JCEM Case Reports, 2024, 2, luae176

https://doi.org/10.1210/jcemcr/luae176
Advance access publication 30 September 2024
Case Report

Vitamin D-dependent Rickets Type 1A Mimicking

Pseudohypoparathyroidism in Presence of Active
Tuberculosis
Sambit Das,1 Vishal Agarwal,1 Binod Prusty,1 Bijay Ketan Das,1 Arun Choudhury,1

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and Dayanidhi Meher1
1
Department of Endocrinology, Kalinga Institute of Medical Sciences, Bhubaneswar 751024, Odisha, India
Correspondence: Vishal Agarwal, MD, Department of Endocrinology and Metabolism, Kalinga Institute of Medical Sciences, Patia, Bhubaneswar 751024,
Odisha, India. Email: vishal.agarwal018@gmail.com.

Abstract
Vitamin D-dependent rickets type 1A is caused by pathogenic variants of CYP27B1 gene, which is inherited in autosomal recessive pattern. These
variants lead to defective 1α-hydroxylase enzymatic activity, leading to impaired renal formation of 1,25(OH)2 vitamin D. We report a case of a 16-year-
old Asian male patient, with short stature and progressive bone deformity, whose biochemical parameters revealed low levels of 1,25(OH)2 vitamin D,
low serum calcium levels, along with high phosphorus and raised levels of intact parathyroid hormone. These biochemical parameters suggested the
diagnosis of pseudohypoparathyroidism. The patient also had concurrent extrapulmonary tuberculosis during the time of presentation to our
endocrine unit. However, on molecular testing, it was revealed that the patient was harboring pathogenic variants of the CYP27B1 gene, in a
compound heterozygous manner, with a novel missense mutation in exon 6 of the CYP27B1 gene, c.1136G > C (p.Arg379Thr), suggesting the
diagnosis of vitamin D-dependent rickets type 1A. The cause of high phosphorus at the time of presentation, which led to a diagnostic dilemma
of pseudohypoparathyroidism, was later explained by presence of active extra pulmonary tuberculosis. This report describes a case of vitamin D-
dependent rickets type 1A, mimicking pseudohypoparathyroidism owing to presence of concurrent illness like extrapulmonary tuberculosis.
Key Words: vitamin D dependent rickets type 1A, pseudovitamin-D-deficiency rickets, CYP27B1, rickets, pseudohypoparathyroidism
Abbreviations: iPTH, intact PTH; Th, T-helper; VDDR 1A, vitamin D dependent rickets 1A.

Introduction features of hypocalcemic rickets, but the biochemical parame­

ters resembled that of pseudohypoparathyroidism with high se­
Rickets and osteomalacia are the prime disorders of bone and
rum phosphate levels because of the presence of concurrent
mineral metabolism. Prolonged deficiency of minerals like cal­
active extrapulmonary tuberculosis.
cium or phosphorus leads to defective mineralization of osteoid
[1]. If it occurs in adults, the condition is known as osteomal­
acia, whereas defective mineralization and development of epi­ Case Presentation
physeal growth plate occurring in a developing child is known We describe a case of a 16-year-old Asian male child, born out
as rickets [2]. Nutritional vitamin D deficiency constitutes the of a nonconsanguineous marriage, with normal weight and
most common etiological cause for rickets worldwide [3]. length at birth. At the age of 1 year, he had a history of delayed
Other rare causes include defective hydroxylation of vitamin motor development milestones and delayed dentition, for
D in hepatocytes and proximal renal tubules leading to defect which he was referred to a pediatric institution and was pre­
in vitamin D undergoing 25-α hydroxylation to 25-OH vitamin scribed medications in the form of oral vitamin D and calcium
D and 1-α hydroxylation to form active 1,25(OH)2 vitamin D supplements. At the age of 7 years, he developed waddling of
respectively. CYP2R1 gene located in chromosome 11p15.2 gait along with progressive bowing of legs and was referred to
encodes the 25-α hydroxylase enzyme, whereas the CYP27B1 an endocrine unit. Initial workup showed hypocalcemia,
gene located in chromosome 12q14.1 encodes the 1-α hydrox­ along with hypophosphatemia, with high 25(OH)-vitamin D
ylase enzyme [4]. Pathogenic variants of the CYP27B1 gene can levels, and elevated intact PTH (iPTH). Initial laboratory
lead to 1α-hydroxylase deficiency; the disorder is commonly data are shown in Table 1. A clinical diagnosis of vitamin
known as vitamin D-dependent rickets type 1A (VDDR 1A) D-dependent rickets was initially suspected, and the patient
or pseudo-vitamin D deficiency rickets type 1A [1]. The name was initiated on oral supplementation of active vitamin D (cal­
“vitamin D dependent rickets” is named so because of the in­ citriol), along with oral calcium tablets started at doses of up
herit inability of the body to maintain adequate levels of active to 0.25 μg/day and 1 g/day, respectively. From ages 7 to 15
vitamin D. It is inherited as autosomal recessive disorder. In this years, he was lost to follow-up by the pediatric endocrinology
report, we describe a case of VDDR 1A, which presented with unit and the patient had poor compliance to medications

