TABLE I
REPORTED CAUSE.S OF ENAMEL HYPOPLASIA (-7)
1. Nutritional defects a. Rickets
b. Scurvy
i. Endocrine defects
a. Hypothyroidism
b. Abnormal calcium-phosphorus metabolism e.g.
hypoparathyroidism
3. Hereditary disease
a. Morquio’s syndrome
b. Amelogenesis imperfecta
4. Toxic
a. Keruicturus (from Rh+ incompatibility, ABO,
etc.)
b. Drugs (tetracycline)
5. Infectious disease
a. “Measles” b. Syphilis 6. Prematurity
7. Generalized metabolic defects (“nonspecific, severe
metabolic upset”)
S EASILY AS 1743 systemic disease was
reported to cause enamel defects.’
These defects, usually manifest as enamel
hypoplasia, have been associated with many
diseases. As collected from the literature,27
tile reported causes of enamel hypoplasia
may be divided into several broad
categor-ies (Table I). Among these no single
etio-logic factor is apparent. In only a few
in-stances, such as syphilis, has the
abnormal-ity
been reported in permanent teeth.Recently, we recognized hypoplastic
enamel in permanent teeth of nephrotic
children. The absence of previous reports
of the association of the nephrotic syndrome
\Vitll dental defects prompted our interest.
REVIEW OF TOOTH DEVELOPMENT PERTINENT TO THIS STUDY
The enamel organ produces both dentin
and enamel, but only the latter can be easily
evaluated. When disturbed, the enamel
organ usually responds by production of
hypoplastic enamel. The resultant defective
teeth, in contrast to bone, provide a
perma-nent record of past disturbances, unique
in that enamel once formed cannot be
im-proved by later events.
Hypoplastic enamel is best understood
with reference to normal dental
develop-ment. Tile development of teeth follows an
orderly sequence. For each tooth, enamel
formation proceeds from the occlusal edge
toward the root. Tile enamel is laid down
in successively overlapping layers, as
illus-(Submitted February ; accepted for publicationApril 24, 1963.)
Assisted in part l)y grants from the Michigan Chapter of National Kidney Disease Foundation and
Na-tional Institute of Health (A-3796) and in part by Traineeship (2A-5278 C2) National Institute of Health
Grant.
Presented to the Midwest Society for Pediatric Research, Cincinnati, Ohio, October 25-28, 1962.
ADDRESS: (W.J.O.) University of Michigan hospital, 1405 E. Ann Street, Ann Arbor, Michigan.
PEDIATRICS, September 1963
399
HYPOPLASTIC
ENAMEL
ASSOCIATED
WITH
THE
NEPHROTIC
SYNDROME
William J. Oliver, M.D., Clyde L. Owings, M.D., William E. Brown, D.D.S.,
and Barry A. Shapiro, A.B.
1)eparlmc’nt of Pediatrics and Conununicable Diseases Gild School of Dentistry, University of Michigan
trated schematically for an incisor in Figure
1. Although this process is represented as
occurring in four stages, in reality it
con-sists of many small increments. Tile time
required for completion of enamel
forma-tion ranges from a few months for
decidu-ous teeth to 6 years for some permanent
teeth.8
If that process is disturbed temporarily,
hypoplasia of the developing layer occurs.
This is represented schematically in Figure
2 as occurring during the third phase of
enamel formation. If the insult is removed,
development then resumes the normal
re-4
of renal disease with development of faulty
enamel.
SUBJECTS AND METHODS
Forty children with a history of the
ne-phrotic syndrome were evaluated. Complete
records were available since most of these
patients have been treated exclusively for
their nephrotic syndrome at tile University
of Michigan Medical Center (UMMC).
Criteria for diagnosis follow those of
Met-coff.” Continuous steroid therapy was used
to induce remission, followed by
intermit-tent steroid therapy for periods of 1 to 2
years, as previously described.12 In some
patients prophylactic antibiotics were given
for periods as long as 2% years. No
supple-mentary calcium salts were given.
Examination, during the summer of 1962,
consisted of an attempt to demonstrate
ab-normal fluorescence by Wood’s light, and a
careful appraisal of the enamel of each
tooth. The findings were confirmed by a
pedodonist (W.E.B.), who estimated the
age at which the abnormality had occurred.
This estimate was accomplished without
knowledge of the clinical course and
treat-CHRONOLOCY OF ENAMEL FORMATION
2
lII I
I I
I _ I
I I
I I
I I
I 3 I
I I
II
I I
DEFECTIVE I
ENAMEL FORMATION
AT THIS STAGE
I I
I I
4
0 2 4 6
YEAR
8 0
400
FIG. 1. Normal enamel formation.
main as a chronological record of previous
illness.
