Erysipelas frequently occurs more often in children and the elderly. In most cases beta-hemolytic
streptococci serve as the pathogenic agent in the skin infection. The clinical features of warmth,
erythema, and edema may appear similar to cellulitis, but there are notable differences: acute onset,
clear demarcation of erythema (plaque-like raised fiery red skin lesions), fever and/or chills, face
(butterfly shape) and ear (Milian ear sign) involvement. Penicillin and amoxicillin are the first-line
medications for the outpatient management of erysipelas.

Contact dermatitis can be caused by many irritants, including wood, fiberglass, plants, paper, dust,
water, detergents, solvents, and acidic and alkaline items. Irritant contact dermatitis consistently
manifests as erythematous, edematous, and vesicular lesions that may develop bullae and ooze.
Avoidance of irritants and, if necessary, treatment with topical corticosteroids are effective strategies
for managing irritant contact dermatitis.

Clostridial myonecrosis, known as gas gangrene, involves once healthy muscle being gradually
invaded and destroyed by Clostridium perfringens (traumatic gas gangrene), Clostridium septicum
(spontaneous gas gangrene), and, less commonly, other Clostridium species. The clinical diagnosis is
based on the observation of pain, systemic signs, and crepitus in the soft tissue. Traumatic and
spontaneous gas gangrene should be surgically debrided and the patient should be treated with
antibiotics.
A 58-year-old woman with a history of chronic alcohol abuse presents to the
emergency department because of leg pain and the skin changes seen in the image
below. She had an intramuscular injection in the same leg 2 days ago, and her
symptoms began last night. She has had diabetes mellitus for 13 years. Her
medications include metformin and insulin. She appears confused. The blood
pressure is 90/70 mm Hg, pulse 115/min, respiratory rate 21/min, and temperature
39.5℃ (103.1℉). The serum creatinine is 2.5 mg/dL.

1) What is the most likely diagnosis?

2) What toxins is most often
associated with this condition?
1) Necrotizing fasciitis is the infection and destruction of muscle fascia and the overlying
subcutaneous fat layer. The most common pathogens involved are group A streptococcus (i.e., S.
pyogenes), Clostridium perfringens, and methicillin-resistant Staphylococcus aureus (MRSA). S.
pyogenes may be introduced into deeper tissue through blunt or penetrating trauma. Any individual
can develop necrotizing fasciitis, but predisposing factors include diabetes, peripheral vascular
disease, cirrhosis, and glucocorticoid use. This patient has 2 risk factors for developing necrotizing
fasciitis—diabetes mellitus and chronic alcohol abuse.
Infections can be monomicrobial or polymicrobial.

Brawny edema, bullae, and black discoloration of the skin may follow as the infection spreads rapidly
through the lymphatic system and blood vessels into deeper layers of tissue.
Renal failure followed by shock and multiorgan failure can result.
Although subcutaneous gas is usually present in mixed bacterial infections, it is typically absent in S.
pyogenes and MRSA infections.
Therefore, while imaging techniques, such as X-ray, CT, and MRI may prove useful in visualizing gas
in the tissues, open surgery with tissue evaluation remains the gold standard for diagnosis.

Necrotizing fasciitis may be difficult to differentiate from cellulitis. If it is clinically suspected due to
profound pain, decreased sensation, or skin necrosis, an urgent surgical consultation is essential.
2) Streptococcal pyrogenic exotoxin A.
The most common causative agent for necrotizing fasciitis is Streptococcus pyogenes (also
called group A strep (GAS)). GAS produces a number of toxins that can cause a wide range
of infections. The most commonly involved strains contain M protein types 1, 3, 12, and 28
(usually elaborating pyrogenic exotoxin A) primarily responsible for producing the
symptoms associated with necrotizing fasciitis.
↑
A 7-day-old newborn boy presents to the emergency department with a history of
fever, irritability, and generalized erythema. During the first two days of clinical
manifestations, the child's parents tried to control the symptoms using acetaminophen;
however, the newborn continued to be ill, and blisters were noticeable around the
buttocks, hands, and feet. During the physical examination, his temperature is 39.0°C
(102.3°F), pulse is 130/min, and respirations are 45/min. Ears, nose, and oral mucosa
preserved their integrity, while the skin presents with diffuse blanching erythema and
flaccid blisters with a positive Nikolsky sign.

↑
1) What is the most likely diagnosis in this patient?
2) What are the possible treatment options?
3) What diseases should be considered for differential diagnosis?
1) The newborn in the case presents with clinical manifestations consistent with staphylococcal
scalded skin syndrome (SSSS or Ritter disease), a potentially life-threatening condition caused by
the dissemination of Staphylococcus aureus exfoliative toxins that cause cleavage of desmoglein 1
complex at the zona granulosa at the epidermis, resulting in fragile, tense bullae. It is usually seen
in newborns.

Typical clinical manifestations include fever, irritability, and diffuse blanching erythema that
starts around the mouth before spreading throughout the body. After 2–3 days of the initial
symptoms, fragile blisters appear, gentle pressure to the skin results in separation of the upper
epidermis and wrinkling (Nikolsky sign), and, in severe cases, the entire epidermis may be shed.

2) When SSSS is suspected, cultures from blood, urine, nasopharynx, umbilicus, and other
infectious foci should be obtained.
Treatment requires prompt administration of intravenous antimicrobial therapy with penicillinase-
resistant penicillins (e.g., nafcillin or oxacillin) or vancomycin in cases of resistance.
3) Scarlet fever is one of the nonsuppurative complications of streptococcal tonsillopharyngitis. It
consists of a diffuse erythematous eruption that results from a delayed-type of skin reaction to pyrogenic
exotoxin (erythrogenic toxin, usually types A, B, or C), which is produced by Streptococcus pyogenes.

Impetigo is most frequently diagnosed in children. It is a contagious superficial bacterial infection

caused by a direct bacterial invasion of previously normal skin (primary) or associated with minor skin
trauma, abrasions, and insect bites (secondary). Non-bullous impetigo, the most common type, typically
presents as benign papules that progress to vesicles surrounded by erythema, after which they
become pustules that will break to form thick adherent crusts.

Pyoderma occurs when S. aureus directly infects the skin of newborns. It is characterized by pustules,
erythematous papules, and honey-colored crust. Lesions usually are found in areas of trauma, such as
the diaper area, axillae, and periumbilical skin. The diagnosis can be confirmed by culturing the fluid
from the lesions.
A 60-year-old woman presents to the emergency
department with pain in her left lower leg. She states that
an insect bit her leg yesterday, and a few hours later she
noticed a sore red spot at the bite location. It steadily
became larger and is extremely painful today. Her past
medical history is significant for insulin-dependent
diabetes and obesity. Her blood pressure is 80/50 mm
Hg, pulse 120/min, respiratory rate 21/min, and
temperature 39.5℃ (103.1℉). Physical exam of the left
lower leg shows erythema, nonpitting edema, and
crepitus with severe pain on palpation of the area. The
serum creatinine is 2.5 mg/dL. Broad-spectrum antibiotic
treatment is initiated. An X-ray of the left lower leg is
shown in picture below.

1) What is the most likely diagnosis?

2) What is the most appropriate next step in
management of this patient?
1) Necrotizing fasciitis is the infection and destruction of muscle fascia and the subcutaneous fat layer
superficial to it. Polymicrobial infections are more common in older people with comorbidities, such
as diabetes. Monomicrobial infection is more common in younger people without comorbidities.
Subcutaneous gas can be present in polymicrobial infections.

2) Surgical exploration is appropriate. When crepitus is present or when symptoms are progressing
rapidly, prompt surgical exploration with direct visualization of the fascia and tissues is the diagnostic
standard. A delay in diagnosis can result in amputation or death.
Treatment begins with empirical antibiotic coverage for suspected pathogens and prompt surgical
debridement.
Leg amputation may be required in some patients with necrotizing fasciitis, especially in those with
infections that spread to deeper tissue and involve muscles.
A 7-year-old girl is brought to a clinic with symptoms of fever and sore throat for 2
days. This morning, she developed a rash in her armpits, which is progressing toward
the trunk. The teachers in her school report that none of her classmates have had
similar symptoms. She has a normal birth history. On physical examination, the child
looks healthy. Her pulse is 135/min, respiratory rate 20/min, temperature 39.0°C
(102.2°F), and blood pressure 100/60 mm Hg. An oropharyngeal examination reveals
·

circumoral pallor with a red tongue, as shown in the photograph. The chest and
cardiac examinations are within normal limits. No hepatosplenomegaly is noted.

1) What is the most likely diagnosis?

2) What complications can develop in the patient?
3) What is the next best diagnostic step in this
patient?
4) What are management options for this
infection?
5) What diseases should be considered for
differential diagnosis?
1) Scarlet fever ("scarlatina") is a diffuse erythematous eruption that occasionally occurs in
association with group A Streptococcus pyogenes (GAS) pharyngitis, a very common bacterial
infection in children 6–12 years of age.
The rash is caused by the effects of 1 of several types of streptococcal pyrogenic exotoxins. Scarlet
fever is characterized by a sore throat, fever, swollen lymph nodes, and a characteristic sandpaper-
like rash. The rash appears 12–48 hours after the onset of fever and begins to peel off (desquamate)
I
after 3–5 days. It starts in the armpits and groin area and spreads to the chest and back and then to the
rest of the body. The tongue may be red and bumpy, with a strawberry appearance.
2) GAS pharyngitis is also responsible for other suppurative and nonsuppurative complications.
Suppurative complications result from the spread of infection from the pharyngeal mucosa to deeper
tissues by direct extension or by the hematogenous or lymphatic route. They may include cervical
lymphadenitis, peritonsillar or retropharyngeal abscess, sinusitis, otitis media, meningitis, bacteremia,
endocarditis, or pneumonia.
Nonsuppurative complications include acute rheumatic fever (ARF) and poststreptococcal
glomerulonephritis (PSGN), which result from immune responses to streptococcal infection in
susceptible individuals. ARF (due to cross-reactivity between antibodies produced against the
Streptococcal M protein and self-antigens) usually occurs within 2–3 weeks after GAS pharyngitis,
and PSGN occurs 1–3 weeks after GAS pharyngitis (and between 3–6 weeks after GAS skin
infection).
3) A rapid PCR assay is the best initial test for streptococcal pharyngitis.
A rapid antigen detection test (RADT) is the usual test performed in a clinician’s office. Because
the antigen test has a sensitivity of only 70%–90%, a PCR assay or a throat culture (the gold
standard) should be obtained if the RADT is negative.

4) Antibiotics are given primarily to prevent suppurative complications and reduce the likelihood
of ARF, but they do not affect the development of PSGN.
Amoxicillin and penicillin are the treatments of choice. A 1st-generation cephalosporin, such as
cephalexin or cefadroxil, may be substituted for penicillin in cases of penicillin allergy. Alternative
agents are erythromycin and azithromycin (preferred because of better tolerability). Prevention of
ARF depends on eradicating the organism from the pharynx, not simply on the resolution of
symptoms, so 10 days of penicillin treatment are required.
5) Measles is a disease caused by a single-stranded, enveloped RNA virus of the Paramyxoviridae
family. It presents as a prodrome of fever, malaise, and cough, coryza, and conjunctivitis (the 3
Cs), followed by pathognomonic Koplik spots (bright red spots with a blue-white center on the
buccal mucosa) and then by a maculopapular rash. The rash appears approximately 2–4 days after the
onset of fever. The rash spreads from the head to the trunk to the lower extremities. Patients are
considered contagious from 4 days before to 4 days after the appearance of the rash.

Erythema infectiosum is caused by parvovirus B19. The infective period is a few days prior to the
onset of the rash, when patients first have flu-like symptoms. The incubation period for the fifth
disease is 4–14 days. A slapped-cheek appearance and a nonpruritic maculopapular rash over the
extensor surface of the body are the characteristic features of the disease.

Kawasaki disease is a type of vasculitis (inflammation of the blood vessels) affecting medium-sized
arteries throughout the body. The diagnostic criteria for typical Kawasaki disease include:
Conjunctivitis (spares limbus)
Polymorphous rashes on all parts of the body
Cervical adenopathy (> 1.5 cm)
Strawberry tongue
Swollen hands and feet
Number Names for the Etiology Description
disease
1st Measles Measles morbillivirus Cough, coryza, conjunctivitis
disease Rubeola Koplik's spots (blue-white spots with a red halo) on the buccal membrane
Maculopapular rash begins on the face and behind the ears → spreads to trunk/extremities
2nd Scarlet Fever Streptococcus pyogenes Sandpaper-feeling maculopapular rash that begins on the neck and groin → spreads to
disease Scarlatina trunk/extremities
Dark, hyperpigmented areas, especially in skin creases, called Pastia's lines
Strawberry tongue: coated white membrane through which swollen, red papillae protrude
3rd Rubella Rubella virus Asymptomatic in 50% of cases
disease German Fine macular rash on the face (behind the ears) → spreads to the neck, trunk, and extremities
measles (spares palms/soles)
Forscheimer's spots: Pinpoint red macules and petechiae can be seen over the soft palate/uvula
Generalized tender lymphadenopathy
4th Staphylococcal Due to Staphylococcus Begins with a diffuse erythematous rash that usually begins around the mouth → fluid-filled
disease Scalded Skin aureus strains that make bullae or cutaneous blisters → rupture and desquamate
Syndrome epidermolytic Nikolsky’s sign: Applying pressure on the skin with a finger (stroking) results in sloughing off
Filatow-Dukes' (exfoliative) toxin of upper layers.
disease
Ritter's disease
5th Erythema Erythrovirus or parvovirus Facial erythema ("slapped-cheek rash") that consist of red papules on the cheeks
disease infectiosum B19 (Primate Begins on the face → spreads to the extremities → extends to trunk/buttocks
erythroparvovirus 1) Initially confluent, then becomes net-like or reticular as it clears
6th Exanthem Human herpesvirus 6B or Sudden onset of high fever
disease subitum human herpesvirus 7 Nagayama spots: papular spots on the soft palate/uvula
Roseola Rash begins as fever resolves (the term “exanthem subitum” describes “surprise” of rash after
infantum the fever subsides)
Rose rash of Numerous rose-pink, almond-shaped macules on the trunk and neck → sometimes spreads to
infants face/extremities
3-day fever
 Skeletal Structure and Function

Week 1 Day 4

Viral Infectious disorders and infestations of skin

Learning Objectives:
• Define and discuss the skin infectious disorders with viral nature
• Differentiate various dermatologic descriptors of viral skin disorders.
• Discuss pathology and pathophysiology and basic management aspects of
infectious skin disorders.
 CASE 1

A 6-year-old girl has a rash on her face that appeared yesterday. The rash is erythematous and located over
the malar eminences bilaterally. The rash is macular; there are no papules, vesicles, or pustules. A few days
prior to the appearance of the rash, she had a runny nose and anorexia.

Based on this history and physical examination, which of the

following is the most likely diagnosis?
Methods of Diagnosis
CASE 1

Parvovirus B19 causes erythema infectiosum

(slapped cheek syndrome, fifth disease),
aplastic anemia (especially in patients with
sickle cell anemia), and fetal infections,
including hydrops fetalis.

Slapped cheek syndrome—note erythematous

macular rash on cheeks bilaterally caused by
parvovirus B19. The disease in children is
also called fifth disease. The four other
macular or maculopapular rash diseases of
childhood are measles, rubella, scarlet fever,
and roseola.
 CASE 1

Parvovirus B19 is a very small (22 nm) nonenveloped virus with a single-stranded DNA genome. The
genome is negative-strand DNA, but there is no virion polymerase. The capsid has icosahedral symmetry.
There is one serotype.

Transmission & Epidemiology

B19 virus is transmitted primarily by the respiratory route; transplacental transmission also occurs. Blood
donated for transfusions also can transmit the virus. B19 virus infection occurs worldwide, and about half the
people in the United States older than 18 years of age have antibodies to the virus. Humans are the natural
reservoir; animals are not a source of human infection.

Pathogenesis & Immunity

B19 virus infects primarily two types of cells: red blood cell precursors (erythroblasts) in the bone marrow,
which accounts for the aplastic anemia, and endothelial cells in the blood vessels, which accounts, in part, for
the rash associated with erythema infectiosum. Immune complexes composed of virus and IgM or IgG also
contribute to the pathogenesis of the rash and to the arthritis that is seen in some adults infected with B19
virus. Infection provides lifelong immunity against reinfection.
Hydrops fetalis manifests as massive edema of the fetus. This is secondary to congestive heart failure
precipitated by severe anemia caused by the death of parvovirus B19–infected erythroblasts in the fetus.
 CASE 1
Clinical Findings
There are five important clinical presentations.
Erythema Infectiosum (Slapped Cheek Syndrome, Fifth Disease)
This is a mild disease, primarily of childhood, characterized by a bright red rash that is most prominent on the cheeks,
accompanied by low-grade fever, runny nose (coryza), and sore throat. A “lacy,” less intense, erythematous rash appears on
the body. The symptoms resolve in about 1 week.
Aplastic Anemia
Children with chronic anemia, such as sickle cell anemia, thalassemia, and spherocytosis, can have transient but severe
aplastic anemia (aplastic crisis) when infected with B19 virus. People with normal red blood cells do not have clinically
apparent anemia, although their red blood cell precursors are infected.
Fetal Infections
If a woman is infected with B19 virus during the first or second trimester of pregnancy, the virus may cross the placenta and
infect the fetus. Infection during the first trimester is associated with fetal death, whereas infection during the second
trimester leads to hydrops fetalis. Third-trimester infections do not result in important clinical findings. B19 virus is not a
common cause of congenital abnormalities, probably because the fetus dies when infected early in pregnancy.
Arthritis
Parvovirus B19 infection in adults, especially women, can cause arthritis mainly involving the small joints of the hands and
feet bilaterally. It resembles rheumatoid arthritis. Other viral infections that cause an immune complex–related arthritis
include hepatitis B and rubella.
Chronic B19 Infection
People with immunodeficiencies, especially HIV-infected, chemotherapy, or transplant patients, can have chronic anemia,
leukopenia, or thrombocytopenia as a result of chronic B19 infection.
 CASE 1

Laboratory Diagnosis
Fifth disease and aplastic anemia are usually diagnosed by detecting IgM antibodies. B19 virus can be isolated from throat
swabs, but this is not usually done. In immunocompromised patients, antibodies may not be detectable; therefore, viral DNA
in the blood can be assayed by PCR methods. Fetal infection can be determined by PCR analysis of amniotic fluid.
Treatment & Prevention
There is no specific treatment of B19 infection. Pooled immune globulins may have a beneficial effect on chronic B19
infection in patients with immunodeficiencies. There is no vaccine or chemoprophylaxis.
 CASE 2

A 58-year-old patient complained of painless masses on the palms of his hands

Based on this history and physical

examination, which of the following is the
most likely diagnosis?
Methods of Diagnosis
 CASE 3

A 24-year-old girl went to a gynaecologist with masses in the vaginal area, the masses were removed and
then referred to a coloproctologist.

Based on this history and physical

examination, which of the following is the
most likely diagnosis?
Methods of Diagnosis
 CASE 2,3

PAPILLOMAVIRUSES
Diseases
Human papillomavirus causes papillomas, which are benign tumors of squamous cells (e.g., warts on the
skin). Some HPV types, especially types 16 and 18, cause carcinoma of the cervix, penis, and anus.

Important Properties
Papillomaviruses are nonenveloped viruses with double-stranded circular DNA and an icosahedral
nucleocapsid. Two of the early genes, E6 and E7, are implicated in carcinogenesis. They encode proteins that
inactivate proteins encoded by tumor suppressor genes in human cells (e.g., the p53 gene and the
retinoblastoma [RB] gene, respectively). Inactivation of the p53 and RB proteins is an important step in the
process by which a normal cell becomes a cancer cell.

There are at least 100 types of papillomaviruses, classified primarily on the basis of DNA restriction fragment
analysis. There is a pronounced predilection of certain types to infect certain tissues. For example, skin
warts are caused primarily by HPV-1 through HPV-4, whereas genital warts are usually caused by HPV-6 and
HPV-11. Approximately 30 types of HPV infect the genital tract.
 CASE 2,3
PAPILLOMAVIRUSES
Transmission & Epidemiology
Papillomaviruses are transmitted primarily by skin-to-skin contact and by genital contact. Genital warts are
among the most common sexually transmitted diseases. Skin warts are more common in children and
young adults and tend to regress in older adults. HPV transmitted from an infected mother to the neonate
during childbirth causes warts in the mouth and in the respiratory tract, especially on the larynx, of the infant.
Many species of animals are infected with their own types of papillomaviruses, but these viruses are not an
important source of human infection.