Received: 29 May 2024. Editorial Decision: 13 September 2024. Corrected and Typeset: 30 September 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for add­
itional terms.
2 JCEM Case Reports, 2024, Vol. 2, No. 10

during that time. At the age of 16 years, he presented to our index of 25.7 kg/m2. The patient was febrile with an oral tem­
institution with features of progressive outward bending of perature of 100.1 °F measured at 4 PM. He had round facies, en­
both legs along with carpopedal spasms of 20 days’ duration amel hypoplasia, with long bone deformity in the form of genu
and fever of 15 days’ duration. At the time of presentation to valgum and sandal toe deformity (Fig. 1). Chvostek and
our institute, the initial laboratory data presented in Table 1 Trousseau signs were positive, indicative of hypocalcemia.
was not made available to the medical team. The patient was The patient also had an enlarged palpable left submandibular
not on any form of oral calcium or vitamin D supplementation. group of lymph nodes that were matted and nontender.
Physical examination revealed a height of 141.7 cm (Z-score of
−3.11), weight of 51.6 kg (Z-score of −0.45), and body mass
Diagnostic Assessment
Table 1. Initial laboratory data (at 7 years of age) of the patient with Bone radiographs revealed features of active rickets in the form
vitamin D hydroxylation-deficient rickets type 1A of metaphyseal widening with irregular margins in the epiphyseal
end of long bones (Fig. 2A). Laboratory data revealed an

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Parameter Result Reference range elevated iPTH of 19.4 pmol/L (183.5 pg/mL) (reference range,
1.6-6.9 pmol/L; 15-65 pg/mL), low serum calcium of 1.8 mmol/
Serum albumin 4 g/dL 3.9-4.9 g/dL
L (7.2 mg/dL) (reference range, 2.2-2.6 mmol/L; 8.6-10.3 mg/
(40 g/L) (39-49 g/L)
dL). Serum phosphate was high with value of 1.6 mmol/L
Serum phosphorus 3.5 mg/dL 3.7-5.6 mg/dL
(4.9 mg/dL) (reference range, 0.9-1.5 mmol/L; 2.7-4.7 mg/dL).
(1.1 mmol/L) (1.2-1.8 mmol/L)
25-(OH) D level was normal with value 116.8 nmol/L (46.8 ng/
Serum calcium 7 mg/dL 8.6-10.3 mg/dL
mL) (reference range, 50-162 nmol/L; 20-65 ng/mL), along with
(1.7 mmol/L) (2.1-2.5 mmol/L)
low 1,25-(OH)2D of 47 pmol/L (19.6 pg/mL) (reference range,
25-hydroxy vitamin D 70 ng/mL 20-65 ng/mL
47.8-190.3 pmol/L; 19.9-79.3 pg/mL). The Mantoux test was
(175 nmol/L) (50-162 nmol/L)
positive with induration of >10 mm noted at the end of 48 hours.
PTH (intact) 247 pg/mL 15-65 pg/mL
Fine-needle aspiration cytology of lymph nodes revealed
(26.2 pmol/L) (1.6-6.9 pmol/L)
features suggestive of tubercular lymphadenitis. Therefore, a clin­
Serum creatinine 0.7 mg/dL 0.5-1.1 mg/dL
ical diagnosis of pseudohypoparathyroidism along with active ex­
(61 µmol/L) (44-97 µmol/L)
trapulmonary tuberculosis was made. Whole-exome sequencing
Abnormal values are shown in bold font. Values in parentheses are International was sent to confirm the clinical diagnosis, which revealed com­
System of Units (SI). pound heterozygous pathogenic variants of the CYP27B1

