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Am J Hum Genet 32:908 - 919, 1980

A Genetic Study of Anodontia in X-Linked


Hypohidrotic Ectodermal Dysplasia
MINORU NAKATA,1 HIROAKI KOSHIBA,2 KAZUHIOR ETO,2 AND WALTER E. NANCE3

SUMMARY
Dental examinations and tooth measurements were conducted on 16 mothers,
10 fathers, and 23 affected males in 15 families with X-linked hypohidrotic
ectodermal dysplasia. Small teeth and congenital missing teeth were
sufficiently consistent findings in obligate heterozygotes to suggest that
carriers can usually be recognized by clinical criteria.

INTRODUCTION
The term "hereditary ectodermal dysplasia" refers to a group of hereditary diseases in
which ectodermal tissues or derivatives are absent or poorly developed. Two major
forms are recognized: the hypohidrotic and the hidrotic types [1]. In hypohidrotic
ectodermal dysplasia (HED), the sweat glands are absent or decreased in number and,
in addition to the anodontia, there is a sparseness of hair. In the hidrotic form,
abnormalities of both the hair and nails are found, but the teeth and sweat glands are
normal. These two types of ectodermal dysplasia also differ in their mode of
inheritance: the hidrotic type is transmitted as an autosomal dominant trait, whereas the
hypohidrotic form is usually transmitted as a sex-linked recessive trait, although
autosomal recessive pedigrees have also been reported. Carrier females of X-linked
HED may show mild symptoms of the disease, including thin, sparse hair, patchy
anhidrosis, and an increased incidence of congenital absence of the teeth. In this report,

Received January 15, 1980; revised March 2, 1980.


This paper was reported at the 22nd International Association for Dental Research, Japanese Division,
Osaka, 1974.
1 Department of Pediatric Dentistry, School of Dentistry, Kyushu University, Maidashi 3-1-1, Higashiku,
Fukuoka, Japan.
2 Department of Pedodontics, School of Dentistry, Tokyo Medical and Dental University, Yushima 1,
Tokyo, Japan.
3 Department of Human Genetics, Medical College of Virginia, Richmond, VA 23298.
Request reprints from W. E. N.
1980 by the American Society of Human Genetics. 0002-9297/80/3206-001 1$02.00
908
HYPOHIDROTIC ECTODERMAL DYSPLASIA 909
the dental findings in the families of 15 affected probands with X-linked HED are
described, along with systematic dental measurements in affected males, carrier
females, and unaffected fathers.

MATERIALS AND METHODS


This study involved 23 males with HED along with 21 mothers and 10 fathers of these
patients, all of whom were examined in the outpatient clinic of the Department of Pedodontics of
the Tokyo Medical and Dental University. A systematic dental examination was performed on
each subject, and dental casts and pantomographic X-rays or routine dental X-rays were
obtained. In addition, the pedigree was documented in each family. Measurements of the
mesiodistal dimension of the deciduous or permanent dentition were obtained from the dental
casts of 15 affected males, six female relatives, 16 mothers, and 10 fathers, based on the criteria
of Fujita [2]. The measurements were made with an electronic caliper that had an accuracy of
0.01 mm.

