June 1981
888 TheJournalofPEDIATRICS
The etiology of enamel hypoplasia: A unifying
concept
In a study o f children with chronic disorders o f calcium and phosphate homeostasis, enamel hypoplasia
was found in hereditary vitamin D dependency rickets and in hypoparathyroidism, conditions
characterized by hypocalcemia, and was not found in X-linked hypophosphatemic rickets, a condition in
which th e plasma calcium concentration is normal. The occurrence of enamel hypoplasia bore no relation
to the plasma phosphate concentration. Enamel hypoplasia has also been reported in other pediatric
disorders in which hypocalcemia is a major sign (for example, vitamin D deficiency, prematurity, and
neonatal tetany). The existence of enamel hypoplasia in a hypoparathyroid or rachitic patient, when
correlated with the chronology of enamel mineralization, helps to establish the time of onset of
hypocaleemia. The observations led us to the hypothesis that a low serum calcium concentration during
enamel formation is a specific determinant of enamel hypoplasia. This hypothesis may be relevant to the
etiology of linear enamel hypoplasia, an endemic lesion of primary teeth in children of many Third World
countries that predisposes the teeth to dental caries. The hypothesis may therefore be relevant also in
explaining the prevalence of caries in the primary teeth of children in many underdeveloped countries.
Gordon Nikiforuk, M.Sc., D.D.S., F.R.C.D.(C),* and
D o n a l d Fraser, M.D., Ph.D., T o r o n t o , Ont., C a n a d a
ENAMEL HYPOPLASIA is the most common abnormal- vitamin D-deficiency rickets, ~, 4 hereditary vitamin D-de-
ity of development and mineralization of human teeth. pendency rickets, ~hypoparathyroidism,'~neonatal tetany, 7
The lesion is manifested as a quantitative defect of enamel and a wide spectrum of perinatal disorders, a, " A specific
tissue resulting from an injury to the formative cells, the form of generalized enamel hypoplasia of primary teeth
ameloblasts. Clinically, the defect is seen as circumferen- called tinear enamel hypoplasia is especially common in
tial or bandlike irregularities in the enamel, or as discrete children in underdeveloped countries TM and on some
pitting. The lesions usually acquire yellow or brown North American Indian reservations" (Fig. 2).
discoloration from deposition of extrinsic pigments
(Fig. 1). Abbreviations used
Some years ago surveys showed that 3 to 15% of young VDDR: vitamin D-dependency rickets
adults had enamel hypoplasia in the permanent teeth, 1 XLH: X-linked hypophosphatemia
and, Pedersen 2 reported that 14% of 2- to 4-year-old HP/PHP: hypoparat hyroid/pseudohypoparathyroid
Ca: calcium
children had mild enamel hypoplasia in the primary teeth.
Pi: inorganic phosphate
The incidence of the lesion is considerably higher in Alk P'tase: alkaline phosphatase
From the Faculties of Dentistry and Medicine, It is evident that environmental factors play an etiologic
University o f Toronto, and the Research Institute, The
role in most cases of enamel hypoplasia (a rare hereditary
Hospital for Sick Children.
form exists). However, the metabolic determinant of the
Funded in part by a grant (MA 7166) from the
Medical Research Council, Ottawa, Canada.
enamel lesions has not been clearly elucidated. In the
*Reprint address: Faculty of Dentistry, Universityof Toronto, course of a combined medical-dental study extending
124 Edward St., Toronto, Ontario M5G 1G6, Canada. over many years, we observed that children with impaired
Vol. 98, No. 6, pp. 888-893 0022-3476/81/060888+06500.60/0 9 1981 The C. V. Mosby Co.
Vohtme 98 Etiology of enamel hypoplasia 889
Number 6
Fig. 1. Typical enamel hypoplasia in the permanent dentition of a child with hereditary vitamin D-dependency rickets.
Hypoplasia is severe and circumferential and is present as two narrow hypoplastic bands (see arrows) and some pitted
areas. The incisal hypoplastic area denotes injury to the ameloblast during the latter part of the first year of life; the
gingival hypoplastic area denotes injury during the second year of life. The intervening normal tissue was formed during
a period of effective treatment and normal plasma chemistry, after which treatment lapsed and hypocalcemia
recurred.