Pathogenesis & Immunity

Papillomaviruses infect squamous epithelial cells and induce within those cells a characteristic cytoplasmic
vacuole. These vacuolated cells, called koilocytes, are the hallmark of infection by these viruses. Most warts
are benign and do not progress to malignancy. However, HPV infection is associated with carcinoma of the
uterine cervix and penis. The proteins encoded by viral genes E6 and E7 interfere with the growth-inhibitory
activity of the proteins encoded by the p53 and RB tumor suppressor genes and thereby contribute to
oncogenesis by these viruses

Both cell-mediated immunity and antibody are induced by viral infection and are involved in the spontaneous
regression of warts. Immunosuppressed patients (e.g., patients with acquired immunodeficiency syndrome
[AIDS]) have more extensive warts, and women infected with human immunodeficiency virus (HIV) have a
very high rate of carcinoma of the cervix.
 CASE 2,3
Clinical Findings
Papillomas of various organs are the predominant finding. These papillomas are caused by specific HPV types.
For example, skin and plantar warts are caused primarily by HPV-1 through HPV-4, whereas genital warts
(condylomata acuminata) are caused primarily by HPV-6 and HPV-11. HPV-6 and HPV-11 also cause
respiratory tract papillomas, especially laryngeal papillomas, in young children.

Laboratory Diagnosis
Infections are usually diagnosed clinically. The presence of koilocytes in the lesions indicates HPV infection. A
polymerase chain reaction (PCR)–based test can be used to detect the presence of the DNA of 14 high-risk
genotypes, including HPV-16 and HPV-18.
Diagnostic tests based on detection of antibodies in a patient’s serum or on isolation of the virus from a patient’s
tissue are not used.
Treatment & Prevention
The usual treatment for genital warts is podophyllin; alpha interferon is also effective and is better at preventing
recurrences than are non-antiviral treatments. Liquid nitrogen is commonly used for skin warts. Plantar warts can
be removed surgically or treated with salicylic acid topically. Cidofovir may be useful in the treatment of severe
HPV infections.
There are two vaccines against HPV. Gardasil, a recombinant vaccine against four types of HPV, contains the
capsid proteins of types 6 and 11, which cause genital warts, and types 16 and 18, which are the two most
common causes of cervical, penile, and anal carcinoma. Cervarix is also a recombinant vaccine but contains the
proteins only of types 16 and 18. Cervarix contains an adjuvant called AS04 that stimulates Toll-like receptors and
thereby enhances antibody production. HPV immunizations have no effect on existing papillomas.
 CASE 4

A 10-day-old neonate has several vesicles on the scalp and around the eyes. The child is otherwise well,
afebrile, and feeding normally. A Giemsa-stained smear of material from the base of a vesicle
revealed multinucleated giant cells with intranuclear inclusions.

Based on this history and physical

examination, which of the following is the
most likely diagnosis?
Methods of Diagnosis
 CASE 5

An 48-year-old man complains of a painful rash on lips. The rash is vesicular and only on that side.
Smear of material from the base of the vesicle reveals multinucleated giant cells with intranuclear
inclusions.

Based on this history and physical

examination, which of the following is the
most likely diagnosis?
Methods of Diagnosis
 CASE 6

An 80-year-old man complains of a painful rash on his left subcostal region. The rash is vesicular and
only on that side. He is being treated with chemotherapy for leukemia.

Based on this history and physical

examination, which of the following is the
most likely diagnosis?
Methods of Diagnosis
 CASE 4,5,6

The herpesvirus family contains six important human pathogens: herpes simplex virus types 1 and 2, varicella-
zoster virus, cytomegalovirus, Epstein–Barr virus, and human herpesvirus 8 (the cause of Kaposi’s sarcoma).

All herpesviruses are structurally similar. Each has an icosahedral core surrounded by a lipoprotein envelope. The
genome is linear double-stranded DNA. The virion does not contain a polymerase. They are large (120–200 nm in
diameter), second in size only to poxviruses.

Herpesviruses are noted for their ability to cause latent infections. In these infections, the acute disease is followed
by an asymptomatic period during which the virus remains in a quiescent (latent) state. When the patient is exposed
to an inciting agent or immunosuppression occurs, reactivation of virus replication and disease can occur.1 With
some herpesviruses (e.g., herpes simplex virus), the symptoms of the subsequent episodes are similar to those of the
initial one; however, with others (e.g., varicella-zoster virus), they are different.

Three of the herpesviruses, HSV types 1 and 2 and varicella-zoster virus (VZV), cause a vesicular rash, both in
primary infections and in reactivations. Primary infections are usually more severe than reactivations. The other two
herpesviruses, CMV and Epstein–Barr virus (EBV), do not cause a vesicular rash.
CASE 4,5,6
 CASE 4,5,6

Four herpesviruses, namely HSV types 1 and 2, VZV, and CMV, induce the formation of multinucleated giant
cells, which can be seen microscopically in the lesions. The importance of giant cells is best illustrated by the
Tzanck smear, which reveals multinucleated giant cells in a smear taken from the painful vesicles of the genitals
caused by HSV type 2

Herpes simplex virus type 2—

multinucleated giant cells in Tzanck
s mear. A r r o w p o in ts to a
multinucleated giant cell w ith
approximately eight nuclei.
 CASE 4,5,6

Four herpesviruses, namely HSV types 1 and 2, VZV, and CMV, induce the formation of multinucleated giant
cells, which can be seen microscopically in the lesions. The importance of giant cells is best illustrated by the
Tzanck smear, which reveals multinucleated giant cells in a smear taken from the painful vesicles of the genitals
caused by HSV type 2
HERPES SIMPLEX VIRUSES (HSV)
HSV type 1 (HSV-1) and type 2 (HSV-2) are distinguished by two main criteria: antigenicity and location of
lesions. Lesions caused by HSV-1 are, in general, above the waist, whereas those caused by HSV-2 are below
the waist. Table 37–3 describes some important differences between the diseases caused by HSV-1 and
HSV-2.
TABLE 37–3 Comparison of Diseases Caused by HSV-1 and HSV-2
 CASE 4,5,6

Diseases
HSV-1 causes acute gingivostomatitis, recurrent herpes labialis (cold sores), keratoconjunctivitis (keratitis), and
encephalitis, primarily in adults. HSV-2 causes herpes genitalis (genital herpes), neonatal encephalitis and other
forms of neonatal herpes, and aseptic meningitis. Infection by HSV-1 or HSV-2 is a common cause of erythema
multiforme.
Important Properties
HSV-1 and HSV-2 are structurally and morphologically indistinguishable. They can, however, be differentiated by
the restriction endonuclease patterns of their genome DNA and by type-specific monoclonal antisera against
glycoprotein G. Humans are the natural hosts of both HSV-1 and HSV-2.

Transmission & Epidemiology

HSV-1 is transmitted primarily in saliva, whereas HSV-2 is transmitted by sexual contact. As a result, HSV-1
infections occur mainly on the face, whereas HSV-2 lesions occur in the genital area. However, oral–genital sexual
practices can result in HSV-1 infections of the genitals and HSV-2 lesions in the oral cavity (this occurs in about
10%–20% of cases). Although transmission occurs most often when active lesions are present, asymptomatic
shedding of both HSV-1 and HSV-2 does occur and plays an important role in transmission.
 CASE 4,5,6

Pathogenesis & Immunity

The virus replicates in the skin or mucous membrane at the initial site of infection, and then migrates up the neuron
by retrograde axonal flow and becomes latent in the sensory ganglion cells. In general, HSV-1 becomes latent in
the trigeminal ganglia, whereas HSV-2 becomes latent in the lumbar and sacral ganglia. During latency, most—if
not all—viral DNA is located in the cytoplasm rather than integrated into nuclear DNA. The virus can be reactivated
from the latent state by a variety of inducers (e.g., sunlight, hormonal changes, trauma, stress, and fever), at which
time it migrates down the neuron and replicates in the skin, causing lesions.

The typical skin lesion is a vesicle that contains serous fluid filled with virus particles and cell debris. When the
vesicle ruptures, virus is liberated and can be transmitted to other individuals. Multinucleated giant cells are
typically found at the base of herpesvirus lesions.

Immunity is type-specific, but some cross-protection exists. However, immunity is incomplete, and both reinfection
and reactivation occur in the presence of circulating IgG. Cell-mediated immunity is important in limiting
herpesviruses, because its suppression often results in reactivation, spread, and severe disease.
 CASE 4,5,6

Clinical Findings
HSV-1 causes several forms of primary and recurrent disease:
• Gingivostomatitis
• Herpes labialis
• Keratoconjunctivitis
• Encephalitis
• Herpetic whitlow is a pustular lesion of the skin of the finger or hand. It can occur in medical personnel as a result
of contact with patient’s lesions.
• Herpes gladiatorum, as the name implies, occurs in wrestlers and others who have close body contact. It is caused
primarily by HSV-1 and is characterized by vesicular lesions on the head, neck, and trunk.
• Eczema herpeticum (Kaposi’s varicelliform eruption) is an infection of the skin of a patient with atopic dermatitis.
Vesicular lesions are seen at the site of the atopic dermatitis (eczema). Most cases occur in children.
• Disseminated infections, such as esophagitis and pneumonia, occur in immunocompromised patients with depressed
T-cell function.
HSV-2 causes several diseases, both primary and recurrent:
• Genital herpes is characterized by painful vesicular lesions of the male and female genitals and anal area
• Neonatal herpes
• Aseptic meningitis caused by HSV-2 is usually a mild, self-limited disease with few sequelae.
 CASE 4,5,6
Laboratory Diagnosis

An important diagnostic procedure is isolation of the virus from the lesion by growth in cell culture. The
typical cytopathic effect occurs in 1 to 3 days, after which the virus is identified by fluorescent antibody
staining of the infected cells or by detecting virus-specific glycoproteins in enzyme-linked immunosorbent
assays (ELISAs). HSV-1 can be distinguished from HSV-2 by using monoclonal antibody against glycoprotein
G often in an ELISA test.

A rapid presumptive diagnosis can be made from skin lesions by using the Tzanck smear, in which cells from
the base of the vesicle are stained with Giemsa stain. The presence of multinucleated giant cells suggests
herpesvirus infection.

If herpes encephalitis is suspected, a rapid diagnosis can be made by detecting HSV DNA in the spinal fluid by
using a polymerase chain reaction (PCR) assay. The PCR assay is more sensitive than viral culture. The
diagnosis of neonatal herpes infection typically involves the use of viral cultures or PCR assay.
Serologic tests such as the neutralization test can be used in the diagnosis of primary infections because a
significant rise in antibody titer is readily observed. However, they are of no use in the diagnosis of recurrent
infections because many adults already have circulating antibodies, and recurrences rarely cause a rise in
antibody titer.
 CASE 4,5,6

Treatment

Acyclovir (acycloguanosine, Zovirax) is the treatment of choice for encephalitis and systemic disease caused by
HSV-1. It is also useful for the treatment of primary and recurrent genital herpes; it shortens the duration of the
lesions and reduces the extent of shedding of the virus but does not cure the latent state. Acyclovir is also used
to treat neonatal infections caused by HSV-2. Mutants of HSV-1 resistant to acyclovir have been isolated from
patients; foscarnet can be used in these cases.

For HSV-1 eye infections, other nucleoside analogues (e.g., trifluridine [Viroptic]) are used topically. Oral
acyclovir is also used for HSV keratitis. Penciclovir (a derivative of acyclovir) or docosanol (a long-chain
saturated alcohol) can be used to treat recurrences of orolabial HSV-1 infections in immunocompetent adults.
Valacyclovir (Valtrex) and famciclovir (Famvir) are used in the treatment of genital herpes and in the suppression
of recurrences.
 CASE 4,5,6
VARICELLA-ZOSTER VIRUS (VZV)

Disease
Varicella (chickenpox) is the primary disease; zoster (shingles) is the recurrent form.

Important Properties
VZV is structurally and morphologically similar to other herpesviruses but is antigenically different. It has a
single serotype. The same virus causes both varicella and zoster. Humans are the natural hosts.

Transmission & Epidemiology

The virus is transmitted by respiratory droplets and by direct contact with the lesions. Varicella is a highly
contagious disease of childhood; more than 90% of people in the United States have antibody by age 10 years.
Varicella occurs worldwide. Prior to 2001, there were more cases of chickenpox than any other notifiable
disease, but the widespread use of the vaccine has significantly reduced the number of cases.

There is infectious VZV in zoster vesicles. This virus can be transmitted, usually by direct contact, to children
and can cause varicella. The appearance of either varicella or zoster in a hospital is a major infection control
problem because the virus can be transmitted to immunocompromised patients and cause life-threatening
disseminated infection.
 CASE 4,5,6

Pathogenesis & Immunity

VZV infects the mucosa of the upper respiratory tract, and then spreads via the blood to the skin, where the
typical vesicular rash occurs. Multinucleated giant cells with intranuclear inclusions are seen in the base of the
lesions. The virus infects sensory neurons and is carried by retrograde axonal flow into the cells of the dorsal
root ganglia, where the virus becomes latent.
In latently infected cells, VZV DNA is located in the nucleus and is not integrated into cellular DNA. Later in
life, frequently at times of reduced cell-mediated immunity or local trauma, the virus is activated and causes the
vesicular skin lesions and nerve pain of zoster.
Immunity following varicella is lifelong: A person gets varicella only once, but zoster can occur despite this
immunity to varicella. Zoster usually occurs only once. The frequency of zoster increases with advancing age,
perhaps as a consequence of waning immunity.
 CASE 4,5,6

Clinical Findings
Varicella
After an incubation period of 14 to 21 days, brief prodromal
symptoms of fever and malaise occur. A papulovesicular rash
then appears in crops on the trunk and spreads to the head and
extremities. The rash evolves from papules to vesicles,
pustules, and, finally, crusts. Itching (pruritus) is a prominent
symptom, especially when vesicles are present. Varicella is
mild in children but more severe in adults. Varicella
pneumonia and encephalitis are the major rare complications,
occurring more often in adults. Reye’s
syndrome, characterized by encephalopathy and liver
degeneration, is associated with VZV and influenza B virus
infection, especially in children given aspirin. Its pathogenesis
is unknown.
 CASE 4,5,6

Zoster
The occurrence of painful vesicles along the course of a
sensory nerve of the head or trunk is the usual picture .
The pain can last for weeks, and postzoster neuralgia
(also known as postherpetic neuralgia) can be
debilitating. In immunocompromised patients, life-
threatening disseminated infections such as pneumonia
can occur.
 CASE 4,5,6

Laboratory Diagnosis
Although most diagnoses are made clinically, laboratory tests are available. A presumptive diagnosis can be made by
using the Tzanck smear. Multinucleated giant cells are seen in VZV as well as HSV lesions. The definitive diagnosis is
made by isolation of the virus in cell culture and identification with specific antiserum. A rise in antibody titer can be used
to diagnose varicella but is less useful in the diagnosis of zoster.

Treatment
No antiviral therapy is necessary for chickenpox or zoster in immunocompetent children. Immunocompetent adults with
either moderate or severe cases of chickenpox or zoster often are treated with acyclovir because it can reduce the duration
and severity of symptoms. Immunocompromised children and adults with chickenpox, zoster, or disseminated disease
should be treated with acyclovir. Disease caused by acyclovir-resistant strains of VZV can be treated with foscarnet. Two
drugs similar to acyclovir, famciclovir (Famvir) and valacyclovir (Valtrex), can be used in patients with zoster to
accelerate healing of the lesions, but none of these drugs can cure the latent state. There is some evidence that these drugs
reduce the incidence of postzoster neuralgia.

Prevention
There are two vaccines against VZV: one designed to prevent varicella, called Varivax, and the other designed to prevent
zoster, called Zostavax. Both contain live, attenuated VZV, but the zoster vaccine contains 14 times more virus than the
varicella vaccine. The zoster vaccine is effective in preventing the symptoms of zoster, but does not eradicate the latent
state of VZV.
 CASE 7

A 32-year-old woman presented with complaints of rash for

1 day, along with a mild sore throat for 3 days. The rash had
first appeared on the face, followed by the trunk and
extremities and caused little itching. She also had an apparent
posterior cervical and posterior auricular lymphadenopathy

Based on this history and physical examination, which of

the following is the most likely diagnosis?
Methods of Diagnosis
 CASE 7

She had no recent history of travel or exposure to animals or

insects. She had no history of rubella vaccination. The diagnosis of
rubella was confirmed based on a serum rubella IgM test.
 CASE 7

Rubella (German measles) is a member of the Togaviridae family with an approximately 10-kb single-stranded, positive-
sense polyadenylated RNA genome and a lipid envelope.

Humans are the only natural host. Direct person-to-person airborne spread by infected droplets appears to be the usual
mode of transmission. The patient with subclinical infection is also a source of rubella virus. Patients are most contagious
for a few days before and after the onset of rash, although virus may be present in pharyngeal secretions for as long as 1
week before and 2 weeks after the onset of rash.
 CASE 7

The clinical manifestations of postnatal rubella range from inapparent infection to a characteristic pattern of adenopathy,
rash, and low-grade fever. The incubation period is from 14 to 21 days. Primary replication occurs in the nasopharynx,
followed by viremia at approximately days 5–7 and rash at days 14–17. A typical clinical course begins with adenopathy
involving primarily the postauricular, occipital, and posterior cervical nodes, which may be slightly painful and tender.
Although symptoms usually clear promptly as the rash fades, nodes may remain palpable for several weeks. Adolescents
and adults may complain of malaise, headache, a low-grade fever, sore throat, and mild coryza during a 1-day to 5-day
prodromal period that frequently accompanies the onset of adenopathy.

The rubella rash is variable but usually brief. It may be no more than a transient blush, but classically it persists for 2 to 3
days in a pattern that has been called kaleidoscopic because of its changing appearance. Initially, small, irregular pink
macules begin on the face and spread rapidly (usually within 24 hours) to the neck, trunk, arms, and ultimately legs. By
the next day, these lesions may have coalesced, developed a maculopapular component, and become scarlatiniform.
An exanthema consisting of punctate or slightly larger red spots on the soft palate may be present during the late
prodrome and early rash phase.
 CASE 7

Diagnosis of rubelliform rashes in acutely ill, febrile children and in young adults requires accurate historical information
from parents: vaccine history, source of exposure, prodrome, and progression of rash.

Laboratory testing is required. Rubella can be diagnosed by isolating the virus, detecting viral nucleic acid by polymerase
chain reaction or demonstrating rising titers of rubella antibody in serum. Rubella serum antibody is measured in a variety
of test systems based on neutralization, hemagglutination inhibition, complement fixation, latex agglutination, radial
hemolysis, immunoblot, enzyme immunoassay (EIA), and IgG avidity. Interpretation of antibody testing should always
be guided by clinical, epidemiological, and immunization status data.
Congenital Rubella CASE 7
Epidemiology
Congenital rubella infection is unusual because the readily available vaccine prevents infection in mothers of
childbearing age. However, cases still occur in populations that are not optimally vaccinated. Most cases of congenital
rubella are the result of primary maternal disease during pregnancy. The risk for fetal infection is highest during early
gestation, although the most severe manifestations occur when infection is in the last trimester.
Presentation
Patients born with congenital rubella usually suffer from severe intrauterine growth retardation as well as a variety of
cardiac, ophthalmologic, and neurologic defects. The most common congenital heart defects include patent ductus
arteriosis and pulmonary artery stenosis. Cataracts occur in more than 30% of cases. Severe cases often have “celery
stalk” appearance of long bones visible on plain radiographs. Organomegaly, thrombocytopenia, and purpuric skin
lesions may also be seen. There is considerable clinical overlap in patients with congenital CMV.
Diagnosis
Diagnosis is made by detection of rubella-specific serum IgM antibodies. Congenital infection can also be diagnosed
by documenting increasing serum concentrations of infant rubella IgG over several months. Virus is readily excreted
from throat, urine, and CSF, but viral isolation of rubella is difficult and usually not achieved.
· Rubella IgM
· Persistence of IgG
· Viral culture of throat, urine, CSF
Management
At the present time, there is no treatment for infants with congenital rubella. Defects of the eyes are managed as
needed. Contact isolation is recommended for children with proven or presumed congenital rubella during the first
year of life.
 CASE 8
A 6-year-old boy developed rhinorrhea and a mild non-productive cough 8 days before admission to the hospital.
Six days before admission, he developed a tactile fever and was taken to a local clinic. He was prescribed a
mucolytic and an antihistamine. Despite this treatment, his cough worsened and his fever persisted. Three days
before admission, he developed a facial rash, which proceeded to spread to his trunk. On the day before admission
his fever and cough persisted, and he was transferred to Hospital for severe respiratory distress and potential need
for mechanical ventilation. The child had no medical or surgical history. He did not take any medications. His birth
history was unremarkable. He had no known drug allergies. His vaccination history included: BCG vaccine;
diphtheria, pertussis and tetanus vaccine; oral polio virus vaccine (three doses); and hepatitis B vaccine (three
doses).