RESULTS
The pedigrees of the 15 affected probands are shown in figure 1. All 23 affected
males who were examined had the characteristic clinical findings of HED, including
very sparse hair, small, misshapen and missing teeth, diminished sweating with a
history of frequent hospitalization for high fever during infancy, and symptoms of
atrophic rhinitis and decreased salivary secretions in later life. All affected males had
normal nails, and there was no history suggesting cataract or profound hearing loss,
although detailed ophthalmologic and audiologic examinations were not performed. In
addition, seven other male family members were reliably reported to be affected. These
included six individuals in families C, D, E, and G who had died at ages. ranging from
14 days to 1 year with a high fever of unrecognized cause. A seventh affected male,
H:II-5, was reported to have been sterile with a low sperm count, but an eighth, G:I- 1,
had sired seven children and was the only affected male in our families to have
reproduced. His only son was normal, but, of his five daughters who were examined,
four had one or more congenitally absent teeth and had produced affected sons. The
other examined daughter (G:II-4) had two congenitally absent lateral incisors and a
female child with a congenitally missing premolar. The final daughter (G:II-3) was not
examined but is presumed to be a carrier too.
In seven of the families (fig. 1, F and J -0), the proband was the only affected male.
Only two mothers of these cases had congenitally missing teeth (F:I-2 and 0:1-2). One
of these mothers also had a daughter (F:II-3) with congenitally missing teeth and very
thin, sparse hair (fig. 2B), and was therefore classified as an obligate heterozygote
along with the mothers or daughters of affected males in multiplex families. As shown
in table 1, the average maternal age of the six simplex cases was 26, whereas the age of
mothers of familial cases at the time their first affected son was born was 28.
Of the 15 obligate heterozygotes who were examined in families A-I, 11 had one or
more congenitally missing teeth. In addition, two of six possible heterozygotes who
were examined in these families also had congenitally missing teeth and may well have
been carriers (table 2). Two other female family members (A:II-5 and G:III-2) were
reported to have missing teeth but were not examined.
910 NAKATA ET AL.

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HYPOHIDROTIC ECTODERMAL DYSPLASIA 911

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FIG. 2.-Facial and oral appearance of affected family members. A, Affected male, B:III-1; B, probably
heterozygote female, F:II-3.

Measurements of tooth size were made on the dental casts of 15 affected males and
10 fathers of affected males. The other eight affected males who were examined had
either total anodontia (A:III-4 and D:II-4) or severe dental decay (E:II-3 and H:III-4),
or they were too young for dental casts to be made (B:III-5, L:III-2, M:II-1, and
0:11-1). In tables 3 and 4, the mesiodistal tooth dimensions in the affected males and
their fathers are compared with those observed in normal controls. In each individual,
the left tooth was measured if it was present and the right tooth was measured instead if
the left was absent or severely decayed. As shown in table 3, several affected males had
teeth missing bilaterally. Although some of the fathers had decayed or extracted teeth,
none were congenitally absent except in one father (B:II- 1). Despite the limited sample
size, affected males had significantly smaller upper incisors and first molars and
smaller lower first and second molars than did control patients of the same age and sex.
In contrast, among the paternal tooth measurements, only two, the upper second
premolar and lower first molar, were found to be smaller, but only at the 5% confidence
level.
The data on dental measurements in 11 obligate heterozygotes and in the five
mothers of simplex cases that were available for analysis are compared with a series of
normal controls in table 5. All of the teeth of heterozygotes were smaller than those of
controls, and the difference was significant for most of the 12 teeth that were measured.
In contrast, individual measurements in the mothers of simplex cases fell within the
range of normal, and the mean values generally did not differ significantly from those
of controls.
912 NAKATA ET AL.
TABLE 1
COMPARISON OF MATERNAL AGE OF SIMPLEX AND FIRST-BORN CASES OF HED

SIMPLEX CASES FAMILIAL CASES


Individual no. Age in yrs - Individual no. Age in yrs

J:I-2 .27 A:II-3 .29


II-6 .24
K:I-2 .25
B:II-2 .24
L:I-2 .23 11-4.24
M:I-2 .26 C:I-2 .26
N:I-2 .28 D:I-2 .28
O:1-2 .26 E:I-2.31
Mean .25.8 F:I-2 .22
SD .1.57 G:II-1 .31
II-2 .30
11-5 .32
II-7 .28
H-2 . .30
11-2 .30
1:11-2 .28
Mean .27.5
SD .3.01
tvalue .-. 1.300 (not significant)