The other important feature of dental
growth is tile orderly and precise sequence
by
which individual teeth undergodevel-opment.9 This pattern for permanent teeth
is illustrated in Figure 3. The onset and
duration of enamel formation differs
be-tween teeth. Thus, the location of
hypo-plasia on a particular tooth allows an
esti-mate of the age at which the insult
oc-curred.
In this study the incidence and
loca-tion of enamel hypoplasia in our nephrotic
children were investigated. By using the
published tables of dental development,bO
an attempt was made to correlate the timing
1i-CsntvoI Incisors
t
Loterol IncisorsCuspid
a‘ litBicuspid
2nd Bicuspid
c
st MotorI 2nd Motor
MAXILLARY
Ic Csntrol Incisors
Lotsrol Incisors Cuspid st Bicuspid
1 2nd Bicuspid
.1 1, stMolar
2ndMolor
MANDIBULAR L
FIG. 3. Chronology of enamel formation. Each bar
represents the development of a single tooth,
plotted against age. The left margin of the bar
FIG. 2. Disturbed enamel formation. The residual represents the beginning of enamel formation,
(‘lassificalion
Condition of Enamel
Normal Ilypoplaslic Total
I. Patients with onset disease before 6 years; and no erupted
perma-itent teeth at time of study 8 0 8
II. Patients with onset disease after 6years; and with erupted
perina-nent teeth at time of study 10 0 10
III. Patients with onset disease before 6 years; and with erupted
per-manent teeth at time of study
14 (63.6%)
8 (36.4%)
2
Total (%)
3 (80%)
8 (o%)
40 401
TABLE II
SUMMARY OF DENTAL EVALUATION OF NEPUROTIC CHILDREN
ment of each patient’s disease. Where
avail-able, siblings were evaluated as controls.
RESULTS
Findings are summarized in Table II. No
enamel hypoplasia of deciduous teeth was
found in any patient in the study. Likewise,
abnormal fluorescence was not observed.
Siblings, used as controls, had no enamel
hypoplasia.
The subjects could be divided into three
groups. The first group consisted of those
patients who did not have erupted
perma-nent teeth at time of study. Since dental
roentgenograms were not routinely
ob-tamed, evaluation of this group is
incom-plete.
The second group consisted of 10 patients
with onset of their renal disease after
enamel formation was complete; there was
no enamel hypoplasia. This group may, in
a sense, serve as controls since their disease
and treatment could not affect dental
de-velopment.
In the remaining group of 22 patients,
who had onset of their renal disease before
6 years of age, 8 of the 22 patients had
enamel hypoplasia. The hypoplastic enamel
could be recognized easily because of its
distinct appearance. The
‘
involved areaswere depressed and, in some patients,
ap-peared yellow in color. Normally, tooth
color is determined by the thick layer of
translucent enamel. The thin hypoplastic
enamel is more transparent and allows the
yellow dentin to be seen.
The following cases illustrate the
neph-rotic syndrome occurring during early,
middle or late stages of dental
develop-ment:
Case 1
DV., an 8-year-old girl, was the product of a
full-term pregnancy, with birth weight of 10 lb
3 oz (4,620 gm). The neonatal period was
un-eventful. She was apparently in good health until
7 months of age at which time she had onset of
the nephrotic syndrome (Fig. 4). Following 3
weeks of unsuccessful therapy, she was transferred
to UMMC. Tetracycline, 10 mg/lb/day, was begun
shortly after admission and continued for a total of
13 months. After 4 weeks of supportive treatment,
ACTH, 160 i.u./day, was given for 11 days.
Shortly thereafter diuresis occurred, and
albumin-uria disappeared. She was discharged on
inter-mittent cortisone therapy in a dosage of 100 mg
on 3 consecutive days of each week. Two months
after discharge, a relapse occurred which
re-sponded to intensive cortisone therapy over a
30-day period. Thereafter, she remained in
remis-sion and cortisone was later discontinued. The
total duration of cortisone therapy was five months.
Subsequently, she remained well without evidence
of the nephrotic syndrome.