calcium and phosphate homeostasis had a high preva-
lence of enamel hypoplasia. W h e n these patients were
classified according to m o d e r n diagnostic criteria into
"calcipenic" and "phosphopenic" groups, '~. 12 a consistent
pattern of distribution of enamel hypoplasia emerged. O n
the basis of our studies, we have formulated the unifying
hypothesis that enamel hypoplasia is caused specifically
by hypocalcemia. ~
CLINICAL MODEL AND METHODS
The children in our long-term study represented three
categories of disorders of calcium and phosphate homeo-
stasis: hereditary vitamin D - d e p e n d e n c y rickets, X-linked
hypophosphatemic rickets, and the hypoparathyroid/
pseudohypoparathyroid group of conditions. Study of Fig. 2. Linear enamel hypoplasia in the primary teeth of a child
from Guatemala. Note the predilection of the lesions to the
these patients permitted us to test whether hypocalcemia
neonatal area of the maxillary teeth and the dental caries
or hypophosphatemia or both were linked specifically superimposed on the hypoplastic lesions. (Courtesy Prof. George
with the dental lesions. The salient features of these Beaton, University of Toronto.)
conditions (summarized below) are described in detail
elsewhere?a, 15
Hereditary vitamin D-dependency rickets is an autoso- vitamin. Synthetic 1,25-(OH)~D~, administered in small
mal recessive condition characterized by hypocalcemia, doses, is an effective therapy.*
elevated plasma parathyroid hormone concentration, sec- X-linked hypophosphatemia is a vitamin D refractory
ondary hypophosphatemia, and severe rickets despite condition in which the plasma calcium concentration is
normal vitamin D intake. These abnormalities can be normal but plasma inorganic phosphate is low; chronic
completely healed by high-dosage vitamin D therapy. The
condition results from impaired synthesis of 1,25-dihy- *Vitamin D-dependency rickets, Type II, in which end-organs are
droxy-vitamin D, the most active metabolite of the refractory to 1,25-(OH)2D~,'6 is not represented in our study.
890 Nikiforuk and Fraser The Journal of Pediatrics
June 1981
Table. Biochemical characteristics before treatment and age of first medical signs of disorders
of calcium and phosphate homeostasis in children with vitamin D-dependency rickets
(VDDR), X-linked hypophosphatemia (XLH), hypoparathyroidism (HP), and
pseudohypoparathyroidism (PHP)
Plasma concentrations (mean +_SD)
Clinical condition
(numbers of patients Ca ] Pi I Alk P'tase Age offirst signs
shown in brackets) (mg/ dl) (mg/dl) (King,Armstrong Units) (range)
VDDR (10) 7.64 • 1.18 3.48 _+ 0.88 111.3 • 44.8 1 to 12 mo
XLH (25) 10.03 -+ 0.59 2.85 _+ 0.49 35.8 -+ 7.6 12 to 18 mo
HP/PHP (21)
Permanent HP (11) 5.55 • 1.24 9.20 • 1.46 17.1 -+ 7.8 0 to 48 mo
Transient HP (6) 6.16 _+ 1.17 9.31 • 1.15 32.6 +- 15.7 0 to 1.5 mo
PHP (4) 5.45 • 1.40 7.14 • 1.80 31.5 • 4.1 5 to 11 yr
Normal values~s
95th percentile 10.9 5.4 40.0
5th percentile 9.6 3.9 19.1
Ca = Calcium;Pi = inorganicphosphate; Alk P'tase = alkalinephosphatase.
rickets of varying degree is usual. There is an intrinsic for normal age-related reference values; the plasma Ca
defect in reabsorption of phosphate by the renal concentrations of children with XLH were within the
tubules. normal range. The plasma Pi values of patients with
The hypoparathyroid/pseudohypoparathyroid group VDDR and XLH were below the fifth percentile for
comprises conditions characterized by hypocalcemia and normal children, whereas the plasma Pi values of children
hyperphosphatemia; rachitic bone lesions are not present. with HP/PHP were above the ninety-fifth percentile for
The biochemical disturbances are caused either by dimin- the normal range.
ished or absent secretion of PTH (HP) or by impaired Dental examination revealed that severe circumferen-
response of the target tissues to the hormone (PHP). In tial enamel hypoplasia, as exemplified in Fig. 1, was
both situations, the resultant biochemical features are present in 25 of the 56 children. When the dental lesions
hypocalcemia and hyperphosphatemia. Our HP/PHP were correlated with the clinical diagnoses, a clear pattern
group includes (1) permanent hypoparathyroidism, (2) of distribution emerged (Fig. 3). All of the ten children
transient neonatal hypoparathyroidism, and (3) pseudo- with VDDR had enamel hypoplasia in the permanent
hypoparathyroidism. dentition; one child had hypoplasia in both dentitions.