DISCUSSION
In 1848, Thurman first described the syndromic association of sparse hair, missing
teeth, and dry skin in an affected male with HED [3]. About 40 years later, in his
famous book, The Variation of Animals and Plants under Domestication, Charles
Darwin noted that, although only males showed symptoms of the disease, the trait
appeared to be transmitted by seemingly unaffected females. Since Darwin's report,
many studies have confirmed the clinical features and X-linked mode of inheritance of
the disorder [4-7], but pedigrees suggesting autosomal recessive inheritance have also
been described [8-9]. Although a variety of minor abnormalities have previously been
reported in heterozygous females with X-linked HED [10, 11], including anodontia
[12], systematic studies of dental measurements in carrier females have not previously
been reported.
In all of the 15 families reported here, the pattern of inheritance is consistent with
X-linkage. Among the six examined children of the only fertile affected male, the only
son was normal, whereas all five daughters were carriers. In a similar manner, in all
other multiplex pedigrees, affected males were related to each other through female
relatives. As shown in table 2, 11 of the 15 examined obligate heterozygotes, or 73%,
HYPOHIDROTIC ECTODERMAL DYSPLASIA 913
TABLE 2
DISTRIBUTION OF CONGENITALLY MISSING TEETH IN EXAMINED FEMALE MEMBERS OF FAMILIES A -H

OBLIGATE HETEROZYGOTES POSSIBLE HETEROZYGOTES


Individual no. Tooth nos. Individual no. Tooth nos.

A:II-3 .. ........... LLI A:III-2 .... None


11-6 .... ....... RLI
B:III-2 .... None
B:II-2 ... ....... None
II-4 ........... RLI, LLI E:II- ..... None
C:I-2 .......... LLI 7F:II-3 .... Ili
D:I-2 ........... None G:III-9 .... LP
III- 11 .... None
E:J-2 ........... None
F:I-2 ... ........ LP
G:II-1 . ............. RLI, LLI
II-3 .... ....... LLI
II-7 ... ....... RLI, LLI
11-9 .... ....... RLI, LLI
11-12 .... ....... LLI

H:II-2 .... ....... LLI


1:11-2 ........... None
Total incidence ............ 11/15 2/6

NOTE: RLI = Maxillary right lateral incisor; LLI = maxillary left lateral incisor, LP = mandibular left second
premolar, lli = maxillary deciduous left lateral incisor.

had one or more congenitally missing teeth. This frequency of missing teeth is more
than 10 times the 1% -7% incidence observed in the general population for teeth other
than the third molar, which is absent in approximately 27% of the population [13, 14].
These findings indicate that, with respect to dental manifestations, HED segregates as a
highly penetrant X-linked trait that shows intermediate expression in the heterozygous
female.
Similar conclusions emerge from the analysis of quantitative dental measurements.
The remaining teeth of affected males were markedly smaller than normal, and those of
the obligate heterozygotes were also significantly smaller, although the magnitude of
the differences was not as great as is illustrated in figure 3, where the average deviation
in tooth dimension of each individual is expressed as a standard score. To obtain the
average score, each dental measurement was first subtracted from the population mean
and divided by the appropriate standard deviation. Individual scores were then summed
over all measured teeth to obtain the mean score for an individual. The average
deviation of the obligate heterozygotes was -1.07, while that of the affected males was
-1.67. If the phenotype of hemizygous affected males can be accepted as a valid
indication of the expected phenotype of homozygous affected females, the quantitative
dental manifestations of HED would also appear to be determined by the nearly
additive effects of a codominant allele.
914 NAKATA ET AL.
TABLE 3
MESIODISTAL TOOTH DIAMETERS OF AFFECTED MALES