Dental evaluation, at 8 years of age, revealed
severe hypoplastic enamel of the upper central
in-cisors, lower central and lateral incisors and all
first molars (Fig. 5). The involved areas were
de-pressed, yellow in color and sensitive to heat and
cold. The lingual surfaces of these teeth were also
AD. 750067 . , ‘I I’
Incisors
Incisors
MAXILLARY
Central Incisors
,,1’Lateral Incisors
T 1st Molar
MANDIBULAR
Central Incisors
,,‘LateraI IncIsors
,\
MANDIBULAR_
Clinical Illness
Steroids
Tetracycline
0 2 4 6 8 lO
YEAR
YEAR plastic.
graph.
FIG. 5. Case 1. Teeth of Patient D.V. with
hypo-plastic enamel of incisors.
bicuspids, and second molars had not yet erupted.
Dental estimate of the age at which disturbance
of enamelization occurred was between 6 and 12
months.
DV. 806097
.-CenIroI Incisors
iiiir
‘ I,,,f .- Lolerol Incisors
r “_t
_____
_______
-1st Molar
(i
::
MAXILLARY
:rArA
I
______
Clinical Illness Steroids #{149}
Tetrocychne
0 2 4 6 8
FIG. 4. Case 1. Clinical course and dental
develop-ment of Patient DV. The duration of clinical
ill-ness, steroid therapy and tetracycline therapy is
plotted against age. Dental development is plotted
against the same scale. The bars representing teeth
with hypoplastic enamel are diagonally striped as
are the involved teeth on the left portion of tile
Case 2
A.D., a 9-year-old white girl was the product of
a full-term pregnancy, with birth weight of 7 lb
73 oz (3,389 gm). Her course was uneventful until
onset of the nephrotic syndrome at 23 years of
age (Fig. 6). After 4 days of hospitalization with
only dietary treatment, she underwent a
spon-taneous remission. She remained well until 4
FIG. 6. Case 2. Clinical course and dental
develop-ment of Patient AD. Format is identical to that of
Figure 4. Only the gingival portion of the upper
i’o and lower central and lateral incisors was
hvpo-fllOnthS later when a recurrence of the nephrotic
syndrome followed an upper respiratory infection.
She was hospitalized and given tetracycline,
po-tassium chloride, and ACTHAR Gel, 100 its. daily,
for 10 days. Diuresis began on the fifth clay of
treatment. Subsequent to discharge, she was given
cortisone, 200 mg, on 3 consecutive days of each
week. After 5 months, she developed a relapse
which responded readily to 8 days of intensive
steroid therapy. Subsequently, three relapses.
which cleared with intensive therap\, occurred
during the next 18 months. Thereafter, she has
remained well. Steroids were given for a total
duration of 33 years, and tetracycline was
ad-ministered daily for a total of 2 years.
Dental evaluation at 9 years of age revealed
yellow areas of hvpoplastic enamel confined to the
gingival margin of all incisors (Fig. 7). The
af-fected areas were depressed, and clearly were not
Nasmyth’s membrane. All first molars were erupted
and completely normal. The remainder of her
permanent teeth were not erispted, bitt dental
roentgenograms appeared normal. Dental estimate
of age at which the disturbance of enamel
forma-tH)n occurred was between 3 and 4 ears I)f age.
Case 3
R.L.
,
a 12-year-old white l)o\, was the productof a full-term pregnancy with birth weight of
8 lb 12 oz (:3,969 gm). Resuscitation was required
at birth, but the remainder of the neonatal course
was uneventful. His general health had been
R L 827810
Jj
r 2nd Bicuspid
2nd Molar
MAXILLARY
Clinical Illness $
Steroids $
Antibiotics
0 2 4 6 8 10
YEAR
l’ie. 7. Case 2 Teeth of Patient AD. with
hvpo-plastic enamel of gingival margin of incisors. The
narrow band of hypoplasia is most evident upon
tile tipper teeth, indicated by the arrows.
403
nephrotic syndrome (Fig. 8). He aS admitted to
his local hospital, and, despite therapy with
ACTI!, serum albumin, and oxvtetracycline, his
e(lema became worse. After 5 weeks he was
trans-ferred to UMMC. His disease 1)ersisted over the
next 2 months without response to numerous
tilerapeutic agents including nitrogen mustard and
dextran. Several paracenteses were required
be-cause of dvspnea, and pneumonia occurred once.
Finally, 3 months after onset of his disease, a
14-day course of cortisone resulted in diuresis and
(lecrease(l proteinuria. He received tetracycline in
therapeutic dosage for one month of his
hospitali-zation at U\IMC.
Dtsring the next 23 years there were eight
hos-l)it11izati11s for exacerbations of his neplirotic
syndrome. At no time during this interval was the
patient free of edema or proteinuria. Tetracycline,
10 mg/lb, was given daily for this 234-year period.