Based on this history and physical

examination, which of the following is the
most likely diagnosis?
Methods of Diagnosis
 CASE 8

Complete blood count was notable for haemoglobin (10 grams/dl), haematocrit (29.4%) and a white blood cell
count of 9900 cells/mm3 (neutrophils (41%), eosinophils (4%), lymphocytes (42%), monocytes (3%)). Measles
IgM was reactive. Chest radiograph showed patchy infiltration in bilateral perihilar regions, without pleural
effusion or cardiomegally . Studies were completed 8 days after symptom onset. Blood cultures had no growth at 7
days

Vitamin A oral daily was given for 2 days (200 000 units/day); intravenous amikacin for 3 days (270 milligrams/
day) and cefotaxime for 7 days (2.8 grams/day).
 CASE 8

Measles virus is a spherical, nonsegmented, single-stranded, negative-sense RNA virus and a member of
the Morbillivirus genus in the family of Paramyxoviridae.

Measles virus is transmitted primarily by respiratory droplets over short distances and, less commonly, by small
particle aerosols that remain suspended in the air for long periods of time. Direct contact with infected secretions
can transmit measles virus, but the virus does not survive long on fomites.
Infection is initiated when measles virus reaches epithelial cells in the respiratory tract, oropharynx, or conjunctivae.

The incubation period for measles, the time from infection to clinical disease, is approximately 10 days to the onset
of fever and 14 days to the onset of rash. The incubation period may be shorter in infants or following a large
inoculum of virus, and may be longer (up to 3 weeks) in adults.

In most children, the signs and symptoms of measles are highly characteristic. Approximately 10 days after
exposure, fever and malaise signal the onset of illness (Fig. 316-1). Cough, coryza, and conjunctivitis follow
promptly. A gradual worsening of symptoms accompanies a steady rise in fever over the next 4 days. With the onset
of rash 14 days after infection, the clinical picture attains maximal severity. Constitutional symptoms throughout this
10-day period vary, but headache, abdominal pain, vomiting, diarrhea, and myalgia are frequent complaints. Fever
reaching 40°C (104°F) to 41°C (105.8°F), often accompanied by chills, is not unusual when the rash is most florid.
 CASE 8

Koplik spots, pathognomonic of measles, appear 24 to 48 hours

before the exanthem. They consist of bluish white dots about 1
mm in diameter surrounded by a rose-red areola. They tend to
appear first on the buccal mucosa opposite the lower molars. With
the onset of rash they fade, and frequently by the second day of the
eruption, they have disappeared.

The rash commences as discrete, irregular, erythematous macules

behind the ears, on the neck, and along the hairline. As the rash
progresses caudad over the ensuing 24 hours to involve the face,
trunk, and arms, careful palpation will reveal a papular
component. Involvement of the legs and feet by the end of the
second day or early in the third day finds the lesions on the cheeks
already coalescent; in severe infections, confluent areas of rash
also appear on the trunk and extremities. The exanthem fades
slowly, in the same order of progression as its initial appearance, a
process that usually begins by the third or fourth day after onset.
CASE 8
 CASE 8

DIAGNOSIS
Measles is readily diagnosed on clinical grounds by clinicians familiar with the disease. Koplik spots are especially
helpful because they appear early and are pathognomonic of measles. The Centers for Disease Control and
Prevention (CDC) case definition for measles requires (1) a generalized maculopapular rash of at least 3 days’
duration; (2) fever of at least 38.3°C (101°F); and (3) cough, coryza, or conjunctivitis.
Serology is the most common method of laboratory diagnosis. A fourfold or greater increase in measles virus–
specific IgG antibody levels between acute and convalescent sera, or the detection of measles virus–specific IgM in
a single specimen of serum or saliva, are considered diagnostic of acute infection

Except for general supportive measures, such as hydration and antipyretics, there is no specific antiviral therapy for
persons with uncomplicated measles. Secondary bacterial infections are a major cause of morbidity and mortality
following measles, and effective case management involves prompt treatment with antibiotics
 Skeletal Structure and Function

Week 1 Day 5

Fungal and parasitic skin disorders

 MCQ 1
An 18-year-old man presents to the office complaining of an itchy rash on his
torso that appeared one week ago. He is on the college wrestling team and is
concerned that he will not be able to compete if it gets infected. His past
medical history is unremarkable. Vital signs are within normal limits. Physical
exam reveals an erythematous, scaly plaque with central clearing on the left
lateral chest wall. Which diagnostic test would be most appropriate at this
time?

A.Culture on Sabouraud agar

B.Culture on Eaton agar
C.Culture on Thayer-Martin agar
D.KOH preparation
E.Wood’s lamp examination
Correct Answer D: The man's rash is most likely tinea corporis (ringworm), which is caused by
dermatophytes (cutaneous fungi), such as Microsporum and Trichophyton. Potassium
hydroxide (KOH) preparation is a fast and easy way to test for fungal infections in the office. The
procedure involves taking a skin scraping from the infected area, adding KOH solution, and
examining the specimen under a microscope. Dermatophytes have branching hyphae, which
confirms the diagnosis of ringworm.
Option A: Sabouraud agar is a growth medium containing peptones used to grow fungi, including
dermatophytes, as well as branching bacteria such as Actinomyces and Nocardia species. Fungi
can take a considerable amount of time to grow in a laboratory. Therefore, the use of this agar is
generally limited to serious infections in which fungi are suspected or the diagnosis is unclear. A
cutaneous fungal infection generally does not warrant the use of Sabouraud agar unless it is
refractory to treatment. This man is presenting with an uncomplicated case of tinea corporis,
making use of Sabouraud agar unnecessary.
Option B: Eaton agar is a growth medium that is specific for Mycoplasma pneumoniae. M.
pneumoniae is a common cause of atypical pneumonia, also known as "walking pneumonia"
because the symptoms are generally milder, even though chest X-rays reveal diffuse infiltrates.
This man is not presenting with any signs of pneumonia. Additionally, his cutaneous symptoms
cannot be explained by infection with M. pneumoniae, making it an unlikely diagnosis.
Option C: Thayer-Martin agar is a type of growth medium used to isolate Neisseria species. It is a
chocolate agar that contains a combination of antimicrobials known as VCN (vancomycin, colistin,
and nystatin) that are used to prevent the proliferation of other species of bacteria or fungi. This
man is not presenting with symptoms indicative of a Neisseriainfection, which is typically
meningitis and sexually transmitted infections. Therefore, Thayer-Martin agar is of little use in this
clinical scenario.
 MCQ 2
A 42-year-old morbidly obese woman presents to the emergency room for
evaluation of a rash that started three days ago. She states that the rash is
located under her breasts and on her lower abdomen, and is very itchy. On
physical exam, the rash is moist and bright red with some peripheral scaling,
located underneath her breasts and in the abdominal folds. She is afebrile
and is in no apparent distress. Which of the following has caused her rash?

A.A heavily encapsulated, urease-positive yeast

B.A gram-negative rod that produces pyocyanin
C.An irregular, non-septate yeast with wide angles
D.An acid-fast bacillus
E.A commensal yeast that is catalase-positive
Correct answer E: A commensal yeast that is catalase-positive: Candida
albicans is a dimorphic yeast that is part of the normal gut flora of humans
and is one of two fungi that are catalase-positive (Aspergillus is the other
one). Candidacan be found on the skin and in the mouth, vagina, and anus
of most healthy people. Overgrowth of this yeast can be caused by a
number of homeostatic changes.
This woman presents with intertriginous candidiasis, a Candidal infection
of the skin folds. The morbidly obese are at increased risk of this type of
infection due to the warmth and chronic moisture of the skin in those
locations. The rash is characterized by pruritus, erythema, maceration, and
satellite lesions. Coinfection with Staphylococcus aureus can occur due to
the person's repeated scratching of the pruritic skin.
Option A: A heavily encapsulated, urease-positive yeast: Cryptococcus neoformans is characterized by a thick
capsule, which is its main virulence factor. This yeast is urease-positive, a feature that differentiates it from
other yeasts, and shows a halo on India ink stain. Cryptococcus is not considered normal flora; it is found in
pigeon droppings and soil. It is an opportunistic infection seen mainly in the immunocompromised; it is an
AIDS-defining illness. This yeast causes cryptococcosis, meningitis, and encephalopathy, which is
characterized by ‘soap bubble’ lesions in the brain that can be seen on imaging. It does not cause cutaneous
infections and would not be seen in an immunocompetent host, making it an unlikely diagnosis in this
woman.
Option B: A gram-negative rod that produces pyocyanin: Pseudomonas aeruginosa is a gram-negative,
aerobic, encapsulated rod. It is catalase- and oxidase-positive. It produces two characteristic pigments:
pyocyanin and pyoverdin. These pigments give pseudomonal infections a blue-green appearance.
Pseudomonas is associated with hospital-acquired pneumonia and otitis externa (swimmer’s ear). Skin
rashes present as folliculitis and can progress to cellulitis and abscess formation; this woman's rash was not
consistent with any of those presentations.
Option C: An irregular, non-septate yeast with wide angles: Mucor and Rhizopus species of fungus share this
characteristic appearance and can be found in many places (including bread). They are only associated with
opportunistic infection in immunocompromised patients. They thrive in environments with high glucose
levels—most often colonizing in patients with diabetes, especially those in diabetic ketoacidosis. The
infection most closely associated with these species is a necrotic lesion on the face due to the invasion of the
cribriform plate. This leads to frontal lobe abscess, cavernous sinus thrombosis, and cranial nerve
destruction. This is not consistent with this woman’s presentation, making it an unlikely diagnosis.
Option D: An acid-fast bacillus: Leprosy, also known as Hansen’s disease, is a disease caused by the
bacteria Mycobacterium leprae. It thrives in cooler temperatures and can cause skin rashes and
demyelination of cutaneous nerves. Skin manifestations may include symmetrically scattered painless
nodules, flat dry hypopigmented patches, or trophic ulcers on the soles of the feet. The progression of this
disease may involve blindness and leonine facies. In the United States, Hansen’s disease is most often caused
by contact with armadillos, an animal reservoir of the disease. This woman’s presentation is not consistent
with this disease, making it an unlikely diagnosis.
Clinical case

A 27-year-old Australian woman came to our clinic

with complaint of a painful, pruritic, erythematous
and contagious lesion that appeared three weeks
prior on the dorsal surface of the right leg. Her
physical and systemic examinations were normal.
She had given an account of her recent Brazilian
Amazon trip, which was one month ago, during
which time she wore sandals.

On examining the skin, we found a 3–4 cm linear,

erythematous, serpiginous localized lesion
characteristic of a papulonodular tip on the dorsal
surface of the right foot (Figure 1). Because of the
patient’s trip to a tropical area and the clinical
findings, we evaluated the patient as a case of CLM.
Eosinophilia was not found in the complete blood
picture investigation. The peripheral smear was
normal, and no Pathology was found in the chest x-
ray. We prescribed Albendazole at a dose of 400 mg
to be taken once a day; later on, we observed that
the lesions and the patient’s complaints had
significantly regressed
Cutaneous Larva Migrans
Ancylostoma braziliense is the most common offender.
Who did bite
me?
Clinical case 2

A 70-year-old woman presented with chronic ulcerative nodules on her lower extremities at the outpatient clinic.
A tender red nodule developed on her left anterior tibial region a month ago, which gradually enlarged;
spontaneous ulceration of the nodule and occasional pain were reported. The lesions did not respond to topical
antibiotics, and more nodular lesions appeared in the mid-calf area and spread to her toes. Her medical history
included kidney transplantation 6 years ago, chronic tinea pedis and onychomycosis.

Physical examination revealed multiple firm, 2 to 4 cm, verrucose to dome-shaped, red nodular lesions, with an
infiltrative erythematous base on her left lower leg. Some lesions were ulcerated with clear to yellow exudations
and crusts. Several small red nodules were also found on the dorsal side of the toes (Figure a). Biopsies were
obtained from the lesions and microscopic examination revealed pseudoepitheliomatous hyperplasia and
extensive infiltration of neutrophils, plasma cells, histiocytes and multinucleated giant cells in the dermis
(Figure c). PAS stain highlighted fungal hyphae inside a neutrophilic microabscess (Figure d). An examination
of the lesion scales with potassium hydroxide showed hyaline septate hyphae. Fungal culture grew Trichophyton
rubrum.
Treatment
Classification of antifungal cures
Explain pharmocology of antifungal drugs
 Skeletal Structure and Function

Week 2 Day 1

Immunologic and Inflammatory Skin Disorders

Learning Objectives:

1) Define and discuss main features of various immunologic and inflammatory

skin disorders.
2) Review the steps involved in the evaluation of various immunologic and
inflammatory skin disorders.
3) Discuss the basic principles applied for management of immunologic and
inflammatory skin disorders.
A 50-year-old woman presents with an acute worsening of a chronic
rash on her arms and hands for the past week. She says she first
noticed the rash 1 year ago, which started as little red spots and
gradually increased in size. She describes the rash as itchy but
generally not painful. She denies any alcohol use, smoking history, or
recreational drug use. Her family history is significant for Crohn
disease in her mother and maternal grandmother. She mentions that she
has been excessively stressed the past few weeks as she is starting a
new job. A review of systems is significant for early morning swelling
of the distal joints in her hands and feet for the past 3 months. The
patient is afebrile, and her vital signs are within normal limits. On
physical examination, there are multiple silvery scaly plaques on the

↑
extensor surfaces of her upper extremities bilaterally, as shown in the
image. Similar lesions are present on both knees, involving < 8% of
her total body surface area. Laboratory tests are unremarkable.

1) What is the most likely diagnosis based on history and physical

examination?
2) What is the clinical significance of the patient’s complaints of the
distal joint swelling?
3) What are the treatment options?
1) This patient has signs and symptoms suggestive of limited (<10% total body surface area
involved) plaque psoriasis, namely multiple silvery, erythematous, pruritic plaques that worsen
with stress.
Plaque psoriasis is the most common type of psoriasis (80%). It is a chronic, multifactorial
inflammatory disease of the skin characterized by hyperkeratosis and parakeratosis. Plaque
psoriasis is characterized by well-defined patches of erythematous, raised skin with silvery scales
typically involving the extensor surfaces of the extremities as well as the neck, scalp, and inguinal

↑
areas. Pain and itching from the psoriatic lesions can occur, and bleeding may occur if the lesions
are scratched (Auspitz sign).
Psoriasis often has a fluctuating course of remissions and exacerbations. The use of lithium, beta-
blockers, or antimalarials can precipitate a flare-up of psoriasis.
Diagnosis is typically clinical, although a punch biopsy of the skin can confirm the diagnosis if
needed.

2) Common complications include psoriatic arthritis, which occurs in 10–30% of patients with
psoriasis. Psoriatic arthritis is destructive and typically affects the distal joints of the hands and feet.

3) In patients with limited disease, a combination of a potent topical corticosteroid and

calcipotriene is indicated as a first-line therapy to control the disease.
↑
A 37-year-old man presents to an urgent care clinic with complaints of speech
problems and yellowing of his eyes for the past week. He admits to using illicit
intravenous drugs. His vital signs include: blood pressure 110/60 mm Hg, pulse rate
78/min, and respiratory rate 22/min. On physical exam, the patient appears jaundiced
and his speech is slurred. Plaques are visible on the lower legs and in the oral
mucosa. His liver enzymes and viral markers are shown:
Aspartate aminotransferase 6,700 IU/L
Alanine aminotransferase 5,000 IU/L
HbsAg Negative
Anti-Hbs Negative
Anti-HCV Ab Positive
HCV RNAPositive

1) What is the most likely diagnosis?

2) What would be seen on a biopsy of one of the patient’s skin lesions?
3) What are the treatment options?
1) The patient presents with symptoms and laboratory findings characteristic of hepatitis C, so he is at
risk of developing lichen planus (LP). LP manifests as pruritic, purple papules, and plaques on the
skin and mucous membranes, often affecting the oral cavity.

A mnemonic can be used to remember the characteristic features of LP:

6 P’s:
Pruritic
Planar
Polygonal
Purple
Papules
Plaques

2) A biopsy of the lesion would show a lymphocytic infiltrate at the dermal-epidermal junction with
the destruction of basal epidermal cells. There is a slight risk of developing squamous cell
carcinoma.

3) Treatment involves topical or intralesional corticosteroids, phototherapy, and antihistamines for

pruritis.
A 37-year-old man presents to the clinic because of multiple itching blisters on his
buttocks for the past week. One year ago, he noticed a similar outbreak on his inner
thighs, but it receded spontaneously within a few days. Physical exam reveals blisters
that are tense and do not rupture with rubbing or pressure. A biopsy demonstrates
epidermal detachment from the basal lamina with subepidermal blisters containing
extensive inflammatory infiltrates.

1) What is the most likely diagnosis?

2) What cellular structures is most likely involved in the formation of these blisters?
-
1) This man presents with subepidermal blisters, and bullous pemphigoid is the most
common cause. It is caused by autoantibodies to the bullous pemphigoid antigens
(named BP230 and BP180, or BPAG1 and BPAG2, respectively) of
hemidesmosomes. This destruction of the cell’s primary anchor to the basement
membrane results in the detachment of the basal layer of the epidermis. Blisters
form in the subepidermal space that is created. Subepidermal blisters are tense and
do not rupture, occurring on the inner thighs, axillae, abdomen, and trunk. Pruritus is a
typical feature as well. Nikolsky sign is negative. On immunofluorescence, linear
deposits of immunoglobulin G autoantibodies with complement component 3 are
found at the basement membrane.
Bullous pemphigoid can be acute or chronic. It is considered a type 2
hypersensitivity reaction because of the formation of antibodies against
hemidesmosomes.

Bullous pemphigoid is similar to pemphigus vulgaris, which affects desmosomes, but

is not as severe. Pemphigus vulgaris tends to affect the oral mucosa, while bullous
pemphigoid mostly spares the oral mucosa.
A 22-year-old man presents with multiple, target-like skin lesions on both arms and
legs. He says that the lesions appeared 4 days ago and that, over the last 24 hours, they
have extended to his torso. His medical history is significant for pruritus and pain on
the left border of his lower lip 1 week ago, followed by the development of an oral
ulcerative lesion. On physical examination, multiple round erythematous papules with a
central blister, a pale ring of edema surrounding a dark red inflammatory zone, and an
erythematous halo are noted. Mucosal surfaces are free of any ulcerative and exudative
lesions.

1) What is the most likely diagnosis?

2) Explains the pathogenesis underlying this patient’s condition.
1) Target-like lesions (round erythematous papules with a central blister or dusky
central area surrounded by an erythematous halo) restricted to the skin are a classic
and typical finding in erythema multiforme (EM), an acute immune-mediated
condition most commonly triggered (up to 90% of cases) by infection with herpes
simplex virus (HSV), mycoplasma pneumonia infection, or other respiratory
infection.

2) EM usually presents 4–10 days after the reactivation of HSV infection and is the
result of IFN-γ release by CD4+ T cells.
An 11-year-old boy was brought in by his mother with red, tender bumps on his
legs. The patient’s mother says that his symptoms started three days ago with a low-
grade fever, malaise, and joint pain. He began to improve over the next two days,
but this morning, she noticed multiple painful red bumps on his shins when he woke
up. Past medical history is significant for a recent severe sore throat and fever one
week ago which resolved without treatment. His temperature is 38.0°C (100.4°F),
blood pressure is 120/70 mm Hg, pulse is 105/min, and respirations are 15/min.
Physical examination of his throat shows slight tonsillar enlargement with mild
erythema but no exudate. Skin exam reveals multiple firm, tender erythematous
nodules with indistinct borders on his anterior shins that are 2–3 cm in diameter.
There is no drainage, bleeding, abscess formation, or ulceration.

1) What is the most likely diagnosis?

2) What is the next best diagnostic step for this patient?
1) This patient has erythema nodosum (EN) manifesting with multiple firm,
tender nodules on the anterior lower legs, preceded by 1–2 days of fever, malaise,
and arthralgias. The nodules typically last 1–2 weeks, gradually becoming softer
and resolving without abscess or ulceration.
Multiple possible etiologies give rise to EN. The most common infectious etiology
in pediatric patients is Group A Streptococcal (GAS) pharyngitis.