AFFECTED MALES NORMAL MALES


TOOTH* No. Mean SD No. Mean SD t-VALUE

Upper:
i* ........................ 8 5.83 0.27 111 6.63 0.37 -5.9914t
c......................... 7 6.72 0.18 113 6.75 0.41 -0.192:
M2 .......................-- 9 9.25 0.77 109 9.36 0.57 -0.541 :
II ........................ 3 7.26 0.25 84 8.74 + 0.57 -4.462t
C........................ 1 6.76 84 8.17 0.52
ml ........................ 5 9.75 0.72 84 10.81 0.35 -6.139t
Lower:
;1 ........................ 1 4.59 90 4.26 0.32
c......................... 8 5.86 0.34 100 5.95 0.32 -0.7624
M2 ....................... 8 9.72 0.56 90 10.36 0.48 -3.567t
C........................ 1 7.58 87 7.160.40 ..

ml ...................... -5 9.67 0.80 87 11.55 0.36 -10.476t


Lower case letters refer to deciduous teeth.
t P < .01.
t Not significant.

The occasional occurrence of completely normal or severely affected carrier females


has been attributed to random inactivation of the X chromosome [10-12]. In our
study, only four of 15 examined obligate heterozygotes failed to show congenital
absence of any teeth, and none of the 11 for whom measurements were available had
scores as large as the population mean (fig. 3). One daughter (fig. 2B) had moderately

TABLE 4
MESIODISTAL TOOTH DIAMETERS OF FATHERS

FATHERS NORMAL MALES


TOOTH No. Mean + SD No. Mean SD t-VALUE

Upper:
I ......................... 9 8.86 0.48 84 8.74 0.57 0.608*
12 ........................ 10 7.16 0.75 84 7.24 0.62 -0.377*
C ........................ 10 8.21 0.38 84 8.17 0.52 0.235*
Pi ........................ 10 7.44 0.40 84 7.51 0.43 -0.490*
P2 ........................ 10 6.74 0.32 84 7.03 0.40 -2.207t
Ml ........................ 10 10.60 0.42 84 10.81 0.35 -1.756*
Lower:
I ......................... 10 5.71 0.35 87 5.55 0.36 1.335*
12 ........................ 10 6.39 0.51 87 6.16 0.38 1.748*
C ........................ 10 7.15 0.29 87 7.16 0.40 -0.077*
Pi ........................ 10 7.26 0.41 87 7.35 0.42 -0.643*
P2--
- ......... . ........... 9 7.24 0.52 87 7.29 0.40 -0.347*
ml *........-.- -............ 9 11.26 0.46 87 11.55 0.36 -2.2414:
* Not significant.
t P < .05.
HYPOHIDROTIC ECTODERMAL DYSPLASIA 915
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FIG. 3.-Distribution of dental measurement scores in normal and affected members of families with
HED. A.M. = Affected male; O.H. = obligate heterozygote; P.H. = possible heterozygote; F. = fathers of
affected males; M.S. = mothers of simplex cases.

severe thinning of the hair, and several mothers were known to wear wigs. The
maximum number of missing teeth in carrier females was two (table 2). In contrast, the
number of missing teeth in affected males, when both the deciduous and the permanent
dentition were counted, ranged from 27 to 48 (table 6).
Previous workers have demonstrated that the remaining teeth in individuals with
partial congenital anodontia are smaller than normal [15-17]. Furthermore, the
distribution of missing teeth in the general population is not random but preferentially
involves both third molars, the upper lateral incisors, and the lower second premolars,
and very infrequently includes the first molars, the canine teeth, and the central incisors
[18-20]. These observations have led to the concept that an extreme expression of the
same genetic and environmental factors that cause variation in tooth size can lead to
absent teeth and that individual teeth vary in their sensitivity to these genetic and
environmental effects, with the incisors, canines, and first molars having achieved the
greatest developmental stability [18-22]. The patterns of dental loss seen in our
families support these views. Heterozygous female carriers had significantly smaller
teeth than did normal controls and a 10-fold increase in the frequency of congenitally
absent teeth. In all but one case, the upper lateral incisors were involved. In affected
males, the anodontia was much more extensive, but there was relative sparing of the
first molars, upper central incisors, and both canines (table 6).
In seven families, there was only one affected male. It seems likely that the probands
in families F and 0 are chance isolated familial cases, in view of the distinct clinical
abnormalities in the mother and sister of F:II-1 and the congenital missing tooth and
HYPOHIDROTIC ECTODERMAL DYSPLASIA 917
small dental measurement score in the mother of W:I- 1. The classification of families
K, L, and N is less certain. The mothers of K:II-2 and L:II-1 both had no congenitally
missing teeth, but their dental scores fell within the -range observed in obligate
heterozygotes. Finally, although the mother of N:II-3 also had no missing teeth, dental
measurements were not available for analysis. On the other hand, the probands in
families J and M may well represent new mutations since there were no relevant