Corticosteroids were given 3 days of each week for
this interval. eXCeI)t during exacerbations when
daily therapy was used. Supplemental calcium salts
were not given.
Subsequently, the patient has done well except
for one short exacerbation at age 10 years which
readily responded to intensive steroid therapy.
Dental evalisation at age 113 years showed all
second l)iduspids and second molars to he small
and yellow and to have hypoplastic enamel (Figs.
9 & 10). All other permanent teeth, except third
molars which were not erupted, had normal
enamel. l)ental estimate of the age at which the
disturbance of enamel formation occurred was
4 to 6 years.
COMMENT
WTe are iml)ressed by tilecorrelation
be-tween the age of severe renal disease and
tue estimated age at which faulty enamel
was formed. This correlation was present in
#{231}_.__2nd Bicuspid
-2nd Molar
MANDIBULAR
FIG. 8. Case :3. Clinical course and dental
develop-ment of Patient R.L. Format is identical to that
of Figure 4. Hypoplastic enamel was limited to the
second bicuspids and second molars.
every patient examined and is clearly shown
on the graphs. In Patient D.V. (Fig. 4),
whose renal disease occurred during the
early phase of enamelization, the lesions are
located toward the occlusal or first formed
surface of the teeth. Tile enamel of these
teeth which formed later, after all signs of
renal disease had subsided, was normal.
This is contrasted with Patient AD. (Fig.
6), whose renal disease occurred late during
enaniel formation of the incisors. Her
le-sions are found near the gingival margin.
The enalilel formed prior to illness is
nor-mal. Likewise in Patient R.L. (Fig. 8) those
teeth, which had completed their enamel
formation prior to illness, were normal. His
defects were confined to the late
develop-ing teeth.
Four of the renlaining I)atiellts had
Pat-terns of involvelllent similar to that shown
in Figure 6. The remaining patient’s pattern
was almost identical to Figure 8.
The incidence of hypoplastic enamel in
OUr I)atiellts with the nephrotic syndrome
is far higher than estimates of incidence in
the general population (35%).13 Although
hypo-FIG. 9. Case 3. Teeth of Patient R.L. This view
of the upper left teeth shows hvpoplasia of the
secOfl(l bicuspid and second molar. The
interven-ing first molar is not hypoplastic, as shown by the
normal size and color. The black area of the
anterior portion of this tooth is amalgam
restora-tion, not related to enamel hypoplasia.
404
plastic enamel, there were no premature
births among our affected patients.
There are several other possible causes
for the enamel defects found in nephrotic
children. These include speeffic drugs, as
tetracycline and corticosteroids, as well as
changes secondary to the nephrotic
syn-drome. Disturbances in calcium and
phos-phorus metabolism consitute an example of
tile latter.
Schwachman et al.14 and Zegarelli et
al.’ observed brown to black staining of
deciduous and permanent teeth in
fibro-cystic patients treated with tetracycline.
More extensive studies by Davies et al.16
and Waliman and Hilton” showed that
many infants given tetracycline shortly
after birth had yellow deciduous teeth. In
such teeth, the drug could be demonstrated
in both dentin and enamel. They observed
an impressive yellow fluorescence of the
involved teeth when viewed in ultraviolet
light. Wallman and Hilton suggested the
enamel hypoplasia observed in their patients
was due to tetracycline. MillerlS considered
the enamel hypoplasia more likely due to
prematurity than to tetracycline. The fact
that ultraviolet light did not cause
fluores-cence of the involved teeth would appear
to be a strong point against tetracycline as
a cause of the hypoplastic enamel in our
patients. Evaluation of the effect of
tetra-cycline would require patients who were
otherwise similar but did not receive
tetra-cycline therapy. Unfortunately, all of our
subjects had long-term tetracycline therapy
during their illness.
Corticosteroid administration may be a
significant factor in formation of hypoplastic
enamel. Demineralization of bone
(osteo-porosis) frequently occurs during prolonged
steroid therapy. It has been postulatedl9
that the loss of calcium and phosphorus
from bones is due to inadequate formation
of protein matrix coincident to the catabolic
or antianabolic effects of adrenal hormones.
Although an association of steroid therapy
with enamel hypolasia has not been
re-ported, the adverse effects of such therapy
may include enamel defects.
To completely evaluate the effect of
steroid administration, the incidence of
enamel defects in nephrotic children not
receiving steroid therapy should be studied.