2) There are no lab tests specific for EN, but patients may have abnormal test
results due to the underlying disease. Lab tests indicated with EN include a CBC,
ESR, diagnostic test for streptococcal pharyngitis if the patient has signs of acute
pharyngitis, antistreptolysin O titers (repeated 2–4 weeks after infection), and a
chest radiograph in adults to assess for sarcoidosis or tuberculosis. The diagnosis
of EN is usually clinical but can be confirmed with a skin biopsy and
histopathologic analysis.
In pediatric patients with erythema nodosum, a throat or nasal culture for GAS is
indicated, especially in those who have a recent history of fever and sore throat.
Treatment of EN is symptomatic with NSAIDs if needed for comfort. Most EN
resolves spontaneously or with supportive care over days to weeks. The underlying
cause should be treated whenever possible (e.g., antibiotics if a positive culture).
A 4-year-old boy with a rash is brought in by his mother. The patient’s mother says that his
symptoms started acutely a few hours ago after they had eaten shellfish at a restaurant, and the
symptoms have progressively worsened. The rash started with a few bumps on his neck and chest
but quickly spread to involve his arms and upper torso. The patient says the rash makes him
uncomfortable and itches badly. He denies any fever, chills, night sweats, dyspnea, or similar
symptoms in the past. Past medical history is significant for a history of atopic dermatitis at the age
of nine months which was relieved with some topical medications. The patient is afebrile, and his
vital signs are within normal limits. Physical examination reveals the findings seen in the image
below. There is no evidence of laryngeal swelling, and his lungs are clear to auscultation.

1) What is the most likely diagnosis?

2) What is the best treatment for this patient’s most
likely condition?
1) This patient presents with signs and symptoms of urticaria ("hives"), most likely
from ingesting shellfish; namely, an acute onset rash consisting of erythematous
papules (wheals) that blanch with pressure and are pruritic.
Acute urticaria is the dermatologic manifestation of a hypersensitivity reaction. The
most common etiology is a type 1 IgE-mediated hypersensitivity reaction caused
by an allergen binding to and cross-linking with IgE molecules attached to mast cells
or basophils, resulting in degranulation. This causes the release of histamine and other
inflammatory mediators.
Diagnosis of acute urticaria is clinical, although a punch biopsy of the skin can be
used for confirmation in equivocal cases.
2) The first-line treatment for patients with mild to moderate acute urticaria who do
not have signs of GI involvement or respiratory compromise is a second-generation
H1 blocker, such as cetirizine or fexofenadine. Cetirizine demonstrates a rapid
onset of action and some mast cell-stabilizing activity. These are preferred over
first-generation H1 blockers because they are less sedating, are mostly free of
anticholinergic effects, have fewer significant drug-drug interactions, and require
less frequent dosing.
Systemic glucocorticoids are indicated as well as an adjunctive treatment in patients
with prominent angioedema systemic shock, angioedema, or respiratory
compromise or if symptoms persist beyond a few days. Glucocorticoids do not
inhibit mast cell degranulation (like cetirizine) but can suppress other inflammatory
mechanisms.
In patients with hypotension, GI involvement, significant laryngeal edema, or signs
of respiratory compromise, intramuscular epinephrine is immediately administered.
Skeletal Structure and Function

Week 2 Day 2
Skin & Subcutaneous Tissue

Adnexal disorders
Learning objectives:
1. Define and discuss etiology and pathophysiology of various adnexal disorders
2. Review the steps involved in the evaluation of various adnexal disorders
3. Discuss the basic principles applied for management of adnexal disorders
 MCQ Case 1

A 28-year-old man is referred to the dermatologist after noticing an increasing number of smooth, circular patches of
complete hair loss on his scalp. He says that the involved patches of the scalp have a burning and itching sensation.
There has been no improvement in the condition with the over-the-counter products that were recommended to him by
his hairstylist. He denies pulling his hair intentionally. Physical examination reveals no epidermal inflammation or
erythema, and no fluorescence is detected under Wood’s lamp. A punch biopsy shows a peribulbar lymphocytic
inflammatory infiltrate surrounding anagen follicles, resembling a swarm of bees. Which of the following is the most
likely diagnosis?

A.Tinea capitis
B.Telogen effluvium
C.Lichen planopilaris
D.Androgenic alopecia
E.Alopecia areata
 MCQ Case 1

Correct answer E: Alopecia areata, a type of non-scarring hair loss that affects individuals of any age and
sex, with most patients experiencing symptoms before 30 years of age. It is characterized by smooth, circular,
discrete areas of hair loss that are often preceded by a burning sensation or pruritus. The etiology of alopecia
areata is autoimmune, with T cell-mediated peribulbar inflammation that disrupts the normal hair cycle
without scarring (see image below).
Spontaneous regrowth occurs in many patients; however, patients typically present with more than one
episode in their lifetime. Alopecia areata tends to be associated with other autoimmune disorders and
diseases, such as vitiligo, systemic lupus erythematosus, and thyroid disease.
 MCQ Case 1

Hair follicles in the active growth

phase (anagen follicles), normal state
vs. alopecia areata.
 MCQ Case 1

Option A: Tinea capitis is a fungal infection of the scalp by dermatophytes (filamentous fungi of the
genera Trichophyton and Microsporum). It is most commonly seen in children. The most common clinical findings are
pruritus and the presence of scaly patches with alopecia, or patches of alopecia with black dots. Treatment consists of
systemic antifungal medications.
Option B: Telogen effluvium is a form of diffuse, non-scarring hair loss that results from altered regulation of the hair
follicle cycle with a significant amount of hair follicles falling into the telogen phase (resting phase), the end of which
is marked by shedding of hair from the follicle. This results in significant premature shedding and subsequent diffuse,
not localized, hair loss. Causes can be a chronic disease, anemia, pregnancy, and severe emotional distress.
Option C: Lichen planopilaris is a type of scarring alopecia that is characterized by the permanent destruction of hair
follicles. Typically, additional findings such as erythema, scaling, and pustules are present. Some histopathological
characteristics include a band-like lymphocytic infiltrate at the dermal-epidermal junction, vacuolization of the basal
layer, and apoptotic keratinocytes. Treatment with corticosteroids is recommended.
Option D: Hair loss in androgenic alopecia is typically slow, consisting of gradual thinning of hair on the vertex and
frontoparietal areas of the scalp. Up to 50% of patients will develop androgenic alopecia by 50 years of age, and 80%
by 70 years of age. Although histopathological evaluation is rarely required, findings include a mixture of the terminal,
vellus, and vellus-like hair follicles in the dermis.

Learning objective: Alopecia areata is an autoimmune disorder with peribulbar lymphocytic inflammatory infiltrates
surrounding growing follicles that do not produce scarring. Clinically, it is characterized by round, smooth, discrete
areas of hair loss without additional findings (i.e., no erythema, pustules, or scaling).
 MCQ Case 2

An 18-year-old man presents to the office complaining of an itchy rash on his torso that appeared one week ago. He is
on the college wrestling team and is concerned that he will not be able to compete if it gets infected. His past medical
history is unremarkable. Vital signs are within normal limits. Physical exam reveals an erythematous, scaly plaque with
central clearing on the left lateral chest wall. Which diagnostic test would be most appropriate at this time?

A.Culture on Sabouraud agar

B.Culture on Eaton agar
C.Culture on Thayer-Martin agar
D.KOH preparation
E.Wood’s lamp examination
 MCQ Case 2

Correct Answer D: The man's rash is most likely tinea corporis (ringworm), which is caused by dermatophytes
(cutaneous fungi), such as Microsporum and Trichophyton. Potassium hydroxide (KOH) preparation is a fast and easy
way to test for fungal infections in the office. The procedure involves taking a skin scraping from the infected area,
adding KOH solution, and examining the specimen under a microscope. Dermatophytes have branching hyphae, which
confirms the diagnosis of ringworm.
Option A: Sabouraud agar is a growth medium containing peptones used to grow fungi, including dermatophytes, as
well as branching bacteria such as Actinomyces and Nocardia species. Fungi can take a considerable amount of time to
grow in a laboratory. Therefore, the use of this agar is generally limited to serious infections in which fungi are
suspected or the diagnosis is unclear. A cutaneous fungal infection generally does not warrant the use of Sabouraud
agar unless it is refractory to treatment. This man is presenting with an uncomplicated case of tinea corporis, making
use of Sabouraud agar unnecessary.
Option B: Eaton agar is a growth medium that is specific for Mycoplasma pneumoniae. M. pneumoniae is a common
cause of atypical pneumonia, also known as "walking pneumonia" because the symptoms are generally milder, even
though chest X-rays reveal diffuse infiltrates. This man is not presenting with any signs of pneumonia. Additionally, his
cutaneous symptoms cannot be explained by infection with M. pneumoniae, making it an unlikely diagnosis.
 MCQ Case 2

Option C: Thayer-Martin agar is a type of growth medium used to isolate Neisseria species. It is a chocolate agar that
contains a combination of antimicrobials known as VCN (vancomycin, colistin, and nystatin) that are used to prevent
the proliferation of other species of bacteria or fungi. This man is not presenting with symptoms indicative of
a Neisseriainfection, which is typically meningitis and sexually transmitted infections. Therefore, Thayer-Martin agar is
of little use in this clinical scenario.
Option E: With Wood’s lamp examination, a healthcare practitioner uses fluorescent light to examine lesions in a
completely dark room. Wood’s lamp exams can help clinicians evaluate hypo- and hyperpigmented lesions, and lesions
of infectious origin. Cutaneous fungal infections often fluoresce a certain color, depending on the cause of infection.
Dermatophytes may glow blue-green or yellow. Wood’s lamp exam findings are very user-dependent and are not used
for the definitive diagnosis of a lesion. Because the test is not sensitive or specific, it is not a confirmatory test and is
inferior to KOH preparation.

Learning objective: Tinea infections are caused by dermatophyte species of fungi, such
as Microsporum and Trichophyton. Fungal skin infections can be diagnosed with KOH preparations or Sabouraud agar,
but KOH preparations are the preferred method to use for uncomplicated infections in the office setting.
 MCQ Case 3

A 62-year-old man presents with dry, brittle toenails

for the past couple of years. Past medical history is
significant for diabetes mellitus type 2, diagnosed
30 years ago, which is managed with metformin and
sitagliptin daily. He is an office clerk and will retire
next year. The image shows the patient's toenails on
physical examination. Which of the following is an
adverse effect of the recommended treatment for
this patient’s most likely condition?

A.Chronic renal failure

B.Hypothyroidism
C.Chronic depression
D.Pancytopenia
E.Hepatitis
 MCQ Case 3

Correct answer E: This patient has signs and symptoms strongly suggestive of a fungal infection of the toenail which
is called onychomycosis or tinea unguium. A potassium hydroxide (KOH) preparation of the scraping from his nail
bed will help in the diagnosis of this condition. Diabetes mellitus, psoriasis, and peripheral vascular disease are
common risk factors for fungal infection of nails.
Terbinafine is the drug of choice for the treatment of onychomycosis. It is administered for a prolonged period (> 12
weeks). Other comorbid conditions, which flare up due to treatment with terbinafine, should be considered. Terbinafine
is efficacious when compared to itraconazole, fluconazole, and griseofulvin in the treatment of onychomycosis.
Moreover, terbinafine is fungicidal while others are fungistatic. Adverse effects involve hepatotoxicity/hepatitis.
Continuous monitoring of hepatic transaminases is needed during treatment. It is also an inhibitor of CYP2D6 hepatic
enzymes which results in some drug-drug interactions.
 MCQ Case 3

Option A: Amphotericin B is an antifungal agent that has been associated with nephrotoxicity. It is not used until there
is a serious systemic fungal infection. Although terbinafine dose must be adjusted in patients with renal failure, it is not
a nephrotoxic drug.
Option B: Lithium, amiodarone, and Interferon-alpha have been linked to drug-induced hypothyroidism, but not
terbinafine.
Option C: No link has been found between the use of terbinafine and depression. The adverse effects of terbinafine
include rash, dyspepsia, abdominal pain, pruritus, nausea, diarrhea, and taste disturbance.
Option D: Apart from anticancer agents, antibiotics like linezolid and chloramphenicol are known to cause
pancytopenia. Terbinafine does not cause decreased blood cell counts.

Learning objective: Serial monitoring of hepatic transaminases is required in patients receiving terbinafine for
onychomycosis, as it is hepatotoxic.
 MCQ Case 4

A 15-year-old boy presents to the clinic complaining of an uncomfortable skin condition that started two years ago.
The patient states that his skin feels "oily" and is embarrassed by his appearance. On examination, he is a healthy-
appearing teenager who has reached the expected Tanner stage. The skin on his face and back has erythema and a few
open and closed comedones. What microbiologic agent is associated with this presentation?

A.HHV-8
B.Streptococcus pyogenes
C.Cutibacterium acnes
D.Human papillomavirus (HPV) strains 6 and 11
E.Bartonella henselae
 MCQ Case 4

Correct answer C: Acne vulgaris is a common inflammatory skin disease characterized by comedones and
inflammation. It is caused by increased sebum production and keratinous deposition in the pilosebaceous follicles of the
skin and the involvement of Cutibacterium species, a bacteria normally found on the skin. Acne vulgaris can occur at
any age but most commonly appears during puberty. It can present on any skin area but commonly infects the face and
back. This patient’s age, chronic presentation, and self-description point to infection with C. acnes causing acne
vulgaris.
 MCQ Case 4

Option A: Human herpesvirus-8 is a strain of the herpesvirus family that causes Kaposi sarcoma. This disease is an
endothelial malignancy seen in immunocompromised patients; in the United States, it is almost exclusively associated
with human immunodeficiency viruses. Kaposi sarcoma presents as red, purple, or brown raised lesions on the skin and
mouth as well as in the gastrointestinal and respiratory tracts. While the lesions associated with Kaposi sarcoma have a
lymphocytic infiltrate, they are not inflammatory. This patient does not have risk factors for this disease, and his
presentation is not suggestive of this etiologic agent.
Option B: Streptococcus pyogenes causes a variety of soft tissue and skin infections. The infection that presents in a way
that is closest to this patient’s symptoms is erysipelas, which is an acute skin infection. It is a superficial infection of the
upper dermis that affects the skin of the face and the upper and lower extremities. The skin symptoms of raised, sharply
demarcated erythema and mild edema are accompanied by systemic symptoms such as fever, chills, fatigue, headaches,
and vomiting. This is an acute disease process with systemic symptoms that does not match this patient’s presentation.
 MCQ Case 4

Option D: Verruca vulgaris, also known as the common wart, is caused by several strains of HPV, especially 6 and 11.
Warts are rough, raised growths that are most often asymptomatic and painless. Histologically, koilocytes and
hyperkeratosis can be seen. While there are many different warts, common warts are most often seen in childhood.
These warts can appear anywhere but are most often seen on the hands. Warts can be chronic but usually resolve by
adulthood. This patient’s symptoms are not suggestive of a diagnosis of verruca vulgaris, making this etiologic agent
unlikely.
Option E: B. henselae is a gram-negative bacteria that causes cat scratch disease. The bacteria enter the skin via a cat’s
scratch (or bite), as the name suggests. There is unilateral lymphadenopathy proximal to the site of trauma followed by
nonspecific systemic symptoms such as fatigue, arthralgias, headache, and chills. Rarely, this can progress to
encephalopathy or meningitis, although most cases resolve. This patient’s presentation is inconsistent with this disease,
making this causative agent unlikely.

Learning objective: Acne vulgaris is a common skin inflammatory condition during puberty caused by the
bacterium Cutibacterium acnes. It is often treated with retinoids and antibiotics.
 Skeletal Structure and Function

Week 2 Day 3

Miscellaneous Skin and Mucous membrane disorders

Learning Objectives:

1) Define and discuss etiology and pathophysiology of miscellaneous skin and mucosa
disorders, including disorders of pigmentation, traumatic and mechanical disorders,
congenital disorders, adverse effects of drugs on skin and subcutaneous tissue.
2) Review the steps involved in the evaluation of miscellaneous skin and mucosa
disorders.
3) Discuss the basic principles applied for management of miscellaneous skin and
mucosa disorders.
A 32-year-old man of Asian descent presents with a
skin rash after being started on prophylactic doses of
trimethoprim/sulfamethoxazole 3 weeks earlier. He was
diagnosed with acquired immunodeficiency syndrome 2
months ago, prompting the initiation of prophylactic
antibiotics. His blood pressure is 112/72 mm Hg,
temperature is 40.0°C (104.0°F), respirations are
22/min, and pulse is 95/min. He has 8% total body
surface area (TBSA) skin slough with scattered vesicles
and erosions throughout his face and extremities, as
shown in the image. He does have erosions on his lips,
but he has no other mucosal involvement.

1) What is the most likely diagnosis?

2) What diagnostic test should be used to confirm
the diagnosis?
3) How to determine a patient's prognosis and what
management options are there for this patient?
1) Stevens-Johnson syndrome (SJS) is an immune-mediated skin reaction that leads
to extensive epidermal detachment and mucocutaneous complications. The condition
is most commonly triggered by medications, such as antibiotics, anticonvulsants,
and non-steroidal anti-inflammatory drugs (NSAIDs). Human immunodeficiency
virus (HIV) infection is an important risk factor for SJS.
The diagnosis of SJS requires that the body surface showing skin lesions is < 10%. If
the body surface area is > 30%, the diagnosis is toxic epidermal necrolysis (TEN).
The pathogenesis of SJS is not completely understood; however, it is thought to
involve a delayed hypersensitivity reaction (type IV), resulting in damage to
keratinocytes.
 Manifestations of SJS
Prodromal symptoms (1–4 weeks after exposure to the medication):
high fever, malaise, myalgia, or arthralgia

Mucocutaneous lesions (1–3 days after the prodromal phases):

Mucosal involvement: erosions or ulceration of the mouth, lips, eyes, pharynx,
esophagus, gastrointestinal tract, anus, or genital area
Cutaneous manifestations:
Painful, erythematous macules that may have a targetoid appearance
Positive Nikolsky sign (epidermal layer easily detaches when pressure is applied to
the affected area)
Extensive, full-thickness epidermal necrosis and detachment
2) The diagnosis is clinical, based on history and physical exam findings.
Skin biopsy is the definitive test for the conformation of the diagnosis of SJS. It
typically reveals the layer of skin blistering (subepidermal in SJS/TEN) and dead
(necrotic), thickened epithelial tissue, which is indicative of SJS and TEN.
 Prognostic factors Score The SCORTEN score is used to help
Age ≥ 40 years 1 determine the severity, prognosis in
Malignancy present 1 SJS/TEN patients.
Body surface area detached ≥ 10% 1
Score 0‒1: 94% survival
Tachycardia ≥ 120/min 1 Score 2: 87% survival
Serum urea > 10 mmol/L 1 Score 3: 53% survival
Serum glucose > 14 mmol/L 1 Score 4: 25% survival
Score 5‒7: 17% survival
Serum bicarbonate < 20 mmol/L 1

Management options:
Airway management
Fluid and electrolyte management
Nutritional support
Pain control
Monitoring and treatment of superinfections
Wound care
A 35-year-old man pulled out of a burning building was found unconscious and
severely injured. He was transported to the nearest emergency department. Upon
arrival, he is stabilized and evaluated for burns and trauma. Approximately 40% of
his body is covered in burns. The burned areas appear blackened and charred. After
awakening, the patient had a loss of pain sensation in the burned areas, and the
lesions did not blanch on palpation. The affected area was soft when palpated.

1) What category of burn does the patient most likely have?

2) What classifications of burns do you know?
3) What is the prognosis for patients with burns based on?
1) This patient has full-thickness (formerly called 3rd-degree) burns covering
approximately 40% of his body surface area. Full-thickness burns extend through the
dermis and injure the underlying tissue. They are anesthetic or hypo-aesthetic. Burn
eschar, described above as "blackened and charred," is the dead and denatured dermis.

2) Burns can be categorized as chemical (acid/alkali), electrical, radiation (UV,

medical/therapeutic), or thermal (scald, fire). The most common types of burns in adults are
related to fire.

3) Prognosis and management are based on the patient’s age, the size of the affected area,
evidence of inhalation injury, and the depth of the affected area. Victims of severe burns are
at risk of developing sepsis and acute respiratory distress syndrome due to a profound
inflammatory response. The patient can also have acute renal failure due to severe fluid
loss (burn victims lose the ability to retain water because their skin is damaged). The
metabolic byproducts from substantial muscle breakdown and hemolysis can damage the
kidneys as well.
 Degree of burn Characteristics Symptoms Healing
Superficial burn (1st Limited to epidermis Itching to pain Unscarred
degree) No destruction of skin Spontaneous recovery
Hyperemia (red), blanches
with pressure
Edema
Superficial partial burns Limited to epidermis Severe pain Usually unscarred
(2nd degree) Hyperemia Spontaneous recovery
Wet wound bed
Intact sensibility
Blistering
Deep superficial burns Epidermis and dermis Severe pain Partial recovery with scar
(2nd degree) damaged formation
Dry wound bed
Bright and reddened areas
Full-thickness burns (3rd Damage to all skin layers, Painless because nerve Skin regeneration no longer
degree) including superficial fascia endings have been destroyed possible
Grey-white discoloration of Need excision and grafting
skin
No blisters
Full-thickness/eschar Involves muscles, tendons, Painless Skin regeneration no longer
burns (4th degree) or bones possible
Leather-like Need excision and grafting
Charring of tissue
 Mild Moderate Severe

Children < 5% TBSA 5%–10% TBSA > 10% TBSA

Adult < 10% TBSA 10%–20% TBSA > 20% TBSA

Elderly < 5% TBSA 5%–10% TBSA > 10% TBSA

All < 2% full thickness 2%–5% full thickness, > 5% full thickness,
high voltage, high voltage,
inhalation, inhalation,
circumferential, circumferential,
comorbid disease comorbid disease

Disposition Outpatient Admission -

Burn unit
A 13-year-old boy is brought to the emergency department because of vomiting, diarrhea, abdominal
pain, and dizziness for the past 3 hours associated with fever, chills, and muscle pain for the last day.
He was seen 5 days ago for severe epistaxis that required anterior nasal packing. He has not yet
removed the nasal pack. His temperature is 40.0°C (104.0°F), pulse is 124/min, respiratory rate is
28/min, and blood pressure is 88/60 mm Hg. He appears confused, and the physical exam shows
conjunctival and oropharyngeal hyperemia with a diffuse, erythematous, macular rash on his body
involving the palms and soles. Removal of the anterior nasal pack shows hyperemia with purulent
discharge from the underlying mucosa.
·

Laboratory studies show:

Total white blood cell count 30,000/mm3
Neutrophils 90%
Lymphocytes 8%
Monocytes 1%
Eosinophils 1%
Basophils 0%
Platelet count 95,000/mm3
Serum creatine kinase 400 IU/L

1) What is the most likely diagnosis?