The acquisition of patients and dental tissues extended None of the 25 patients with XLH had enamel hypoplasia
over a 25-year period and comprised a total of 56 in either dentition. Fourteen of the 17 children with
children; ten had VDDR, 25 had XLH, and 21 were in the permanent or transient neonatal hypoparathyroidism had
HP/PHP group. The type of rickets or hypoparathyroid- various degrees of enamel hypoplasia in the permanent
ism was established in each patient by appropriate clini- and/or primary teeth; only one of the four children with
cal, biochemical, and radiographic examinations. In most pseudohypoparathyroidism had enamel hypoplasia.
instances, treatment with high doses o f vitamin D or Thus, enamel hypoplasia occurred only in children who
vitamin D analogue had already been instituted when the had hypocalcemia. There was no correlation between
dental studies were conducted. Oral phosphate supple- enamel hypoplasia and plasma phosphate concentra-
mentation had been given in some patients with XLH. tion.
The prevalence of enamel hypoplasia was evaluated in all Other dental findings, not discussed in this paper, such
patients by clinical, radiographic, and histologic examina- as interglobular dentin, large pulp chambers and pulp
tion of the primary or permanent dentition. horns, loss of lamina dura, and premature loss of primary
teeth were present in patients with VDDR and XLH, but
RESULTS not in children in the HP/PHP group. 1~
The mean plasma concentrations of calcium, inorganic
phosphate, and alkaline phosphatase in patients with DISCUSSION
VDDR, XLH, and HP/PHP before treatment are shown Development o f enamel. A knowledge of the normal
in the Table. Plasma Ca values of the children with development of enamel is required to understand our
VDDR and HP/PHP were less than the fifth percentile hypothesis of the etiology of enamel hypoplasia. The
Volume 98 Etiology of enamel hypoplasia 89 1
Number 6
10
-'t-
i.u A PRIMARY
TEETH
"-r"
I,-
,,.,i
INCISORS - CUSPID MOLARS
< 9- ~ ~ NEONATAL
z
i,u
"I-
m
~
B PERMANENTTEETH
z
U
M.I 6yr.
a b c 2yr.
VDDR XLH HP/PHP ~ NEONATAL
~
INCISORS CUSPID BICUSPIDS MOLARS
Fig. 3. Prevalence of enamel hypoplasia (EH) in children with __ NEONATAL
vitamin D-dependency rickets (VDDR), X-linked hypophospha- 2yr.
temia (XLH) and the hypoparathyroid/pseudohypoparathyroid 6yr.
(HP/PHP) group, a, Permanent hypoparathyroidism; b, transient
neonatal hypoparathyroidism; and c, pseudohypoparathyroid-
ism. Figures above the columns refer to total numbers of patients
examined. The 95% confidence range for prevalence of enamel
hypoplasia in VDDR is 7.3 to 100%, for XLH is 0 to 12.5%, for Fig. 4. Chronology of the development of, A, the primary and,
HP/PHP (all types) is 50 to 87%, as determined by binomial B, the permanent human dentition. The horizontal Iines in the
distribution analysis. The prevalence of hypoplasia in VDDR illustration indicate the extent of development of enamel at the
and HP/PHP is significantly different from that in the general ages noted. (Redrawn from Massler M, Schour I, and Poncher
population. HG: Am J Dis Child 62:33, 1941.)
ameloblasts within the enamel organ are responsible for occurred relatively soon after birth in patients with
synthesis of matrix. In its early stage, enamel matrix VDDR and in transient and permanent hypoparathyroid-
contains about 20% protein and 5 to 10% calcium salts, ism, as compared to the later age of onset of signs of
and there is a high water content. In the maturation hypocalcemia in pseudohypoparathyroidism (Table). We
process, water and protein are displaced by a calcium- believe that this explains the lower prevalence Of enamel
phosphate-carbonate component with characteristics of hypoplasia in pseudohypoparathyroidism. In three of the
hydroxyapatiteY Mature enamel has an inorganic com- four pseudohypoparathyroid children, symptoms of
ponent of about 96% and an organic component of about hypocalcemia did not occur until 5 years of age, after the
1%; the small remaining component is water. Mature crowns of the permanent teeth had developed.