TABLE 6
PATTERN OF DECIDUOUS (D) AND PERMANENT (P) DENTITION
IN UPPER ( f) AND LOWER ( t ) JAWS OF AFFECTED MALES

RIGHT SIDE* LEFF SIDE*


D m2mI C i2 il il i2 C mI m2
INDIVIDUAL NO. P M2MI P2 PI C 12 Ii II 12 C PI P2 Ml M2 TOTAL MISSING TEETH

A:III-1 .............. 43
m V E'
_ _-_
III-4 ..............
IHIAZT_ 48
B:III-1 .............. Ei.I'IZZZ 31
111-4 .............. 39
+
C:II-2 ............... 29
11-3 ............... tZ4ZI 30
.Z~~II
D:II-4 ............... 48
.zI_~I
E:II-3 ...............
EZIIZ__ 34
F:II-1 ............... E' 4zIz; 35
G:III-4 .............. EhiZZII 15t
III-6 .............. L
23t
III-12 .............
*tIZZIfi 27
X ,I_ i _
III- 14 ............. , i_
EZ _ 32
1:111-1 ............... *14~ 36
J:II-2 ................ EazzzzA _ 38
K:II-2 ............... A-.Nz _~ 47
L:II- 1 ............... eZZtlzzzz 33
M:II- 1 ............... 42
N:II-3 ............... 29
0:11-1 ............... 40

* M = molars, P = premolars, C = cuspid; I = central incisor, 12 = lateral incisor. Deciduous teeth desig-
nated by lower-case letters.
t Deciduous teeth not examined.
918 NAKATA ET AL.
clinical abnormalities in other family members and the maternal dental measurement
scores were greater than those observed in any of the obligate heterozygotes (fig. 3).
Although the affected probands in these simplex families were all males, we cannot
exclude the possibility that one or more represent autosomal recessive genocopies.
At equilibrium, one-third of all cases of a lethal recessive X-linked trait should be
sporadic if the mutation rates in males and females are equal [23]. Considerable
disagreement exists as to whether the expected proportions of sporadic cases are
actually observed in real populations [24-26], suggesting that the assumption of equal
mutation rates in males and females may not be valid [27]. In the present series of
families, HED was clearly associated with a significant neonatal mortality, since six of
15 secondary cases in the multiplex families had died within the first year of life,
usually with a history of unexplained high fever. The reported sterility of the seventh
male (H:II-5) raises the possibility that the HED mutation may have pleiotropic effects
on the seminal secretions analogous to those of cystic fibrosis [26]. However, the
progenitor of family G demonstrates that surviving males are not invariably sterile;
and, since HED clearly cannot be considered a genetic lethal, fewer than one-third of
the cases should be sporadic even if there is no sex difference in mutation rate. Among
the 15 probands and 31 affected males in these families, clinical and genetic criteria
suggest that two to five cases are attributable to new mutations, a proportion that would
seem to be in reasonable agreement with the expected frequency of sporadic cases.

ACKNOWLEDGMENTS
We are grateful to graduate students Junko Kindaichi, Yoshio Hamano, Masaaki Ishikawa,
and Yasuo Takeda for their help in collecting the data. We also thank the reviewers for their
helpful suggestions.

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HYPOHIDROTIC ECTODERMAL DYSPLASIA 919
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