2) What are the treatment options for the patient?
1) The acute onset of this patient’s symptoms after nasal packing in the emergency
department is consistent with toxic shock syndrome (TSS) caused by
Staphylococcus aureus.
S. aureus toxins ("superantigens") activate large numbers of T cells, resulting in
massive cytokine release. About half the cases of TSS are associated with tampon
use; other risk factors include surgical and postpartum wound infections, nasal
packing, septorhinoplasty, sinusitis, and burns.
The clinical features of TSS include a high fever > 38.9°C (102.0°F),
hypotension, diffuse rash involving the extremities, myalgias, vomiting,
diarrhea, and erythema of the mucous membranes. Desquamation may occur 1–
2 weeks after the onset of symptoms. Patients may have renal or hepatic
involvement, thrombocytopenia, and neurologic symptoms.
In patients with staphylococcal TSS, laboratory evaluation may show leukocytosis
with neutrophilia, thrombocytopenia, and elevated serum levels of creatine kinase,
creatinine, blood urea nitrogen, bilirubin, and transaminases.
2) The treatment of TSS includes fluid resuscitation, removal of the foreign body
(tampon or nasal packing), and antibiotic therapy (clindamycin plus vancomycin).
 Skeletal Structure and Function

Week 2 Day 4

Musculoskeletal System
Bones, Joints, Tendons, Ligaments and Cartilage
Learning objectives:
1. Discuss the embryologic development of bones, joints, tendons, ligaments and cartilages.
2. Summarize the perinatal changes occurred in bones, joints, tendons, ligaments and cartilage development.

·
 ·

↑↑
A 2-year-old girl presents to the pediatrician with a history of multiple fractures since birth. The parents report that the
child developed a fractured collarbone after a minor fall at 6 months old and has sustained several other fractures,
including ribs and femurs, with minimal trauma. They also express concern about the child's short stature and delayed
motor development.
Physical examination:
•Vitals: Temperature: 37.0°C (98.6°F), Heart rate: 120 beats/minute, Respiratory rate: 20 breaths/minute, Blood
pressure: 100/60 mmHg
•General: Short stature, blue sclerae, prominent forehead, bowing of long bones
•Musculoskeletal: Limited range of motion in major joints, muscle weakness, joint laxity

1.Identify the most likely diagnosis and outline the differential diagnoses for a child with multiple fractures and blue
sclerae.
2.Briefly explain the underlying genetic defect leading to the presented condition? How does this defect affect the
function of osteoblasts?
3.Identify the major bones affected in presented condition and their anatomical locations.
4.Describe the muscle groups most likely to be affected by muscle weakness in this case and their roles in movement.
5.What would be the group of drugs suggested for presented condition? Discuss the mechanism of action and side
effects.
6.Are there any other pharmacological agents used in the management of presented condition?
↑
•Other Types of Osteogenesis Imperfecta:
• Type I: Usually milder, presenting with fractures later in childhood.
• UPDATE. Type II: Mortal, close to 100% mortality rate. Otherwise death in 1 year after birth.
• Type III: Moderate severity, fractures with minimal trauma but less severe skeletal deformities.
• Type IV: Lethal form with severe bone fragility and deformities, often presenting perinatally.
•Child Abuse: Fractures in atypical locations, inconsistent history, caregiver discrepancies. osteomal
•Nutritional Deficiencies: Vitamin D deficiency (rickets), vitamin C deficiency (scurvy), calcium deficiency. acId
•Metabolic Disorders:
• Homocystinuria: Elevated homocysteine levels can weaken bones.
• Ehlers-Danlos Syndromes: Connective tissue disorders with joint hypermobility and fragile bones.
•Skeletal Dysplasias:
• Achondroplasia: Short stature, disproportionate limbs, kyphosis.
• Osteopetrosis: Increased bone density but paradoxically fragile bones due to abnormal bone structure.
•Genetic Syndromes:
• Marfan syndrome: Tall stature, long limbs, eye abnormalities, aortic valve problems.
High-Yield Points:
•Blue sclerae are highly suggestive of osteogenesis imperfecta but not pathognomonic.
•Consider the severity of fractures, skeletal deformities, and other associated features for further differentiation.
•Carefully evaluate for potential child abuse, especially with discrepancies in history or atypical fracture locations.
•Metabolic disorders and genetic syndromes warrant specific investigations based on clinical suspicion.
•A multidisciplinary approach involving pediatrics, genetics, and orthopedics is crucial for accurate diagnosis and
management.
2. Briefly explain the underlying genetic defect leading to the presented condition? How does this defect affect
the function of osteoblasts?

Genetic Defect:
Osteogenesis imperfecta type III is primarily caused by mutations in the genes encoding type I collagen (COL1A1
and COL1A2). These genes provide the blueprint for building the protein collagen, a crucial component of bone
structure and strength. Most cases are due to autosomal dominant mutations, meaning one altered gene copy from either
parent is sufficient to cause the condition.
Consequences for Osteoblast Function:
The mutated genes lead to the production of defective type I collagen. This collagen is improperly folded, structurally
unstable, and less efficient in forming strong bone matrix. Impaired osteoblast function reduces their ability to
mineralize bone tissue, resulting in decreased bone density and fragility.
Deficient collagen synthesis and abnormal bone matrix disrupt the balance between bone formation and resorption,
further contributing to the bone weakness.
Some mutations may trigger premature osteoblast aging and apoptosis, further diminishing bone production capacity.
3. Identify the major bones affected in presented condition and their anatomical locations.
4. Describe the muscle groups most likely to be affected by muscle weakness in this case and their roles in
movement.

•Long bones and axial structures are often most susceptible due to their high load-bearing roles.
•Muscle weakness typically affects proximal and extensor muscles first due to increased energy demands for movement.
•Weakness in axial muscles can lead to postural problems, decreased respiratory function, and limitations in trunk
movement.
•Weakness in proximal and extensor muscles can impair activities like reaching, grasping, walking, and climbing stairs.
•Early diagnosis and interventions like physiotherapy and muscle strengthening exercises can help prevent or minimize
muscle weakness and improve functional abilities.
5. What would be the group of drugs suggested for presented condition? Discuss the mechanism of action and
side effects.

Bisphosphonates: Bisphosphonates are the mainstay of treatment for increasing bone density and reducing fracture risk.
Mechanism of action: Bind to hydroxyapatite crystals in bone, inhibiting osteoclast activity, reducing bone
resorption, and leading to increased bone density.
Side effects:
• Gastrointestinal upset (nausea, vomiting), heartburn, abdominal pain.
• Acute phase reactions (fever, chills, muscle aches) with intravenous administration.
• Osteonecrosis of the jaw (rare but serious long-term risk).
• Atypical femur fractures (rare but serious, particularly in long-term use).
6. Are there any other pharmacological agents used in the management of presented condition?
Additional Considerations:
Anabolic agents:
• Mechanism of action: Stimulate bone formation by osteoblasts, potentially increasing bone density in some
cases.
• Side effects:
• Acne, mood swings, aggression, liver toxicity.
• Limited use due to safety concerns and potential for virilization in females and precocious puberty in males.
Pain management:
• Mechanism of action: Target pain pathways to alleviate discomfort associated with fractures and
musculoskeletal weakness.
• Side effects:
• Drowsiness, constipation, nausea, dizziness.
• Dependence and addiction risk with extended use of opioids.
A 16-year-old female presents to the emergency department with acute knee pain and swelling after a minor twisting
injury while dancing. She reports a history of frequent ankle sprains, recurrent shoulder dislocations, and generalized
joint hypermobility. Her skin is soft and velvety, stretching easily, and she demonstrates visible hyperextensibility of her
fingers and elbows. Physical examination reveals significant knee effusion and instability, suggesting a potential joint
dislocation.

1. Briefly explain the underlying genetic defect(s) leading to the syndrome and their impact on connective tissue
function, focusing on the most relevant tissues in this case (joints and skin).
·

2. Discuss the rationale and potential effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) for managing
the patient's acute knee pain and inflammation, considering the possible limitations.
3. Outline the differential diagnoses for the patient's presentation, including other musculoskeletal conditions and
·

potential systemic etiologies that could mimic ligamentous instability and recurrent dislocations.
4. Identify the specific ligaments and capsular structures at the knee joint that are most likely involved in the patient's
suspected dislocation, and explain their anatomical roles in joint stability and movement.
Genetic Defects: Ehlers-Danlos syndrome (EDS) encompasses a group of disorders with diverse genetic mutations
affecting collagen, a crucial protein in connective tissues. This case likely involves either:
• Collagen Synthesis Defects: Mutations in genes encoding specific collagen types (e.g., COL1A1, COL5A1) lead
to abnormal collagen production, compromising its strength and flexibility.
• Collagen Processing Defects: Mutations in genes encoding enzymes involved in collagen processing or cross-
linking disrupt the proper collagen fibril formation, impacting tissue integrity.
•Joint Impact: Deficient collagen affects joint ligaments and capsules, reducing their strength and elasticity. This
predisposes to hypermobility, instability, and recurrent dislocations, as seen in the patient's knee.
•Skin Manifestations: The soft, velvety texture and hyperextensibility of the patient's skin reflect weakened collagen
fibers in the dermis, a characteristic feature of several EDS types.
Differential Diagnoses:
• Hypermobility Spectrum Disorders: Other conditions like hypermobility spectrum disorder (HSD) can mimic
EDS with joint hypermobility but lack the underlying genetic defects and collagen abnormalities.
• Inflammatory Rheumatic Diseases: Inflammatory arthritis like rheumatoid arthritis can also cause joint pain and
swelling, but the absence of systemic inflammatory markers and distinct clinical features help differentiate it
from EDS.
• Congenital Connective Tissue Disorders: Marfan syndrome or Larsen syndrome can share some features like
joint hypermobility, but skeletal and cardiovascular manifestations and distinct genetic profiles will help
distinguish them from EDS.
The knee joint's stability relies on numerous ligaments and the surrounding capsule. Potential structures involved in the
patient's suspected dislocation include:
• Medial Collateral Ligament (MCL): The primary stabilizer against inward knee valgus deformity, commonly
injured in twisting injuries like the one described.
• Anterior Cruciate Ligament (ACL): Controls anterior-posterior stability and can be compromised during sports
injuries or sudden knee hyperextension.
• Posterior Cruciate Ligament (PCL): Prevents hyperextension, which may be more vulnerable in EDS due to its
inherent joint laxity.
• Knee Capsule: The fibrous connective tissue envelope provides overall joint support, and its laxity in EDS
contributes to potential instability.
Skeletal Structure and Function module

Week
2DS
Week 3 Day 2
Musculoskeletal system

Muscle anatomy, physiology and the

neuromuscular junction
Learning objectives:
1. Define the muscular system and its functions
2. Discuss the embryologic development of the muscular system.
 MCQ Case 1

A 20-week-old infant is brought to an urgent care clinic by her mother because she has not been eating well for the past 2
days. The mother said her daughter has also been ‘floppy’ since yesterday morning and has been unable to move or open
her eyes since the afternoon of the same day. The child has recently started solid foods, like cereals sweetened with
honey. There is no history of loose, watery stools. On examination, the child is lethargic with lax muscle tone. She does
not have a fever or apparent respiratory distress. What is the most likely mode of transmission of the pathogen
responsible for this patient’s condition?

A.Direct contact
B.Airborne droplet transmission
C.Vector-borne disease
D.Contaminated food
E.Vertical transmission
 MCQ Case 1

Correct answer D: The infant most likely has botulism caused by Clostridium botulinum, which is a gram-positive,
anaerobic, spore-forming bacilli most commonly found in soil. Clostridium botulinum can also contaminate
improperly refrigerated food and honey. Clostridium botulinum produces a heat-labile exotoxin called botulinum
toxin that inhibits the release of acetylcholine in the neuromuscular junction, thereby preventing muscle contraction.
Loss of muscle contraction leads to a flaccid type of paralysis.
There are 3 different forms of botulism:
1.Food-borne botulism (mostly from canned foods)
2.Wound botulism (colonization in a wound)
3.Infant botulism (contaminated food, especially honey)
Infants do not have sufficient normal bacterial flora in their gut. When a child ingests the spores of C. botulinum, the
spores colonize the intestinal tract and produce toxins. Infant botulism mainly presents in a previously healthy infant
with symptoms of constipation, weakness in sucking, swallowing, or crying, and muscle weakness (floppy baby). C.
botulinum can be isolated in the stool of an infected infant. Passive immunization with immunoglobulins should be
started as soon as the clinical diagnosis is made. Other therapies include ventilatory support in patients who develop
respiratory paralysis.
 MCQ Case 1

Option A: Direct person-to-person contact is a mode of transmission of diseases that occur when microorganisms pass
from an infected host to a healthy person via direct physical contact or through contact with blood or other body fluids.
Examples include touching, kissing, sexual contact, and contact with oral secretions or body lesions. Sexually
transmitted diseases, such as gonorrhea, chlamydia, and syphilis, are examples of infections transmitted via this route.
Option C: Airborne diseases spread via droplets containing the pathogen that are expelled in the air when an infected
person sneezes, coughs, or talks. Measles, influenza, and tuberculosis are a few examples of airborne diseases.
Option D: Vector-borne diseases are human infections caused by bacteria, parasites, and viruses that are transmitted by
mosquitoes, ticks, sandfly mites, and lice. Malaria, dengue, human African trypanosomiasis, schistosomiasis, yellow
fever, and leishmaniasis are some examples of vector-borne diseases. The distribution of vector-borne disease is
determined by demographic, environmental, and social factors.
Option E: Transmission of pathogens from mother-to-baby during, before, or after birth is called vertical transmission
of disease. Transmission can occur through the placenta, breast milk, or through direct contact during or after birth.
Hepatitis B and HIV are common examples acquired through this route.

Learning objective: Infant botulism occurs through the ingestion of honey contaminated with spores of C. botulinum.
As infants do not have sufficient normal flora in their gut, when an infant ingests food containing spores of C.
botulinum, the spores colonize the intestinal tract and produce toxins. The classic presentation is that of a previously
healthy infant with constipation, weakness in sucking, swallowing, crying, and muscle weakness.
 MCQ Case 2

A 3-year-old boy presents to the office with his mother because of weakness and difficulty walking. He was born at 39
weeks' gestation via spontaneous vaginal delivery. He is up to date on all vaccinations. He is meeting all verbal and
social milestones, but gross and fine motor skills are delayed. Past medical history is noncontributory. He takes a
multivitamin every day. His mother states that some boys on her side of the family have had similar symptoms and
worries that her son might have the same condition. His blood pressure is 104/62 mm Hg, pulse 90/min, respiratory rate
22/min, and temperature 37.0°C (98.6°F). On physical exam, the boy appears well developed and pleasant. He listens
and follows directions. His heart has a regular rate and rhythm and his lungs are clear to auscultation bilaterally. He
struggles to get up to a standing position after sitting on the floor. Genetic studies reveal a deletion in the gene that codes
for dystrophin. Which of the following is the most likely diagnosis?

A.Duchenne muscular dystrophy

B.Becker muscular dystrophy
C.Limb-girdle muscular dystrophy
D.Myotonic muscular dystrophy
E.Emery-Dreifuss muscular dystrophy
 ↑
MCQ Case 2

Correct answer: A
Duchenne muscular
dystrophy (DMD) is a disease
characterized by muscle
weakness, muscle atrophy, and
dilated cardiomyopathy that
begins before the age of 5 years
and is due to a lack of functional
dystrophin. Dystrophin is a
structural protein of skeletal and
cardiac muscle (see image).
 MCQ Case 2

Dystrophin is encoded by the dystrophin gene, which is the largest protein-coding gene in the human genome.
Duchenne muscular dystrophy is an X-linked disorder and follows an X-linked recessive inheritance pattern, so mainly
males are affected. There are thousands of mutations associated with DMD. These mutations either inhibit the
production of dystrophin or significantly modify the protein so that it cannot function.
The muscle weakness in Duchenne muscular dystrophy begins with the muscles of the pelvis and thighs, and the 1st
symptoms are associated with gait. Additionally, patients with this disease often have pseudohypertrophy of the calf
muscles, in which muscle is replaced with fibrous fatty tissue. This boy’s symptoms coupled with his age, sex, and
family history on the mother’s side make Duchenne muscular dystrophy the most likely diagnosis.
 MCQ Case 2

Option B: Becker muscular dystrophy is characterized by muscle weakness that begins in adolescence or early
adulthood. Becker muscular dystrophy is similar to Duchenne muscular dystrophy because they both involve mutations
in the dystrophin gene, but the mutation involved in Becker muscular dystrophy is a non-frameshift mutation, often an
insertion, which leads to partially functional dystrophin. Symptoms present later in life and are generally less severe.
This disorder is also X-linked recessive and is seen mostly in males. Although the presentations are very similar, Becker
muscular dystrophy is an unlikely diagnosis because of the age of the boy.
Option C: Limb-girdle muscular dystrophy (LGMD), also known as Erb muscular dystrophy, is a group of disorders
characterized by muscle weakness in both the arms and legs. The muscles of the pelvic girdle and shoulder girdle are
affected first. Usually, there is no calf muscle pseudohypertrophy. As the disease progresses, the skeletal muscles of the
limbs, neck, and back become involved. Eventually, respiratory compromise can occur. The diseases in this group of
muscular dystrophies can be autosomal recessive or autosomal dominant. This boy’s presentation makes this diagnosis
unlikely.
 MCQ Case 2

Option D: Myotonic muscular dystrophy is characterized by myotonia (inability to relax muscles), muscle weakness,
and muscle wasting. It is inherited in an autosomal dominant pattern, and symptoms typically present in adulthood.
Additional symptoms include cataracts, balding, and testicular atrophy. The most common form of this disease is
myotonic muscular dystrophy type 1, which primarily affects the distal muscles and is caused by a cytosine–thymine–
guanine (CTG) trinucleotide repeat in the dystrophia myotonica protein kinase (DMPK) gene. This leads to defects in
the expression of myotonin protein kinase. The presentation and age of this boy make this diagnosis very unlikely.
Option E: Emery-Dreifuss muscular dystrophy is a group of muscular dystrophies characterized by muscle
contractures leading to muscle weakness and atrophy. Several genes are involved in the pathogenesis of this disease;
however, the EMD and LMNA genes, which are involved in making the nuclear envelope of the cell, are the most often
involved. There are autosomal dominant, autosomal recessive, and X-linked forms of this disease. Emery-Dreifuss
muscular dystrophy can progress to cardiac involvement that can cause arrhythmia and death. This boy’s presentation
does not involve muscle contracture, making this diagnosis unlikely.

Learning objective: Duchenne muscular dystrophy is a disease characterized by muscle weakness, muscle atrophy,
and dilated cardiomyopathy that begins before the age of 5 years and is due to a lack of functional dystrophin.
Dystrophin is encoded by the dystrophin gene found on the X chromosome. Duchenne muscular dystrophy follows an
X-linked recessive inheritance pattern, so mainly males are affected.
 MCQ Case 3

A 45-year-old woman presents to the clinic with weakness that has progressively worsened over the past 2 weeks. She
states that she has a hard time lifting both her arms, but they otherwise function normally. She notes no history of trauma
or other deficits. On examination, she has 2/5 muscle strength on shoulder shrug and arm abduction bilaterally, but the
neurologic exam is otherwise normal. You notice some skin changes and ask her about them. She states that she has had
a rash around her eyes and on her lower face, going down to her neck and chest. The rashes started around the same time
as the weakness began. A complete blood count and basic metabolic panel are normal. Which of the following is the
most likely diagnosis?