enamel is acellular and avascular. Thus defects resulting From these findings we hypothesize that hypocalcemia
from severe metabolic or physical trauma can occur only was the cause of enamel hypoplasia. The hypothesis is
during enamel formation. The chronology of the develop- strengthened by other reports of enamel hypoplasia in
ment of enamel is shown in Fig. 4./8 children with hypoparathyroidismr Furthermore, the
A unified concept of the etiology of enamel hypoplasia. association of enamel hypoplasia with many disorders of
The consistent pattern of distribution of severe enamel the perinatal period and infancy, such as neonatal teta-
hypoplasia within three distinct systemic conditions with ny,7,,9 premature birth, ~'' gastroenteritis, ~, cerebral pal-
different underlying etiologies and biochemical features s y y mental retardation, -~3 and in infants of diabetic
suggests a unifying hypothesis regarding the molecular mothers, ~4 is consistent with our hypothesis, because
determinant of enamel hypoplasia. The biochemical fac- marked or prolonged neonatal hypocalcemia is a frequent
tor common to all patients with enamel hypoplasia was feature in many of these conditions.2'~-~'
hypocalcemia. The occurrence of enamel hypoplasia was On the basis of our hypothesis, the existence of enamel
not related consistently to the level of plasma Pi. From hypoplasia in a patient may be taken as presumptive
our medical observations, the onset of hypocalcemia evidence that hypocalcemia was present at the time the
892 Nikiforuk and Fraser The Journal of Pediatrics
June 1981
defective zones were developing. It follows that the 2. Pedersen PO: Taendernes tilstand hos 2-6 ~rige born,
distribution of hypoplastic lesions in enamel of patients Tandlaegebladet 46:485, 1944.
3. Eliot MM, Souther SP, Anderson BG, and Arnim SS: A
with hypoparathyroidism or rickets, when correlated with
study of the teeth of a group of school children previously
the chronology of enamel formation, helps to establish the examined for rickets, Am J Dis Child 48:713, 1934.
time of onset of hypocalcemia. This estimate often ante- 4. Grahndn H, and Selander P: The effect of rickets and
dates the onset of more traditional signs of hypocalcem- spasmophilia on the permanent dentition. 1. The effect on
ia-paresthesia, tetany, c o n v u l s i o n s , s o m e t i m e s by several the teeth, Odontol Revy 5:7, 1954.
5. Scriver CR: Rickets and the pathogenesis of impaired
years.
tubular transport of phosphate and other solutes, Am J Med
Because of the severity and extent of the hypoplastic 57:43, 1974,
lesions in our patients, it is impossible to estimate the 6. Pisanty S, and Garfunkel A: Familial hypoparathyroidism
threshold plasma concentration of calcium required to with candidiasis and mental retardation, Oral Surg 44:374,
cause the dental lesions. In another survey of children 1977.
7. Purvis RJ, MacKay GS, Cockburn F, Barrie WJM, Wilkin-
who had had neonatal hypocalcemia, those infants whose
son EM, Belton NR, and Forfar JO: Enamel hypoplasia of
plasma calcium values had averaged 6.72 + 0.81 m g / d l the teeth associated with neonatal tetany: a manifestation of
over a period of a few days had little or no enamel maternal vitamin D deficiency, Lancet 2:811, 1973.
hypoplasia, whereas infants whose plasma calcium con- 8_ Grahnrn H, and Larsson PG: Enamel defects in the
centrations had averaged 6.06 __+ 0.81 m g / d l had pro- deciduous dentition of prematurely born children, Odont
Revy 9:193, 1958.
nounced enamel hypoplasia. ~
9. Miller J, and Forrester RM: Neonatal enamel hypoplasia
Possible implications of our hypothesis in respect to the associated with haemolytic disease and with prematurity, Br
etiology of linear enamel hypoplasia and susceptibility to Dent J 106:93, 1959.
dental caries. Our hypothesis that hypocalcemia is an 10. Sweeney EA, Cabrera J, Urrutia J, and Mata L: Factors
essential determinant of enamel hypoplasia may have associated with linear hypoplasia of human deciduous
incisors, J Dent Res 48:1275, 1969.
relevance in explaining the occurrence of endemic linear
11. Infante PF: Enamel hypoplasia in Apache Indian children,
hypoplasia in children from economically underdevel- Ecol Food Nutr 3:155, 1974.
oped countries. In a study in rural Guatemala, where 12. Fraser D, and Scriver CR: Disorders associated with here-
linear enamel hypoplasia is endemic (in the rural areas), ditary or acquired abnormalities in vitamin D function:
diarrhea was reported in 79% of infants during the first six hereditary disorders associated with vitamin D resistance or
defective phosphate metabolism, in DeGroot LJ, Cahill GF,
months of life and was even more prevalent in children Odell WD, et al, editors, Endocrinology, vol 2, New York,
during the second six months? ~ Linear enamel hypoplasia 1979, Grune & Stratton, Inc., pp 797-807.