We were unable to obtain such a group of
patients since only one of the nephrotic
children followed in our clinic was treated
without steroid therapy. A comparison with
patients who developed the nephrotic
syn-drome before the era of steroid therapy
may not be valid because of differences in
supportive therapy. Further, the increased
attrition of teeth with hypoplastic enamel
complicates the comparison of the present
subjects with older patients.
,
‘r’
FIG. 10. Case 3. Patient R.L. View of defective
teeth illustrating the small size and defective
Disturbances of calcium and phosphorus
metabolism, not associated with drug
ther-apy, were reported by Calteux to cause
hypoplastic enamel.2#{176} In studies of
ne-phrotic children, Emerson and Beckman2l
demonstrated derangements of calcium and
phosphorus metabolism during periods of
active disease with edema. Phosphorus
bat-ance was negative while only 2% of ingested
calcium was retained. On roentgenograms,
they noted a diffuse rarefaction of shafts of
bones despite a normal rate of growth and
calcification at epiphyseal plates. The bone
changes were not those found in rickets.
Deficits of calcium were found to result
from excessive fecal losses of calcium. No
etiology was proposed for this finding, but
balances rapidly reverted to normal
follow-ing diuresis with loss of edema. Recently,
Stickler et al.22 emphasized the fecal loss
of calcium in many forms of renal disease,
including the nephrotic syndrome. The
con-tribution of these abnormalities of calcium
metabolism to enamel hypoplasia in the
nephrotic syndrome cannot be defined.
The nephrotic syndrome may have
im-portant adverse effects upon enamel
forma-tion which may be unrelated to any of the
previous factors. The problem is further
complicated by the observation that no
sig-nificant difference of severity, course or
treatment was found between patients with
enamel hypoptasia and those with normal
teeth.
SUMMARY
A high incidence of enamel hypoplasia
in permanent teeth was found in children
with the nephrotic syndrome. There was a
correlation between the time of severe renal
disease and the estimated time at which
faulty enamel was formed. The absence of
fluorescence of the defective teeth upon
exposure to ultraviolet light suggests that
tetracycline therapy was not a causative
factor. Other possible causes of the defect
include corticosteroid therapy and
meta-bolic disturbances associated with the
neph-rotic syndrome. Final identification of the
etiological factor remains uncertain.
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1. Quoted by Cavallaro, J.: Syphilis in its
rela-tion to dentition. D. Cosmos, 50: 1161, 1908.
2. Sarnat, B. D., and Schour, I.: Enamel
hypo-plasia (chronological enamel aplasia) in
re-lation to systemic disease: a chronologic,
morphologic and etiologic classification. J.
Amer. Dent. Ass., 28:1989, 1941; 49:67,
1942.
3. McMillan, R. S., and Kashgarian, M. : The
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J.
Amer. Dent. Ass., 26: 18, 1939.6. Teuscher, George W. : Systemic disease in
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8. Schour, I., and Massler, M. : The growth
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Mich. State Med. Soc.,61:1114, 1962.
13. Hartsook, J. T.: Personal conmiunication.
Oc-tober, 1962.
14. Shwachman, H., Fekete, E., Kulczycki, L. L.,
and Foley, C. E.: The effect of long-term
antibiotic therapy in patients with cystic
fibrosis of the pancreas; in Antibiotics
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New York, Medical Encyciopjedia, Inc.,
1958, p. 692.
15. Zegarelli, E. V., et a!.: Tooth discoloration in
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16. Davies, P. A., Little, K., and Aherne, W.:
Tetracyclines and yellow teeth. Lancet, 1:
17. Wailman, I. S., and Hilton, H. B.: Teeth
pig-mented by tetracycline. Lancet, 1:827, 1962.
18. Miller, J.: Tetracycline in teeth and bone.
Lancet, 1:7238, 1962.
19. Albright, F.: The effect of hormones on
osteogenesis in man. Recent Progr.
Hor-mone Res., 1:293, 1947.
20. Calteux, J. P., Die Schmelzhypoplasie, Deutsch
Zahnheilk, 1934. (Leipzig, Georg Thieme)
21. Emerson, K., Jr., and Beckman, W. W.:
Cal-cium metabolism in nephrosis: I. A.
descrip-tion of an abnormality in calcium metabolism
in children with nephrosis. J. Clin. Invest.,
24:564, 1945.
22. Stickler, C. B., Burke, E. C., and Roseveal,
J. W.: Familial renal osteodystrophy with
review of calcium and phosphorus balances
in renal disease (abstract). Midwest Soc.
Pediat. Res., 25-26, 1962, Cincinnati, J.