A.Myasthenia gravis
B.Polymyalgia rheumatica
C.Lambert-Eaton myasthenic syndrome (LEMS)
D.Dermatomyositis
E.Fibromyalgia
 MCQ Case 3

Correct answer: D
Dermatomyositis is an autoimmune disease characterized by symmetric progressive proximal muscle weakness. It is
caused by inflammation of the perimysium of the muscle, a connective tissue sheath surrounding a bundle of muscle
fibers, by CD4+ T cells. Serum markers include an increased creatine kinase level, as well as a positive antinuclear
antibody, positive anti-Jo-1, and positive anti-SRP (signal recognition particle) antibodies. Dermatomyositis can be
inherited or can be triggered by a viral infection; it can also be associated with underlying cancer, most commonly
ovarian, breast, or lung.
 MCQ Case 3
Dermatomyositis and polymyositis are
similar in presentations of muscle
weakness; however, there are significant
differences. Polymyositis causes
inflammation of the endomysium of the
muscle, which is a layer of areolar
connective tissue that ensheathes each
individual myocyte, by CD8+ T cells. It
also does not produce cutaneous
symptoms. Dermatomyositis presents
with cutaneous symptoms such as malar
rash, Gottron papules, periorbital
(heliotrope) rash, and a "shawl rash" that
covers the neck and chest (see images
below).
This woman’s symptoms of proximal
muscle weakness and cutaneous
symptoms make dermatomyositis the
most likely diagnosis.
MCQ Case 3
MCQ Case 3
 MCQ Case 3

Option A: Myasthenia gravis is an autoimmune disease caused by autoantibodies to the postsynaptic nicotinic
acetylcholine (ACh) receptors at the neuromuscular junction (NMJ). When the ACh receptors are blocked or destroyed
by autoantibodies, the nerve impulses cannot be propagated, leading to muscle weakness. Because this occurs at the
NMJ, skeletal muscle is most affected. Clinical presentation includes fatigue, muscle weakness that worsens with use,
ptosis, and diplopia. Acetylcholinesterase inhibitors can improve symptoms because they increase the amount of
available ACh. Myasthenia gravis symptoms do not include cutaneous symptoms, making this diagnosis unlikely.
Option B: Polymyalgia rheumatica is a syndrome characterized by joint pain and muscle stiffness with systemic
symptoms such as fever and fatigue. It is highly associated with giant cell arteritis, an autoimmune-mediated vasculitis
that typically affects the temporal artery. There is no muscle weakness or rash associated with this condition. Both
polymyalgia rheumatica and giant cell arteritis present more commonly in older women. Because polymyalgia
rheumatica does not affect muscle strength and does not cause a rash, it is an unlikely diagnosis in this woman.
 MCQ Case 3

Option C: LEMS is an autoimmune disease characterized by autoantibodies to presynaptic calcium channels in the
neuromuscular junction. Calcium cascade is responsible for the release of acetylcholine from presynaptic vesicles;
therefore, this disease causes a decrease in ACh availability, resulting in muscle weakness. Clinical presentation
includes proximal muscle weakness that improves with muscle use, as well as sparing of the eyes (no diplopia or
ptosis). Weakness is more prominent in the lower extremities than in the upper extremities. LEMS most often occurs as
a paraneoplastic syndrome associated with small cell lung cancer. This woman’s presentation does not suggest LEMS or
small cell lung cancer, making this diagnosis unlikely.
Option E: Fibromyalgia is a disorder characterized by chronic and diffuse joint and muscle pain. Other associated
symptoms include paresthesias, tender points, fatigue, and sleep disturbances. The underlying cause is unknown. The
disorder is more common in middle-aged women, suggesting a possible autoimmune etiology. Fibromyalgia is generally
a diagnosis of exclusion, but also includes a number of characteristic tender points. This woman is exhibiting specific
and symmetric weakness, suggesting that fibromyalgia is not a likely diagnosis.
Learning objective: Muscle weakness has many causes, including anemia, electrolyte imbalance, trauma, autoimmune
disorders, and genetic disorders. Looking at a patient’s history and conducting a physical exam helps narrow the
possible causes of weakness.
 MCQ Case 4

The patient presented with intermittent abdominal pain. A preoperative diagnosis of juxta-visceral aortic
aneurysm was made, and he was treated with an axillo-uni-iliac and visceral bypass with spliced Dacron 8
mm to 8 mm polytetrafluoroethylene (PTFE) bifurcated graft with subsequent explantation. On
postoperative day 7, abdominal distension was noted.
Which of the following is the most likely diagnosis?

A.Intraabdominal bleeding
B.Gastrointestinal bleeding
C.Postoperative ileus
D.Mesenteric cyst
E.Abdominal hernia
 Correct answer: C
Postoperative ileus (POI) is defined the reduction of gastrointestinal (GI) motility after abdominal or other
types of surgery and is characterized by abdominal distension, lack of bowel sounds, accumulation of gas and
fluids in the bowel, and delayed passage of flatus and stools. Each segment of the gastrointestinal tract
recovers activity at a different rate after surgical manipulation. The small intestine recovers motility within
several hours, the stomach within 24 to 48 hours, and the colon in 3 to 5 days. However, in postoperative
period, some patients experience a prolonged inhibition of coordinated bowel activity that causes
accumulation of secretions and gas, resulting in nausea, vomiting, abdominal distension, and pain.
While NSAIDs can effectively manage pain and inflammation in acute knee injury, their use in EDS requires caution
due to several factors:
• Increased Bleeding Risk: EDS patients may have platelet abnormalities leading to increased bleeding risk,
further exacerbated by NSAIDs that inhibit platelet aggregation.
• Gastrointestinal Complications: NSAIDs can irritate the gastrointestinal tract, especially in EDS patients due to
potentially weaker connective tissues in the stomach and intestines.
• Limited Long-Term Benefits: NSAIDs provide symptomatic relief but don't address the underlying joint
instability in EDS. Alternative approaches like physical therapy and bracing may be more beneficial in the long
term.
Skeletal Structure and Function module

Week 3 Day21 4
Musculoskeletal system

Immunological and Inflammatory

Joint Disorders
 MCQ Case 1
A 52-year-old woman presents with fatigue and pain of the proximal interphalangeal and metacarpophalangeal joints for
the past 6 months. She also has knee and wrist pain that have been present for the past 2 months, with morning stiffness
that improves over the course of the day. Physical examination is significant for subcutaneous nodules. Laboratory tests
are significant for the following:
Hemoglobin 12.5 g/dL
Red blood cell count 4.9 x 106/µL
White blood cell count 5,000/mm3
Platelet count 180,000/mm3
Coombs' test Negative
C-reactive peptide (CRP) Elevated
Erythrocyte sedimentation rate (ESR)
Elevated Anti-cyclic citrullinated peptide antibody (anti-CCP antibody) Moderately positive
Anti-nuclear antibody (ANA) Negative
Rheumatoid factor (RF) Negative
What is the most likely human leukocyte antigen (HLA) subtype associated with this disease?
A.HLA-DR4 ·

B.HLA-DR2
C.HLA-DR5
D.HLA-DQ2
E.HLA-B27
 MCQ Case 1
Correct answer A: This patient most likely has rheumatoid arthritis (RA). She is presenting with a series of classic
symptoms, including symmetric arthralgia, morning stiffness, fatigue, and a moderately positive Anti-cyclic citrullinated
peptide antibody (anti-CCP antibody) or ACPA. ACPA is more specific than rheumatoid factor (RF), and patients can be
RF negative and yet have RA if they meet the following American College of Rheumatology criteria:
Joint involvement 1 large joint 0
2 to 10 large joints 1
1 to 3 small joints (with or without the involvement of large joints) 2

4 to 10 small joints (with or without the involvement of large joints) 3

10 joints (at least 1 small joint) 5
Serology Negative RF and negative Anti-CCP 0

Low positive RF or low positive Anti-CCP 2

High positive RF or high positive Anti-CCP 3

Acute phase reactants Normal CRP and normal ESR 0

Abnormal CRP or normal ESR 1

Duration of symptoms < 6 weeks 0
> 6 weeks 1
A score of ≥ 6 is required for a diagnosis of RA.
 MCQ Case 1
RA, immunologically speaking, is a type III hypersensitivity reaction in which the body’s immune system attacks the
joint synovium; this results in the erosion of cartilage and bone. It is often associated with HLA subtype HLA-DR4. RA
is treated symptomatically for pain management and with disease-modifying drugs, such as methotrexate and
sulfasalazine, and TNF-⍺ inhibitors, such as infliximab.
Association of HLA subtypes with diseases
Major histocompatibility complex MHC II
(MHC) I
Binds to TCR and CD8 Binds to TCR and CD4
A3: Hemochromatosis DQ2/DQ8: Celiac disease
B8: Graves' disease DR2: Multiple sclerosis, hay fever, systemic
lupus erythematosus (SLE), Goodpasture's
syndrome
B27: Psoriasis, ankylosing spondylitis, DR3: Diabetes type 1, SLE, Graves' disease,
inflammatory bowel disease, Hashimoto's thyroiditis, Addison's disease
reactive arthritis
DR4: RA, diabetes type 1, Addison's disease

DR5: Pernicious anemia, Hashimoto's

thyroiditis
 MCQ Case 1

Option B: HLA-DR2 is associated with multiple sclerosis, hay fever, SLE, and Goodpasture's syndrome, not RA.
Option C: HLA-DR5 is associated mainly with pernicious anemia. Findings include anti-parietal cell and anti-intrinsic
factor antibodies, which lead to vitamin B12 deficiency and, subsequently, megaloblastic anemia.
Option D: HLA-DQ2 is associated with celiac disease. The body reacts to the protein gliadin found in most bread and
other products containing wheat. Celiac disease is associated with such positive findings as elevated IgA anti-tissue
transglutaminase and anti-endomysial, anti-deamidated gliadin peptide antibodies titers. Treatment consists of a gluten-
free diet.
Option E: Several types of arthritis are associated with HLA-B27. These are referred to as seronegative
spondyloarthropathies. The most significant of these is ankylosing spondylitis, which is seen in adult men more than
women. It classically involves the sacroiliac joints and leads to ankylosis of the spine characterized on X-ray as
"bamboo spine". Treatment is mainly physiotherapy and pain management. Specific treatment can consist of therapeutic
antibodies such as adalimumab, infliximab, and etanercept. Reactive arthritis, enteropathic arthritis, psoriatic arthritis,
Behçet disease, and juvenile idiopathic arthritis are other types of seronegative arthropathies.

Learning objective: Major histocompatibility complex defects are associated with a series of conditions. Rheumatoid
arthritis, in particular, is a type III hypersensitivity reaction associated with the HLA-DR4 subtype.
 MCQ Case 2
A 35-year-old woman presents for evaluation of symmetric proximal muscle weakness. She has a blue-purple
discoloration of the upper eyelids and also a pruritic, papular rash on the knuckles, as shown in the photo. What is the
most likely diagnosis?

A.Polymyositis
B.Duchenne muscular dystrophy
C.Hypothyroidism
D.Inclusion body myositis
E.Dermatomyositis
 MCQ Case 2

Correct answer E: The photograph depicts Gottron’s

papules, which are characteristic of dermatomyositis. Extra testing
may not be necessary for patients with characteristic skin findings of
dermatomyositis and proximal muscle weakness. If the diagnosis is
unclear and further testing with muscle biopsy is needed, the
inflammatory infiltrate is perifascicular and sometimes perivascular
with muscle atrophy. B lymphocytes and an increased number of
plasmacytoid dendritic cells are seen.
The features of dermatomyositis include (see image):
•Heliotrope rash: Blue-purple discoloration of the aupper eyelids
•Gottron’s papules: Erythroderma of the knuckles with scaly
violaceous eruptions
•Shawl sign: Erythematous rash on the shoulders
•Extramuscular associations, including scleroderma
•Increased rate of malignancy
 MCQ Case 2

Option A: Polymyositis is an inflammatory myopathy. A history of proximal muscle weakness and physical
examination with no upper motor neuron signs bring this to the differential diagnosis. General lab testing plus creatine
kinase and serologic testing for myositis-specific autoantibodies clarify the diagnosis. If still unclear, electromyography
and nerve conditions studies are helpful. Muscle biopsy histology shows muscle fiber necrosis, degeneration,
regeneration, and inflammatory cell infiltrationa.
Option B: Duchenne muscular dystrophy is not associated with Gottron’s papules.
Option C: Hypothyroidism is not associated with Gottron’s papules.
Option D: Inclusion body myositis occurs in patients > 50 years of age. Affected patients present with weakness of the
distal muscles rather than proximal muscles.
Learning objective: Dermatomyositis is an inflammatory myopathy associated with Gottron’s papules and a heliotrope
rash on the eyelids.
 MCQ Case 3
A 13-year-old girl is admitted to the hospital due to muscle weakness, pain, and arthralgia in her wrist joints. The patient
says, "I am having trouble walking home after school, especially climbing steep hills." She also complains of malaise.
On physical examination, a heliotrope rash is observed around her eyes, and multiple hyperkeratotic, flat, red papules
with central atrophy are present on the back of the metacarpophalangeal and interphalangeal joints. Deposits of calcium
are also noted on the pads of her fingers. Her serum creatine kinase levels are elevated. Which of the following
antibodies is most likely to be found in this patient?

A.Anti-Sm
B.Anti-Jo-1
C.Anti-centromere
D.Anti-Scl-70
E.Anti-histone
 MCQ Case 3

Correct answer B: This patient has classic findings of dermatomyositis, an idiopathic inflammatory myopathy with
very specific cutaneous findings (i.e., heliotrope erythematosus periorbital rash and Gottron papules on the hands).
Laboratory findings may include increased creatine kinase due to muscle damage, and antinuclear antibodies, including
anti-Jo-1, anti-SRP, and anti-Mi-2.
Treatment consists of immunosuppressant therapy with methotrexate or corticosteroids. Mild cutaneous symptoms can be
treated with topical corticosteroids and by avoiding ultraviolet light exposure. Other autoimmune diseases also present
with specific antibodies, the findings of which are key for diagnosis in combination with clinical symptoms. Antibodies
found in autoimmune diseases include the following:
•Systemic lupus erythematosus (SLE) — antinuclear, rheumatoid factor, anti-dsDNA, antiphospholipid, and anti-Sm
•Drug-induced lupus erythematosus — anti-histone
•Rheumatoid arthritis — anti-citrullinated peptide and rheumatoid factor
•Polymyositis and dermatomyositis — antinuclear, anti-Jo-1, anti-SRP, and anti-Mi-2
•Systemic sclerosis — anti-centromere, anti-Scl-70, and rheumatoid factor
•Sjögren’s syndrome — anti-Ro and anti-La
•Overlap syndrome or mixed connective tissue disorder — anti-U1 RNP
 MCQ Case 3

The Myositis Association Criteria advise that patients should present with at least 4 musculoskeletal symptoms/signs
and at least 1 skin symptom from the lists below. Additionally, a polymyositis diagnosis can be established if the patient
has no skin lesions.
The diagnostic criteria for dermatomyositis are as follows.
Musculoskeletal symptoms/signs (at least 4):
•Proximal muscle weakness — upper or lower extremity and trunk
•Elevated serum CK or aldolase level
•Muscle pain (grasping or spontaneous pain)
•Myogenic changes on electromyography — of short duration and polyphasic motor unit potentials with spontaneous
fibrillation potentials
•Positive anti-Jo-1 (histidyl-tRNA synthetase) antibody
•Non-destructive arthritis or arthralgias
•Systemic inflammatory signs — fever > 37.0°C (98.6°F) at the axilla, and elevated serum CRP level or accelerated
ESR (erythrocyte sedimentation rate) of > 20 mm/h (Westergren method)
•Pathological findings compatible with inflammatory myositis — e.g., inflammatory infiltration of skeletal evidence of
active regeneration
Skin lesions (at least 1):
•Heliotrope rash — red-purple edematous erythema on the upper palpebra
•Gottron’s sign — red-purple keratotic, atrophic erythema, or macules on the extensor surface of finger joints
•Erythema on the extensor surface of extremity joints — slightly raised red-purple erythema over elbows or knees
 MCQ Case 3

Option A: Anti-Sm antibody is specific for SLE.

Option C: Anticentromere antibodies are usually associated with CREST syndrome (calcinosis, Raynaud's
phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) and, occasionally, systemic scleroderma.
Option D: Anti-Scl-70 antibodies are associated with systemic scleroderma. It is occasionally found in
CREST syndrome.
Option E: Anti-histone antibody is found in drug-induced lupus erythematosus. The following drugs have some risk of
drug-induced lupus: hydralazine, procainamide, minocycline, isoniazid, methyldopa, and penicillamine.

Learning objective: Dermatomyositis is an idiopathic inflammatory myopathy with cutaneous findings such as
periorbital rash and Gottron’s sign. Laboratory findings may include increased creatine kinase levels due to muscle
damage, and antinuclear antibodies, including anti-Jo-1, anti-SRP, and anti-Mi-2. Dermatomyositis can be managed
with corticosteroids.
 MCQ Case 4
A 32-year-old woman presents to her primary care provider complaining of a psoriatic flare that has worsened over the
past 2 days. The patient states that her psoriasis is normally well controlled. She also complains of some fatigue and
states that she has recently developed pain and tenderness in the joints of her hands, with the right hand being more
tender than the left. Her hands are stiff in the morning, and sometimes her fingers swell up. She attributes these changes
to her new job, where she constantly uses her hands to manufacture cabinets. Physical examination reveals plaques with
silvery scale on her elbows and knees. The distal joints of her right hand are mildly swollen, and the nails on both hands
appear pitted. What is the most likely pathogenesis of her joint pain?

A.Local invasive infection of the joint space

B.Repetitive injury
C.Autoantibodies to the Fc portion of IgG
D.Deposition of crystals in the joint space
E.Release of TNF and activation of the RANKL pathway
 MCQ Case 4

Correct answer E: This patient is presenting with some signs and symptoms of psoriatic arthritis, a seronegative
spondyloarthropathy characterized by multiple joint arthritis in patients with psoriasis. Psoriatic arthritis is seen in a
small percentage of patients with psoriasis. It is an autoimmune inflammatory condition of the joints that is negative for
serum markers of rheumatoid arthritis. Psoriatic arthritis is believed to result from the release of TNF and activation of
the RANKL pathway. Activation of the RANKL pathway leads to focal erosions in the bone through stimulation of
osteoclasts.
 MCQ Case 4

Option A: Septic arthritis is an infection of joint spaces that causes redness, swelling, decreased range of motion, and
pain in the infected joint. It is an acute infectious process with a progression of symptoms in the joint and does not
remit. The large joints, such as the knees, are most commonly involved. Staphylococcus aureus is a common cause. This
patient is at increased risk for a soft tissue infection due to chronic skin disease. However, her clinical presentation is
not suggestive of infection.
Option B: Osteoarthritis is a common degenerative disease of the joints, most commonly affecting the knees, lumbar
vertebra, and distal interphalangeal and proximal interphalangeal joints of the hands. Osteoarthritis is most often
associated with wear-and-tear injuries that are related to repetitive movements and aging, but it is also associated with
obesity and trauma. Symptoms often include aching pain that is worse with use and with certain motions. Diagnosis is
usually clinical but can be confirmed by x-ray, which shows a narrowing of the joint spaces and degeneration of the
articular cartilage. This patient’s presentation is more consistent with psoriatic arthritis.
 MCQ Case 4

Option C: Rheumatoid arthritis (RA) is a systemic autoimmune disease most commonly seen in middle-aged women.
Joint destruction occurs due to the degradation of the articular cartilage and the fusion of the affected joints. Early in the
disease, it can be difficult to delineate RA from osteoarthritis. RA is accompanied by a variety of nonspecific symptoms
such as fever, fatigue, and weight loss. This patient’s presentation is more consistent with psoriatic arthritis.
Option D: Gout is a condition in which excess uric acid in the blood is deposited in body tissues and joint spaces as
negatively birefringent monosodium urate crystals. Uric acid is a byproduct of purine metabolism. Joint aspiration with
visualization of these crystals is the only definitive diagnosis. Gout can be both acute and chronic. Acute gout attacks
will present with severe pain to a particular joint, most commonly the great toe (podagra). Gout is unlikely in this
patient.
Learning objective: Psoriatic arthritis is a seronegative spondyloarthropathy associated with the skin disease psoriasis.
It is an autoimmune inflammatory arthritis, and it is believed to result from the release of TNF and activation of the
RANKL pathway. Activation of the RANKL pathway leads to focal erosions in the bone through stimulation of
osteoclasts.
 MCQ Case 5
A 62-year-old carpenter presents to your clinic complaining of worsening joint pain in her hands. She states that the pain
is present in all of her fingers, but is worse in the right hand and gets better when she has a few days off from work. She
denies any paresthesias, fevers, or fatigue. Vital signs are normal. Physical exam reveals hard, non-tender lesions
overlying the proximal interphalangeal joints of the 2nd and 3rd fingers of the right hand. All five digits of the right
hand have a decreased range of motion. An X-ray of her hands is shown. What is the most likely pathogenesis
underlying the X-ray findings?