Figure 1. Clinical picture of the patient showing round facies (A), enamel hypoplasia with chalky white appearance of teeth (B), and genu valgum along with
sandal toe deformity (C).
JCEM Case Reports, 2024, Vol. 2, No. 10 3

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Figure 2. X-rays of left hand wrist joint (anteroposterior view) before (A) and after (B) 6 months of treatment. (A) Metaphyseal fraying and splaying of the
distal radial and ulnar metaphyseal (arrow). (B) Resolution of the metaphyseal changes and improvement in deformity after 6 months of therapy (arrow).

gene. The first, c.1136G > C (p.Arg379Thr), was a missense left cervical lymphadenopathy. The biochemical profile re­
variant in exon 6 of the CYP27B1 gene. It was a novel pathogen­ vealed hypocalcemia, hyperphosphatemia, along with high
ic variant of the CYP27B1 gene. According to American College PTH levels and normal vitamin D levels, resembling pseudo­
of Medical Genetics and Genomics criteria, this variant has been hypoparathyroidism. However, on genetic analysis, it was
classified as a variant of uncertain significance, but the severity confirmed that the patient was compound heterozygous for
of the impact of this variant on the protein is high based on CYP27B1 gene mutations, clinching the diagnosis for
rare exome variant ensemble learner score. The second variant VDDR 1A. So, the biochemical parameter that led to the ini­
noted was c.1375C > T in exon 8 of the CYP27B1 gene, which tial diagnostic dilemma of pseudohypoparathyroidism was
results in the amino acid substitution p.Arg459Cys. This mis­ high serum phosphorus levels. The reason for high serum
sense variant has been classified as likely pathogenic according phosphorus levels in the patient was concurrent presence of
to American College of Medical Genetics and Genomics criteria. extrapulmonary tuberculosis. Tuberculosis has been shown
Therefore, a clinical diagnosis of VDDR 1A along with active to be associated with various biochemical changes, including
extrapulmonary tuberculosis was made. serum calcium and phosphorus levels [7]. Many studies have
shown that both pulmonary and extrapulmonary tuberculosis
can be associated with high serum phosphorus levels [8]. The
Treatment mechanism that generates high serum phosphorus has been at­
The patient was started on oral calcitriol and calcium supple­ tributed to lipoproteins released from cell membranes via tis­
mentation of 1.25 µg/day and 1.5 g/day, respectively, in 3 div­ sue destruction occurring in tuberculosis, that may alter the
ided doses. Antitubercular therapy was initiated in view of phosphorus homeostasis; however, the exact mechanism still
active extrapulmonary tuberculosis. remains elusive, providing scope for further research and clin­
ical studies [9]. These biochemical derangements usually re­
solve after the treatment of active tuberculosis, which also
Outcome and Follow-up occurred in the present case. This case report highlights the im­
At follow up at 3 months and 6 months after initiation of ther­ portance of interpreting biochemical parameters in clinical
apy, the patient’s serum calcium and phosphorus levels re­ practice, in context with patient’s comorbid conditions, which
mained in the normal range along with normalization of may sometimes influence the serum concentration of these
iPTH level, as shown in Table 2. Rachitic changes also im­ biochemical parameters. It also highlights the relationship of
proved at the end of 6 months of therapy, as shown in Fig. 2B. vitamin D deficiency and tuberculosis. Studies have shown
that vitamin D influences both innate and adaptive immunity.
It enhances innate immunity by increasing transactivation of
Discussion antimicrobial peptides and enhancing autophagy and gener­
Pseudohypoparathyroidism is a clinical entity arising out from ation of reactive oxygen species in macrophages. It is also re­
peripheral resistance to PTH [5]. Biochemically, it is charac­ ported to play a role in differentiation of naïve T cells to
terized by hypocalcemia, hyperphosphatemia, normal vitamin regulatory T cells, enhance T-helper (Th)2 cell responses,
D levels along with high PTH levels. Some patients with pseu­ whereas in vitro studies have shown that it suppresses Th1
dohypoparathyroidism can present with rickets, although and Th17 cell responses, indicating its possible role in adap­
such presentation is very rare in the reported literature [6]. tive immunity [10].
Such deformities can occur because variable resistance of During the months following the initiation of treatment
PTH on the skeletal system. At the time of initial presentation, with calcitriol and calcium supplementation along with anti­
the current case had features of hypocalcemic rickets in the tubercular therapy, the patient’s biochemical parameters
form of bony deformities and growth retardation. The patient gradually improved with resolution and hypocalcemia and
also had recent history of fever for the past 15 days along with normalization of serum phosphorus and PTH levels.
4 JCEM Case Reports, 2024, Vol. 2, No. 10