has been reported in association with acute diarrheal 13. Nikiforuk G, and Fraser D: Etiology of enamel hypoplasia
disease in preschool Apache children. 11 We hypothesize and interglobular dentin: the roles hypocalcemia and hypo-
that chronic diarrhea causes malnutrition, which is phosphatemia, Metab Bone Dis Rel Res 2:17, 1979.
t4. Fraser D, and Scriver CR: Familial forms of vitamin
reflected in hypocalcemia, which in turn results in linear
D-resistant rickets revisited. X-linked hypophosphatemia
enamel hypoplasia. Linear enamel hypoplasia is a predis- and autosomal recessive vitamin D dependency, Am J Clin
posing factor for dental caries. Epidemiologic and bio- Nutr 29:1315, 1976.
chemical studies of populations in underdeveloped coun- 15. Fraser D, Kind HP, and Kooh SW: Disturbances of
tries are required to corroborate the link We hypothesize parathyroid hormone and calcitonin, in Arneil GC, and
Forfar JO, editors: Textbook of paediatrics, ed 2, Edin-
between hypocalcemia, linear enamel hypoplasia, and burgh, 1978, Churchill Livingstone, pp 1001-1014.
dental caries. 16. Brooks MH, Bell NH, Love L, et al: Vitamin-D-dependent
rickets, Type II. Resistance of target organs to 1,25-
We thank Dr. J. Main, Professor of Oral Pathology, University dihydroxyvitamin D, N Engl J Med 298:996, 1978.
17. Burgess RC, And MacLaren CM: Proteins in developing
of Toronto, for assistance in hard tissue sectioning and interpre-
bovine enamel, in Stack MV, and Fearnhead RW, editors:
tation; Dr. S. W. Kooh, Department of Paediatrics, University of
Tooth enamel, Bristol, 1965, Wright & Sons, pp 74-82.
Toronto, and the Research Institute, The Hospital for Sick 18. Mussier M, Schour I, Poncher HG: Developmental pattern
Children, for his interest and assistance in the study; and Drs. B. of the child as reflected in the calcification pattern of the
Ross and A, Dungy and the interns of the Dental Department of teeth, Am J Dis Child 62:33, 1941.
The Hospital for Sick Children for expediting arrangements that 19. Stimmler L, Snodgrass GJAI, and Jaffe E: Dental defects
permitted this long-range study. associated with neonatal symptomatic hypocalcaemia, Arch
Dis Child 48:217, 1973.
20_ Via WF Jr, and Churchill JA: Relationship of enamel
REFERENCES hypoplasia to abnormal events of gestation and birth, J Am
1. Pindborg J J: Pathology of the dental hard tissues, Philadel- Dent Assoc 59:702, 1959.
phia, 1970, WB Saunders Company, pp 88-89. 21. Smith DMH, and Miller J: Gastro-enteritis, coeliac disease
Volume 98 Etiology of enamel hypoplasia 8 93
Number 6
and enamel hypoplasia, Br Dent J 147:91, 1979. 25. Tsang RC, Light IJ, Sutherland JM, and Kleinman LI:
22. Herman SC, and McDonald RE: Enamel hypoplasia in Possible pathogenetic factors in neonatal hypocalcemia of
cerebral palsied children, J Dent Child 30:46, 1963. prematurity, J PEDIATg 82i423, 1973.
23. McMillian RS, and Kashgarian M: The relation of human 26. Craig WS: Clinical signs of neonatal tetany: with especial
abnormalities of structure and function to abnormalities of reference to their occurrence in newborn babies of diabetic
the dentition. I. Relation of hypoplasia of enamel to mothers, Pediatrics 22:297, 1958.
cerebral and ocular disorders, and lIl. Relation of enamel 27. Tsang RC, Chert I-W, Friedman MA, Gigger M, Steichen J,
hypoplasia to epilepsy and to diagnoses associated with the Kottter H, Fenton L, Brown D, Pramanik A, Keenan W,
Rh factor, J Am Dent Assoc 63:38 and 497, 1961. Strub R, and Joyce T: Parathyroid function in infants of
24. Nor6n J, Grahn6n H, and Magnusson BO: Maternal dia- diabetic mothers, J PEDIATg 86:399, 1975.
betes and changes in the hard tissues of primary teeth, llI. A 28. Cherian AG, and Hill JG: Percentile estimates of reference
histologic and microradiographic study, Acta Odontol values for fourteen chemical constituents in sera of children
Scand 36:127, 1978. and adolescents, Am J Clin Pathol 69"24, 1978.