A.Chronic degradation of articular cartilage

B.Overgrowth of gram-positive bacteria
C.Deposition of monosodium urate crystals
D.Genetic predisposition associated with HLA-B27
E.Production of rheumatoid factor and other
autoantibodies
 MCQ Case 5

Correct Answer A: Chronic degradation of articular cartilage. The woman has osteoarthritis, which is a common
degenerative disease of the joints that most commonly affects the knees, lumbar vertebra, and distal (DIP) and proximal
interphalangeal (PIP) joints of the hands. It is most often associated with wear-and-tear injuries that are related to
repetitive movements and aging, as well as with obesity and trauma.
Symptoms often include aching joint pain that worsens with use as well as a limited range of motion. The nodules
described in this woman’s history are Bouchard’s nodes (of the PIP joints, and Heberden's nodes appear on the DIP
joints), which are only found in osteoarthritis and not rheumatoid arthritis. Diagnosis is usually clinical but can be
·

confirmed with X-rays, which would show a narrowing of the joint spaces due to the degeneration of the articular
cartilage in the joints.

-
 MCQ Case 5

Option B: Overgrowth of gram-positive bacteria indicates septic arthritis, which is an infection of the joint spaces that
causes redness, swelling, a decreased range of motion, and pain in the joint. It is a monoarticular (single joint) disease,
and large joints, such as the knees, are the most commonly involved. Staphylococcus aureus, a gram-positive coccus, is
the most common bacterial cause of septic arthritis. Bacterial arthritis can be the result of seeding from a superficial
infection, from trauma due to a penetrating wound, or from bacteremia. It is an acute infectious process with a
progression of symptoms in the joint that does not remit.
Option C: Deposition of monosodium urate (uric acid) crystals occurs with gout, which is sudden in onset and typically
monoarticular. Uric acid is produced by the metabolism of purine; when there is an excessive amount of uric acid in the
blood, it can precipitate in synovial fluid as crystals and cause severe pain and swelling of the joint. Definitive diagnosis
is by synovial fluid analysis, and the uric acid crystals are needle-shaped and negatively birefringent when exposed to
polarized light. Gout can be acute or chronic. Acute gout attacks present with significant pain involving a particular
joint, most commonly the big toe (podagra). These attacks are often triggered by the ingestion of alcohol or meat.
Chronic gout results in the formation of tophi and renal failure.
 MCQ Case 5

Option D: Genetic predisposition associated with HLA-B27 highly correlates with the seronegative
spondyloarthropathies, which are characterized by inflammatory arthritis of the axial skeleton (sacroiliac joints and
vertebral column) and enthesitis (inflammation of tendon and ligament insertions). They include ankylosing spondylitis,
reactive arthritis, psoriatic arthritis, and inflammatory bowel disease-associated arthritis. Enthesitis sets the negative
spondyloarthropathies apart from other forms of arthritis and usually involves the calcaneal tendon. Involvement of
other systems, such as ocular inflammation (uveitis), may also be involved.
Option E: Production of rheumatoid factor and other autoantibodies is seen with rheumatoid arthritis (RA), a systemic
autoimmune disease that most commonly occurs in middle-aged women. Autoantibodies to the Fc portion of IgG
(rheumatoid factor) are the characteristic laboratory findings in RA. It can be difficult to differentiate RA from
osteoarthritis early in the disease, but RA typically presents as pain and joint stiffness in the morning that improves with
movement, unlike osteoarthritis, and the PIP joints are affected but the DIP joints are spared. RA is also accompanied by
a variety of non-specific symptoms such as fever, fatigue, and weight loss. As the disease progresses, various organ
systems are affected, leading to vasculitis, pleural effusion, pericarditis, and interstitial lung fibrosis.

Learning objective: Osteoarthritis is the most common cause of arthritis. It is a chronic joint condition that is relieved
with rest. X-ray findings are consistent with joint space narrowing due to articular cartilage degradation. The causes of
osteoarthritis include wear and tear, aging, obesity, and previous trauma.
 MCQ Case 6
A 33-year-old man presents to the clinic complaining of multiple painful joints for the past 2 weeks. The patient notes
no history of trauma or any joint disorders. The patient states that he is generally healthy except for a recent emergency
room visit for severe bloody diarrhea, which has resolved. On further questioning, the patient admits to some discomfort
with urination but notes no recent sexual activity. On examination, the patient is not in acute distress, with no joint
deformity, evidence of trauma, swelling, or erythema. He has a decreased range of motion of his right knee secondary to
pain. Vital signs are as follows: heart rate 75/min, blood pressure 120/78 mm Hg, respiratory rate 16/min, and
temperature 37.3°C (99.0°F). What is the next step in the treatment of this patient?

A.Intravenous (IV) antibiotics

B.Nonsteroidal anti-inflammatory drugs (NSAIDs) or immunosuppressants
C.Positron emission tomography (PET) scan
D.Serology for rheumatoid factor
E.Prostate biopsy
 MCQ Case 6

Correct answer B: This patient is presenting with reactive arthritis (formerly known as Reiter’s syndrome), a
seronegative spondyloarthropathy. This disease is characterized by inflammatory polyarthritis that results after a
gastrointestinal infection (e.g., Shigella, Salmonella, Yersinia enterocolitica, or Campylobacter jejuni) or chlamydia
infection.
The initial infection results in an autoimmune response that causes arthritis, uveitis, and urethritis. Reactive arthritis is
associated with HLA-B27. Treatment of reactive arthritis involves the treatment of any underlying active infection with
NSAIDs or immunosuppressants to address inflammatory arthritis. Because this patient likely had a gastrointestinal
infection due to his history, no treatment is necessary, since his diarrhea has resolved. Treatment for this patient would,
therefore, center around supportive care and decreasing inflammation.
 MCQ Case 6

Option A: Intravenous antibiotics are indicated in patients with serious infections. In this case, the most likely
infections would be septic arthritis or osteomyelitis. Septic arthritis is the infection of a joint space. It can begin from a
local infection, puncture wound, or bacteremia. This patient’s presentation includes fever as well as erythema, warmth,
and swelling in the affected joint. Osteomyelitis is an infection of the bone itself, most often caused by Staphylococcus
aureus. The presentation also includes fever, localized pain, erythema, and swelling. Both of these infections can cause
the patient to become acutely ill. This patient is not presenting with symptoms consistent with an acute, localized
infection, making treatment with IV antibiotics a poor choice.
Option C: PET scanning is a nuclear medicine imaging technique that is used to visualize metabolic processes in the
body. PET scans can identify areas of the body with increased fludeoxyglucose uptake, and therefore is used primarily
to identify malignancies in the body. PET scans can also be used to reveal active infections by identifying the body’s
inflammatory response to the infection. This patient does not have a currently active infection or a high likelihood of
malignancy. A PET scan is therefore not indicated.
 MCQ Case 6
Option D: Rheumatoid factor is an autoantibody to the Fc portion of IgG and is the characteristic lab finding for
rheumatoid arthritis. Rheumatoid arthritis (RA) is an autoimmune disease with joint destruction due to the degradation
of the articular cartilage and fusion of the affected joints. Early in the disease, it can be difficult to delineate RA from
osteoarthritis. RA is accompanied by a variety of non-specific symptoms such as fever, fatigue, and weight loss are
often present. As the disease progresses, various organ systems are affected, leading to vasculitis, pleural effusion,
pericarditis, and interstitial lung fibrosis. The disease is seen most often in middle-aged women. This patient has no
signs or symptoms of RA, making testing for rheumatoid factor an unlikely way to aid in the diagnosis of his disease.
Option E: A prostate biopsy is indicated in patients who have a high likelihood of prostate cancer or symptoms of
chronic prostatitis. Prostate cancer is commonly seen in men over the age of 65 years and is associated with metastasis
to the lower back, causing chronic back pain. Discomfort with urination is not a common symptom of prostate cancer
but can be associated with chronic prostatitis. Chronic prostatitis is associated with urinary symptoms such as dysuria,
urgency, and frequency, as well as suprapubic or abdominal pain and pain with ejaculation. Prostatitis is not associated
with joint pain. This patient is at very low risk for prostate cancer and therefore a prostate biopsy is not indicated.

Learning objective: Reactive arthritis is a seronegative spondyloarthropathy characterized by multiple joint

involvement, uveitis, and urethritis. It is associated with active chlamydia infection or a history of gastrointestinal
infection with Salmonella, Shigella, Yersinia, or Campylobacter. Treatment for reactive arthritis involves treating the
underlying disease and offering supportive treatment.
 WEEK 3 DAY02
5

Musculoskeletal System
Neoplasms of the Bone
Learning objectives:
1. Define and discuss common benign and malignant bone tumors.
2. Discuss the secondary bone tumors and pathophysiology of them.
 MCQ Case 1
A 58-year-old, previously healthy Caucasian man visited our emergency
department after stumbling in a local pub. He complained of pain in his left
upper leg and was not able to bear weight on it.
An examination showed a large swelling on his upper leg that was very tender
upon palpation, and his leg was shortened.
Radiographs showed a comminuted spiral
fracture of the femoral shaft

(A) Anteroposterior view of the patient's left

femur. (B) Attempt at a lateral view of the
left femur.
A closed reduction of the fracture and an internal fixation with an
Unreamed Femoral Nail were performed.

(A) Anteroposterior view of the proximal

femur with the intramedullary nail in situ .
(B) Lateral view of the distal femur.
• Postoperative radiographs showed a persistent marked diastasis
between the fracture fragments. One large fragment was shifted
dorsomedially. After a six-month period, no signs of
consolidation were seen. The patient complained of pain at the
level of the fracture as well as at the distal femur, just above the
knee. A second operation was performed for autologous bone
grafting with bone harvested from the iliac crest. The patient's
weight-bearing was increased, but consolidation of the fracture
did not progress. Ten months post-trauma there was still no
callus at the fracture site, and the patient's pain at the level of
the distal femur persisted.
• The pain was thought to be caused by the migrating distal
screws; therefore, the screws were removed. The osteolytic area
in the distal femoral metaphysis was explained as bone loss
resulting from immobilization.
(A) Anteroposterior view of
the proximal femur four
months after bone grafting.
(B) Migration of the distal
screws.
• Thirteen months postoperatively some bony callus appeared,
and the patient increased weight-bearing without crutches.
Two years post-trauma the patient visited our first-aid
department again. Over the previous five weeks, there had been
progressive pain in his left knee, which had suddenly become
exacerbated during the previous week after a misstep. Since that
moment, he had been unable to bear weight on it. A physical
examination showed a swollen left knee, and all movements of
the knee were extremely painful for the patient.
Laboratory data revealed no abnormalities.
The radiographs, however, showed an osteolytic lesion in the
distal femur and a fracture line at the level of the proximal aspect
of the lateral femoral condyle.
(A) Osteolytic lesion in the distal
femur and a fracture line (arrow). (B)
Besides the osteolytic lesion in the
distal femur, lytic areas are visible at
the fracture level.
Sequential computed tomographic scans of the thorax and triple-
phase, whole-body bone scintigraphy did not reveal signs of
metastases.
The bone scan showed an increased uptake in the left lateral
femoral condyle and less intensively in the midshaft. Reduced
uptake was seen at the left medial femoral condyle.
A Jamshidi needle biopsy was performed from the most
suspicious region at the medial femoral condyle. No biopsy was
performed at the fracture site. The histopathological examination
showed an undifferentiated lytic lesion matching a pleomorphic
osteosarcoma.
An exarticulation of the hip followed. Prior to the operation, the
last radiographs were taken. The histology showed a classic high-
grade osteosarcoma. At the last follow-up examination, three
years after undergoing amputation, the patient was alive without
metastatic disease and was able to ambulate with crutches.

Conclusion?
Initially, the femoral shaft fracture had a pathological nature.
Several facts speak for this.
1. The patient stumbled in a local pub. Such a traumatic
mechanism is unlikely to cause the femoral shaft fracture
presented;
2. A primary tumor existed at the site of the fracture and was
spread distally by the insertion of the intramedullary nail.
3. The initial trauma imaging studies did not reveal any signs
of a pathological fracture, but the last radiographs showed
lytic lesions in different fracture fragments.
According to these, the osteosarcoma in the distal femur would
be an iatrogenic skip metastasis.
 MCQ Case 2
A six-year-old female patient presented with pain in the right hip of four
months duration, along with difficulty in walking.
There was no other significant contributing history.
On local examination, there was tenderness on deep palpation of the right hip
and restricted range of hip movements. The overlying skin was normal with no
redness or dilated veins.
Plain radiographs revealed a well-defined, expansile,
lytic lesion involving the proximal portion of the right
femur in the trochanteric and subtrochanteric region
approximately 5 cm x 5 cm in size
An MRI of both hips was done,
which showed a hyperintense
lesion in the proximal end of the
shaft of the right femur with
internal septations on a T2-
weighted image. It appeared
hypointense on the T1-weighted
image and showed
inhomogenous enhancement on
the contrast study, which was
suggestive of an aneurysmal
bone cyst
The patient was prepared for surgery. We aspirated the lesion
under the guidance of an
image-intensifier and then injected
polidocanol, a sclerosing agent,
percutaneously. This was augmented
by fixation with two ender’s nails
for prophylactic stabilization of the
affected region. It was sent for
histopathological examination,
which confirmed it to be an
aneurysmal bone cyst.

Shows fixation with ender’s nails after

injecting a sclerosing agent in the lesion.
 After 13 months, the patient again had the same complaints.
Radiographs were repeated, which showed a recurrence of the lesion.

Follow-up radiograph at 13 months

Shows recurrence of the lesion with ender’s nails in situ.
Informed patient consent was obtained for
surgery from the parent. The ender’s nails
were removed, an extensive curettage of
the tumour was done, and the bone defect
was filled with an autogenous cancellous
bone graft, along with prophylactic
fixation with a dynamic hip screw (DHS)
At 19 months follow-up, the
patient had no pain and was
walking without support
with a full range of hip
movements. No signs of
recurrence were seen
radiologically
• Aneurysmal bone cyst (ABC) is a benign, expansile, non-neoplastic lesion
of the bone, characterized by channels of blood and spaces that are
separated by fibrous septae. Giant ABC is an uncommon condition and can
be difficult to handle because of the destructive effect of the cyst on the
bones and the compressive effect on the nearby structures, especially in
weight-bearing bones of the body.
• Aneurysmal bone cysts can occur in any bone, but it is more commonly
located in the metaphysis of long bones, especially weight-bearing ones. It
can present as a primary or secondary lesion (e.g., associated with
chondroblastoma or osteoblastoma). Primary ABC’s arise de novo.
• Radiographically, an ABC is a lytic and expansile lesion that presents with
cortical thinning and septations and shows fluid-fluid levels on MRI.
 MCQ Case 3
A 9-year-old male presented to the emergency department with a 10-day history
of progressive dry cough, chest pain, fatigue, and exertional dyspnea. Symptoms
started one month prior to presentation when the patient suffered progressively
exacerbating chest pain and cough, which became more prominent in the supine
position. The symptoms have been severely aggravated in the last 10 days.
Otherwise, the patient denied any change in appetite, fever, weight loss,
headache, gastrointestinal symptoms, or urinary problems.
On presentation, he was afebrile (temperature 37.8°C), tachycardic
(heart rate of 112 beats per minute), normotensive (126/76 mmHg),
slightly tachypneic (respiratory rate of 27 breath/min), and saturating at
100% on room air.
The physical exam was remarkable for the use of accessory muscles for
breathing and decreased breath sounds on the right upper, middle, and
lower fields. In addition, a palpable mass measuring around 3 cm in
diameter was noted on the anterior right chest, associated with right-
sided axillary lymphadenopathy. No other pertinent positives were
detected.
Prior to his presentation to the emergency department at our institution,
he was seen in another hospital where a chest X-ray showed an
abnormal consolidation and pleural effusion in the right hemithorax.
CT - scan
A CT chest with contrast was performed which showed a very large heterogeneously
enhancing mass occupying the majority of the right hemithorax with peripheral
necrosis measuring approximately 16 × 14 × 11 cm (craniocaudal by anteroposterior
by transverse dimensions). No interval calcification was seen on the precontrast
images. The mass invaded the right chest wall at the level of the lateral aspect of the
fifth and sixth ribs on the right side, where it extended into the sella at the anterior
muscle. Bone erosion and deformity of the right sixth rib and, to a lesser extent, of
the inferior aspect of the fifth rib were also seen.

Based on the history, physical exam, and imaging results, the patient was admitted
and a PET scan was performed.
It revealed a large soft tissue mass occupying the right hemithorax and invading the
anterior chest wall and the overlying ribs, which is consistent with Ewing sarcoma.
No evidence of FDG-avid disease in the rest of the body was appreciated.
Thereafter, the decision was made to perform a CT-guided biopsy. The
procedure was carried out under sedation, and 5 fragments of soft tissue
measuring in aggregate 0.7 × 0.5 × 0.2 cm were submitted to the pathology
lab.
Histopathology revealed a small-blue-round cell tumor. The pathology result
was consistent with Ewing sarcoma.

Treatment:
Chemotherapy
The surgery involved the resection of part of the 5th rib, total resection of the
6th rib, right lower lobe wedge resection, and partial resection of the right
middle lobe. In addition, two other pulmonary nodules were detected in the
right middle lobe and were removed. Segmental lung resection had to be
performed on the stuck right lower lobe, with pleurectomy as an en bloc with
the whole specimen
This is the en bloc resected
specimen showing the
involved ribs completely
resected (on the left side) with
the residual Ewing sarcoma
tumorous mass, including the
thoracic muscles (on the right
side of the picture), resected
to secure free margins.
 MCQ Case 4
A postmenopausal married woman was admitted to the department of
gynecology at the age of 61 due to abnormal uterine bleeding. There was
not any specific past medical and familial history and the patient did not
take any specific medications. She mentioned that the bleeding was
presented as occasional spotting. The physical examinations including the
physical examination of the vagina, cervix, and uterus, were all normal. A
pipelle biopsy reported the presence of adenocarcinoma, and therefore,
the patient underwent total abdominal hysterectomy and bilateral
salpingo-oophorectomy (TAH-BSO), subsequently. The pathologic report
showed grade I adenocarcinoma that cancer cells had spread halfway or
more into the myometrium without any extension outside of the uterine
without extension outside the body of the uterus. The tumor was located
at the fundus of it (FIGO stage IB). The patient underwent observation
alone.
Six months after surgery, she was referred to the department due to
new-onset bone pain at her pelvic region. Physical examination showed
tenderness at the middle part of sacrum and the proximal parts of
femur.
A whole-body Tc-99m MDP bone scan (WBBS) and computed
tomography (CT) scanning of the abdomen/pelvis were requested
Anterior (A) and posterior (B) planes of
whole-body bone scan showing an
increased uptake at the greater trochanter
of the left femur (red cycle)

Because of the rarity of bone metastasis

in patients with endometrial
adenocarcinoma and solitary nature of
lesion, a CT-guided core needle biopsy
was requested. The pathologic
examinations confirmed the diagnosis of
bone metastasis from endometrial
carcinoma.
In endometrial cancer, mostly metastasis occurs to lymph nodes, liver,
and lungs. The common pathway of metastasis was through lymph-
vascular route or by direct invasion. Till now, only 2%–6% of
endometrial cancers has reported with metastasis to bone.
The bone metastases cause several skeletal complications in cancer
patients and affect the quality of life of the patient. Bone fractures,
cancer-induced bone pain, spinal cord compression, cancer cachexia,
and hypercalcemia were common skeletal complications associated
with bone metastases.
x

WaD4, WID5
 Skeletal Structure and Function

Week 3 Day 4

Degenerative and Metabolic disorders of Joints and Connective Tissues

Learning Objectives:

1) Define and discuss etiology and pathophysiology of degenerative and metabolic

disorders of joints and connective tissues, including gout, pseudogout, osteoarthritis,
rhabdomyolysis, Dupuytren contracture, knee effusion.
2) Review the steps involved in the evaluation of these degenerative and metabolic
disorders.
3) Discuss the basic principles applied for management of these degenerative and
metabolic disorders.
A 41-year-old man presents to the office with pain in his right big toe. The pain started
yesterday and has been progressively getting worse to the point that it is difficult to
walk. He describes his right big toe as being swollen, red, and warm to the touch. He
drinks 3 beers per night. He was diagnosed with diabetes 5 years ago and is currently
taking metformin. He was recently diagnosed with hypertension and was placed on a
hypertensive drug. He uses over-the-counter multivitamin supplements. Physical
examination is notable for an overweight gentleman in moderate pain, with an
erythematous, swollen, and tender right toe. He is afebrile.