Table 2. Temporal trends in biochemical investigations of the patient at 16 years of age

Parameter Day 1 of admission Day 3 of admission 3 months 6 months Normal value

on therapy on therapy

Hemoglobin 11.8 g/dL 12.6 g/dL 12.4 g/dL 13-15 g/dL

(118 g/L) (126 g/L) (124 g/L) (130-150 g/L)
WBC 8100/µL 8000/µL 4000-10000/µL
(8.1 × 109/L) (8 × 109/L) (4 × 109-10 × 109/L)
Serum albumin 4 g/dL 4.2 g/dL 4.6 g/dL 3.9-4.9 g/dL
(40 g/L) (42 g/L) (46 g/L) (39-49 g/L)
Serum phosphorus 4.9 mg/dL 5 mg/dL 3.9 mg/dL 4.6 mg/dL 2.7-4.7 mg/dL
(1.6 mmol/L) (1.6 mmol/L) (1.25 mmol/L) (1.5 mmol/L) (0.9-1.5 mmol/L)
Serum calcium 7.2 mg/dL 7.9 mg/dL 8.7 mg/dL 9.1 mg/dL 8.6-10.3 mg/dL

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(1.8 mmol/L) (1.9 mmol/L) (2.2 mmol/L) (2.3 mmol/L) (2.2-2.6 mmol/L)
Serum magnesium 2.2 mg/dL 2.0 mg/dL 2.2 mg/dL 1.6-2.6 mg/dL
(0.90 mmol/L) (0.8 mmol/L) (0.90 mmol/L) (0.6-1 mmol/L)
25-hydroxy vitamin D 46.8 ng/mL 44.7 ng/mL 44.4 ng/mL 20-65 ng/mL
(117 nmol/L) (111.7 nmol/L) (111 nmol/L) (50-162 nmol/L)
1,25-dihydroxy vitamin D 19.6 pg/mL 19.9-79.3 pg/mL
(47 pmol/L) (47.8-190.3 pmol/L)
PTH (intact) 183.5 pg/mL 111.1 pg/mL 47.5 pg/mL 15-65 pg/mL
(19.4 pmol/L) (11.7 pmol/L) (5 pmol/L) 1.6-6.9 pmol/L
Serum creatinine 0.5 mg/dL 0.5 mg/dL 0.5 mg/dL 0.5-1.1 mg/dL
(44 µmol/L) (44 µmol/L) (44 µmol/L) (44-97 µmol/L)

Abnormal values are shown in bold font. Values in parentheses are International System of Units (SI).
Abbreviation: WBC, white blood cell.

The VDDR 1A genotype in our patient was of a compound het­ diagnosis and management of the patient and manuscript sub­
erozygous type. There are few cases of vitamin D deficiency rickets mission. S.D. and V.A. were involved in writing the manu­
misdiagnosed as pseudohypoparathyroidism [11]. However, to script. D.M. and A.C. reviewed the literature for the
our knowledge, this is the first reported case of an inherited vita­ manuscript and provided clinical photographs for the manu­
min D metabolism that mimicked pseudohypoparathyroidism, script. B.P. and B.K.D. were involved in preparing radiologic­
in the presence of concurrent illness like tuberculosis. al images for the manuscript. All authors reviewed and
approved the final draft.
Learning Points
Funding
• VDDR 1A results from biallelic pathogenic variants in the
CYP27B1 gene, encoding the enzyme 1α-hydroxylase. No public or commercial funding.
• Biochemically, it is characterized by hypocalcemia, hypo­
phosphatemia, and secondary hyperparathyroidism, to­ Disclosures
gether with low 1,25-(OH)2 vitamin D and normal
None declared.
25-(OH) vitamin D levels.
• Both pulmonary and extrapulmonary tuberculosis can in­
crease serum phosphorus concentrations. Therefore, se­ Informed Patient Consent for Publication
rum phosphorus reports must be carefully interpreted in Signed informed consent obtained directly from the patient’s
presence of such a comorbid condition. relatives or guardians.
• Vitamin D deficiency may be associated with increased
risk of tuberculosis because it influences both innate and
adaptive immune systems. Data Availability Statement
Original data generated and analyzed during this study are in­
cluded in this published article.

Acknowledgments
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