1) What is the most likely diagnosis?

2) What diagnostic test should be used to confirm the diagnosis?
3) What is a joint fluid analysis most likely to show?
4) What predisposing factors does the patient have?
5) Which of the classes of drugs could have resulted in these symptoms?
6) What are the first-line drugs of choice for the acute treatment of patient's
condition?
 1) This patient most likely has gout, which is a metabolic disorder, type of arthritis that is caused by
inflammation triggered by monosodium urate crystals in a joint space.
The precipitation of monosodium urate crystals in a joint provokes a strong inflammatory response
that produces the five classic clinical features of acute inflammation: swelling, redness, pain,
warmth, and loss of function.
Patients typically present with erythematous, swollen, tender joints, most commonly at the base of
the big toe. They can also present with tophi (urate deposition in tissue, commonly in the helix of
ears), nephropathy, and kidney stones.
In the purine degradation pathway,
adenine and guanine are broken down
through separate reactions to xanthine.
Xanthine oxidase then converts xanthine to
uric acid for excretion in the urine.
Gout results when a derangement in this
pathway causes either overproduction or
underexcretion of uric acid, which in turn
leads to elevated uric acid levels.
Elevated uric acid levels alone are NOT
diagnostic of gout!
2) The most specific diagnostic test for acute gout is synovial fluid aspiration from the affected
joint.
3) In gouty arthritis, the fluid will be yellow and cloudy with a neutrophil count ranging from 2,000
to 100,000 cells/µL and a polymorphonuclear leukocyte (PML) value of 50% or more.
A negative Gram stain excludes septic arthritis.
The presence of intracellular or extracellular needle-shaped urate crystals that are negatively
birefringent under polarized light (yellow and blue) is diagnostic of gout.
Causes of overproduction of uric acid include diet and increased nucleic acid turnover states
(malignancy and post-chemotherapy).
Causes of underexcretion include alcohol, medications, dehydration, and chronic kidney disease.

Excessive alcohol intake results in the increased breakdown of ATP, resulting in the excessive
production of organic acids. These organic acids compete with urate for tubular secretion (urate
transporter involved in tubular secretion), resulting in hyperuricemia and a subsequent gout attack. The
same mechanism is observed in other conditions, such as lactic acidosis, diabetic ketoacidosis, and
salicylate toxicity.

5) Hyperuricemia is common in people treated with a loop or thiazide diuretic (usually at doses of >25
mg/day) and may contribute to new-onset gout or recurrence of established gout.
Diuretics reduce urate excretion by both direct and indirect mechanisms: by increasing urate reabsorption
by the proximal tubule, and by causing volume depletion which increases urate reabsorption by the
proximal tubule. Importantly, the effect is dose-dependent. If diuretic-induced gout occurs, it is usually
treated with a urate-lowering drug such as allopurinol, or using an alternative antihypertensive drug, such
as an angiotensin inhibitor or a dihydropyridine calcium channel blocker.
Other drugs causing hyperuricemia include aspirin, niacin, furosemide, and cyclosporine.
6) One of the first-line treatments of a gout flare is a nonsteroidal anti-inflammatory
drug (NSAID), such as indomethacin or naproxen, but glucocorticoids (either oral or
by intraarticular injection) are similar or superior in efficacy in most patients.
Low-dose colchicine is considered a second-line drug to treat an acute gout flare
because it has more adverse side effects and must be given within 36 hours of onset.

Colchicine is a selective inhibitor of microtubule assembly, which results in reduced

leukocyte mitosis and phagocytosis. This leads to a decrease in the activity of
inflammatory cells and helps relieve the inflammation in the gouty joint.

NSAIDs inhibit the cyclooxygenase enzymes, COX-1 and COX-2. Inhibition of these
enzymes downregulates the production of prostaglandins, which are important
mediators of inflammation. NSAIDs are also commonly used to treat fever by reduction
of prostaglandin E2 (PGE2) synthesis. Adverse effects of NSAIDs include
gastrointestinal problems (gastric ulcers and heartburn), kidney injury, and
cardiovascular events.
Allopurinol lowers serum urate levels, mostly by inhibiting xanthine oxidase. It helps
prevent recurrent gout flares and can treat tophaceous gout, but is not used to treat a gout
flare.
Allopurinol is a xanthine oxidase inhibitor (XOI) that irreversibly inhibits xanthine oxidase,
which normally converts hypoxanthine to xanthine and then to uric acid. Xanthine oxidase
converts allopurinol to alloxanthine (oxypurinol), which is an irreversible "suicide"
inhibitor of the enzyme. Thus, the pathway of the synthesis of uric acid is blocked,
decreasing serum uric acid levels.
Febuxostat is also an XOI but it has more side effects and a higher cost than allopurinol, so
it is only used as an alternative to allopurinol if that drug is not tolerated.
Probenecid enhances the elimination of uric acid but is not used as much as allopurinol
since it is less effective and is associated with multiple drug interactions.
A 62-year-old carpenter presents to your clinic complaining of worsening joint pain
in her hands. She states that the pain is present in all of her fingers, but is worse in
the right hand and gets better when she has a few days off from work. She denies
any paresthesias, fevers, or fatigue. Vital signs are normal. Physical exam reveals
hard, non-tender lesions overlying the proximal interphalangeal joints of the 2nd
and 3rd fingers of the right hand. All five digits of the right hand have a decreased
range of motion. An X-ray of her hands is shown.

1) What is the most likely pathogenesis

underlying the X-ray findings?
2) What cells are responsible for
synovial fluid production?
3) What are the management options for
this patient?
1) Chronic degradation of articular cartilage. The woman has osteoarthritis, which is a
common degenerative disease of the joints and destruction/thinning of the hyaline
cartilage that lines the articular surfaces. It most commonly affects the knees, lumbar
vertebra, and distal (DIP) and proximal interphalangeal (PIP) joints of the hands.
It is most often associated with wear-and-tear injuries that are related to repetitive
movements and aging, as well as with obesity and trauma.
Symptoms often include aching joint pain exacerbated by increased movement and
relieved with rest, as well as a limited range of motion.
Crepitus resulting from surface erosion and cartilage detachment is often present.
The nodules described in this woman’s history are Bouchard’s nodes (of the PIP joints,
and Heberden’s nodes appear on the DIP joints), which are only found in osteoarthritis
and not rheumatoid arthritis.
Diagnosis is usually clinical but can be confirmed with X-rays. The main radiological
findings are osteophytes, joint space narrowing, subchondral osteosclerosis, subchondral
cysts. Joint effusions may be present.
The pathogenesis of OA involves the entire joint: cartilage, subchondral bone, and soft tissues,
including the synovium. In OA, cartilage integrity is lost predominantly by biomechanical
stress; however, genetic influences may result in early chondrocyte injury and disordered
matrix repair.
Proliferating chondrocytes synthesize matrix proteoglycans, but the degradation rate exceeds
production in OA. Diminishment of proteoglycans permits more water to interact with the
collagen, causing swelling of the cartilage. Additionally, chondrocytes secrete matrix
metalloproteinases (MMPs), which break down the extracellular matrix type II collagen.
Chondrocytes and the adjacent synovium release soluble factors and pro-inflammatory
cytokines, including transforming growth factor-beta (TGF-β), which stimulates the
production of MMPs. Other important modulators are tumor necrosis factor-alpha (TNF-α),
prostaglandins (PGE2), and nitric oxide. Eventually, chondrocyte depletion and irreversible
matrix degradation occur in advanced OA. Additional changes to the surrounding structures
include meniscal degeneration, sclerosis of the underlying bone, osteophyte expansion at the
joint margin, weakness of the surrounding joint muscles, ligamentous injury, and synovitis.

Genetics contribute to the development of OA via mutations in the COL2A1 gene,

responsible for producing type II collagen, the main component of articular cartilage.
3) Non-pharmacological treatment includes ongoing education about OA management,
weight reduction in individuals who are overweight or obese, a tailored exercise
program, physical therapy, and walking aids.
Pharmacological treatment can be with oral NSAIDs, and if ineffective, then intra-
articular corticosteroid injections. Glucosamine sulfate and glucosidase supplementation
are no longer recommended for patients with osteoarthritis.
 Synovial fluid analysis
Non-inflammatory
Inflammatory arthritis Septic arthritis
arthritis
Cloudy, dense yellow-
Appearance Clear, transparent Cloudy, dense yellow
green
More than 50,000
WBC Less than 2,000 cells/µL 2,000–100,000 cells/µL
cells/µL
PML (%) Less than 25% 50% or more 70% or more
Positive except for
Culture Negative Negative gonococcal arthritis (only
25% are positive)
Positively birefringent crystals
Crystals Negative with pseudogout, negatively Negative
birefringent crystals with gout
Rheumatoid arthritis, gout,
Non-gonococcal and
Examples Osteoarthritis pseudogout, seronegative
gonococcal septic arthritis
arthritis
A 28-year-old man presents to the emergency department after being rescued from
his home. He had been working at home alone on some renovations when a wall
collapsed on him. His legs were trapped under the debris for about 30 hours before a
neighbor found him and called an ambulance. He is mildly confused and reports pain
in both legs. The physical examination is notable for dry mucous membranes and
tenderness to palpation throughout both legs with many superficial abrasions, but no
active hemorrhage. His full-body computed tomography scan shows fractures in both
tibias. He is admitted to the trauma service for observation. On hospital day 1, his
urine appears very dark. Urine output over the preceding 24 hours is 200 mL. The
laboratory studies show a creatinine of 2.7 mg/dL and serum creatine kinase (CK) of
29,700 IU/L.

1) What is the most likely pathogenesis of these laboratory findings?

2) What is the next step in the management of this patient?
This patient who sustained a trauma and prolonged crush injury to his legs now has dark urine,
oliguric acute kidney injury, and an elevated serum CK, all related to rhabdomyolysis.
The most frequent cause of rhabdomyolysis is muscle trauma or ischemia due to prolonged
downtime; other causes include medications (statins), infectious agents, drug abuse.

Patients typically present with diffuse generalized muscle pain, red or brown urine, hyperkalemia,
pigmented urinary casts, and hypocalcemia. Urinalysis will characteristically be positive for blood
without the presence of red blood cells.

Rhabdomyolysis is commonly associated with a crush injury.

Skeletal muscle cell destruction causes the release of potassium and myoglobin, an oxygen-carrying
protein stored within the skeletal muscle cells, into the circulation. Myoglobin is nephrotoxic,
causing acute kidney injury (AKI) with acute tubular necrosis (ATN) and presents with dark urine,
oliguria, and elevated serum creatinine.

Oliguria occurs when urine production is reduced dramatically, defined as a decrease in urine output
to less than 500 mL per day or less than 0.5 ml/kg/hour. In contrast, anuria is the absence of urine
production, defined as a urine output of fewer than 100 milliliters per day.
Rhabdomyolysis is diagnosed by checking serum CK, normally contained within the
skeletal muscle. Rhabdomyolysis presents with serum CK levels at least 5 times the
upper limit of normal.

2) First and foremost, these patients need aggressive fluid resuscitation to improve
kidney perfusion and ameliorate kidney injury.
 Skeletal Structure and Function

Week 3 Day 5

Musculoskeletal System
Congenital Disorders and Adverse Effects of Medications
Learning objectives:
1. Define and discuss Congenital Disorders and Adverse Effects of Medications on Musculoskeletal system
2. Review the steps involved in the evaluation Congenital Disorders and Adverse Effects of Medications on
Musculoskeletal system
3. Discuss the basic principles applied for management of Congenital Disorders and Adverse Effects of Medications
on Musculoskeletal system
A 1-year-old boy presents with his mother to the pediatrician for a routine checkup. On examination, the child is happy
and playful and meets normal cognitive development markers. However, the child’s arms and legs are not meeting
development goals, while his head and torso are. The mother states that the boy gets this from his father. Which of the
following mutations is most likely associated with this presentation?

A.FBN1 gene mutation

B.Underactivation of FGFR3
C.GAA repeat
D.Deletion of DMD
E.Overactivation of FGFR3
Correct answer E: Achondroplasia is a disease characterized by the constant activation of fibroblast growth factor
receptor 3 (FGFR3). This overactivation leads to the inhibition of chondrocyte growth, which is essential for
endochondral bone growth associated with limb development. Because of this, the axial skeleton and skull will grow to
be close to average size due to membranous ossification, while the limbs will be disproportionately short. Cognitive
function is intact. This mutation in FGFR3 can occur sporadically or can be inherited in an autosomal dominant fashion.
This patient is presenting with an autosomal dominant form from his father.
Option A: FBN1 gene mutations occur on chromosome 15 and are associated with the fibrillin gene. Fibrillin is an
essential part of elastin, leading to dysfunctional elastin. This results in the connective tissue disorder, Marfan
syndrome. Marfan syndrome is characterized by tall, thin body habitus with long extremities, fingers, and toes, as well
as hypermobility in the joints and cardiac complications. While Marfan syndrome also has autosomal dominant
inheritance, the clinical picture is the opposite of this patient, making it an unlikely diagnosis.
Option B: FGFR3 is associated with achondroplasia. However, the mutation is an over-activation of the receptor, which
leads to decreased chondrocyte growth, not under-activation. Under-activation of FGFR3 has not been studied in the
wild; however, experimentally it has been shown to increase long bone growth. This answer does not apply to our
patient and is therefore incorrect.
Option C: Friedreich ataxia is a neurodegenerative disorder characterized by the trinucleotide repeat GAA on the FXN
gene that encodes frataxin. Frataxin plays a role in iron sequestration, which prevents the overproduction of reactive
oxygen species (ROS). Accumulation of ROS leads to symptoms such as ataxia, muscle weakness, vision and hearing
loss, and slurred speech. Patients often present in adolescence and this disease has an autosomal recessive pattern of
inheritance. This patient does not fit this clinical picture, making this mutation an unlikely cause of his disease.
Option D: Duchenne muscular dystrophy is an X-linked genetic disorder caused by the absence of functional
dystrophin, a protein that is responsible for anchoring muscle fibers. This is due to a mutation in the dystrophin gene
(DMD), which is the largest gene in humans that codes for a protein. The disease is characterized by progressive muscle
weakness, calf pseudohypertrophy, and a waddling gait. Patients often present in early childhood; this is the most severe
muscular dystrophy. This patient is not presenting with any of these symptoms, making this an unlikely diagnosis.

Learning objective: Achondroplasia is the most common cause of dwarfism. It is due to a gain-of-function mutation in
the FGFR3 gene, which is inherited in an autosomal dominant pattern. The disease is characterized by small limbs and
an average-sized head and axial skeleton.
A 12-year-old boy develops muscle weakness, pain, vomiting, seizures, and severe headache. He also presents with
hemiparesis. A muscle biopsy shows "ragged red fibers." What is true about the mode of inheritance of the disease
described?

A.It is usually more severe in males.

B.It skips generations.
C.Mothers transmit it to 50% of their daughters and sons.
D.It is transmitted only through the mother.
E.It can be transmitted through both parents.
Correct answer D: Based on the symptoms of the above patient, he is most likely experiencing a type
·

of mitochondrial myopathy known as MELAS syndrome. MELAS stands for mitochondrial encephalopathy, lactic
acidosis, and stroke-like symptoms. Those affected may also present with epilepsy, myopathy, recurrent headaches that
resemble migraines, hearing impairment, cardiac disease, diabetes, vision impairment, and short stature.
MELAS syndrome follows a mitochondrial inheritance; therefore, it is only transmitted through the mother. All
of her offspring will be affected, and all of her daughters will transmit the condition to future generations, but the sons
will not. The mitochondria have their own DNA (i.e., mtDNA). The most commonly affected gene in MELAS
syndrome is MT-TL1 (occurring in more than 80% of patients). A mutation affects the mitochondrial tRNA function,
leading to a disruption of the global process of intramitochondrial protein synthesis. The decreased protein synthesis
may ultimately lead to the observed decrease in the respiratory chain, triggering excessive lactic acid production.
The workup for MELAS syndrome consists of:
•Serum lactate and serum pyruvate
•mtDNA mutation studies
•Brain imaging studies
•Muscle biopsy
Management of MELAS syndrome is symptomatic and not specific, although CoQ10 and L-arginine have shown some
efficacy.
(a) Modified Gomori trichrome stain
showing several ragged red fibers
(arrowhead). (b) Cytochrome c oxidase
stain showing lightly stained Type-1 fibers
and Type II fibers, darker fibers, and a few
fibers with abnormal collections of
mitochondria (arrowhead). Note the
cytochrome c oxidase negative fibers,
which are usually seen in mitochondrial
encephalopathy, lactic acidosis, and stroke-
like episodes (MELAS). (c) Succinate
dehydrogenase staining showing a few
ragged blue fibers and intense staining in
the mitochondria of the blood vessels
(arrow). (d) Electron microscopy showing
an abnormal collection of mitochondria
with paracrystalline inclusions (arrowhead),
osmiophilic inclusions (large arrowhead),
and mitochondrial vacuoles (small
arrowhead).
 Mode of inheritance Characteristics Examples
Autosomal dominant •Affected individuals in many Achondroplasia, familial
generations hypercholesterolemia,
•Male and females are equally Huntington disease, Marfan
affected syndrome
Autosomal recessive •Usually observed in only one Albinism, cystic fibrosis,
A.It is usually more severe in males. generation Kartagener syndrome,
•High risk in consanguineous phenylketonuria, sickle cell
B.It skips generations. families anemia
C.Mothers transmit it to 50% of their X-linked recessive •More severe in males (answer Fabry disease, Hemophilia A
A) and B, Lesch-Nyhan syndrome,
daughters and sons. •Sons of carrier mothers have a Wiskott-Aldrich syndrome,
50% chance of developing the Ornithine transcarbamylase
D.It is transmitted only through the disease deficiency
mother. •Skips generations
•Females must be homozygous
E.It can be transmitted through both to be affected

parents. X-linked dominant •Mothers transmit to daughters Hypophosphatemic rickets

and sons with a 50% probability
•Fathers transmit to all
daughters, but not to their sons
(answer C and E)

Mitochondrial inheritance •Transmitted only through the Mitochondrial myopathies, e.g.,

mother (answer D) MELAS
Option A: The X-linked recessive hereditary pattern is usually more severe in males.
Option B: All recessive inheritance patterns can skip generations. This includes autosomal recessive and X-linked
recessive.
Options C and E: In the X-linked dominant inheritance pattern, the mothers transmit to daughters and sons with a 50%
probability. Fathers transmit to all daughters, but not to their sons.

Learning objective: MELAS syndrome is a mitochondrial myopathy with a mitochondrial pattern of inheritance. The
mothers pass the mitochondria to each of their offspring. Their sons cannot transmit the disease, but their daughters will
transmit this disease to their future generations. The clinical hallmarks of MELAS include mitochondrial
encephalopathy (dementia), lactic acidosis, and stroke-like symptoms.
A 5-year-old boy is brought to the emergency department by his foster mother because of multiple injuries. She says
that he sustained these injuries while playing. Radiographic findings show multiple fractures in various stages of
healing. She notes that he has always bruised easily. His family history is unknown. His blood pressure is 118/78 mm
Hg, pulse is 76/min, and respirations are 15/min. Physical examination shows the findings in the image. What is the
most likely diagnosis in this patient?

A.Marfan syndrome
B.Wilson's disease
C.Osteogenesis imperfecta
D.Osteochondritis dissecans
E.Child abuse
Correct answer C: This patient's diagnosis is osteogenesis imperfecta (OI), or brittle bone disease. This disease is
caused by the defective synthesis of type 1 collagen. Since type 1 collagen is a major extracellular matrix component,
manifestations are seen in the bones, joints, and sclerae.
Too little bone formation results in brittle/fragile bones and recurrent fractures. Radiographs of the bones show multiple
injuries in different stages of healing. The choroidal veins are reflected through the thin sclera, giving the sclerae a
bluish appearance (see image below).

Clinical features of OI include:

•Multiple atypical fractures in various stages of healing
•Irregular bones along the cranial sutures (Wormian bones)
•Blue sclerae
•Deafness
•Increased laxity of ligaments and skin
Option A: Marfan syndrome is caused by a defect in fibrillin. Characteristic features are joint laxity, upward eye lens
displacement, mitral valve prolapse, aortic aneurysm, and arachnodactyly.
Option B: Wilson disease characteristically shows yellow Kayser-Fleischer rings around the iris, not blue sclera.
Patients with Wilson disease will have elevated levels of copper.
Option D: Osteochondritis dissecans is caused by aseptic necrosis of the ossification centers.
Option E: Retinal hemorrhages are seen in child abuse. Wounds in various stages of healing are another supportive
finding for the diagnosis of child abuse, but the blue sclera would not be seen.

Learning objective: Osteogenesis imperfecta is due to a genetic defect in type 1 collagen, resulting in brittle bones,
hearing loss, discolored teeth, and blue sclerae.