Clinical Genetics 1975: 8: 20-29

Evidence for an autosomal recessive form of cleidocranial dysostosis R. M. GOODMAN, R. TADMOR, A. ZARITSKY, AND S. A. BECKER Departments of Human Genetics and Radiology, Tel-Aviv University, Sackler School of Medicine and The Chaim Sheba Medical Center, Tel-Hashomer, Israel

Three cases of cleidocranial dysostosis from two unrelated consanguineous families are reported. The family setting, the distribution of the affected members, plus the severity of involvement suggest that there is also an autosomal recessive form of this disorder. Received 4 December 1974, uccepted for publication 3 February 1975

Cleidocranial dysostosis is a well-recognized hereditary disorder of bone formation. Extensive genetic reviews on the subject (FitLhet 1929, Lasker 1946, Herndon 1951) strongly support the fact that one form of this disease is due to an autosomal dominant gene with rather complete penetrance and an usually high mutation rate. During the past 3 years we have seen two unrelated consanguineous families with the disorder. In each, the family setting, the distribution of the affected members, plus the severity of involvement suggest that there is also an autosomal recessive form of cleidocranial dysostosis. The purposes of this report are to present and discuss our findings in view of the above hypothesis. Case Reports

Family A The proband is a 4-year-old boy who is presently institutionalized for severe mental

retardation. He does not speak and is unable to walk. His height is 74 cm (< 3rd percentile) and head circumference is 49 cm. His head appears to be brachycephalic in shape with a wide open anterior fontanelle. There is marked frontal and parietal bossing. The nose is depressed at the base and the nares are flared. Ocular hypertelorism can be noted. He has six permanent teeth which appear normal but the decidious teeth appear dysplastic. Macroglossia is present. Chest examination showed the patient to have bilateral absence of the clavicles and hypoplasia of the scapulae. The abdomen was protuberant which was accentuated in the sitting position by the smallness of the chest cage. Other pertinent physical findings consisted of bilateral clinodactyly and hypoplasia of all the nails. Figs. 1A-B illustrate some of the above physical abnormalities. Extensive laboratory studies were done in an attempt to find a specific cause for his mental retardation but all results were

Supported by a grant from the Lester Aronberg Foundation.

CLEIDOCRANIAL DYSOSTOSIS

within normal limits. His roentgenographic findings were characteristic for the diagnosis of cleidocranial dysostosis and these abnormalities are listed in Table 1 and illustrated in Figs. 2A-B. The proband’s 8-year-old brother also suffers from the same disorder but is of normal intelligence. He is also very short for his age, measuring 107 cm in height (< 3rd percentile). His skull is brachycephalic, measuring 36.5 cm in circumference. He has marked frontal and parietal bossing with both nonclosure of the anterior fontanelle and sutures. Ocular hypertelorism was present. Examination of the oral cavity showed many dental caries. On chest examination there was bilateral absence of the clavicles, winging of the scapulae and bilateral flaring of the rib cage. Other findings include a marked lumbar lordosis, coxa vara and hypoplasia of the nails. Figures 1C-D show some of these physical findings. Roentgenographic studies were consistent with the diagnosis and can be noted in Table 1 and Figs. 2 G D . The pedigree of this family is shown in Fig. 3. The parents are first cousins of Jewish Iraqi origin. The father is 32 years old and the mother is 27 years old. Physical examination of the mother, father and normal son failed to reveal any abnormalities suggestive of cleidocranial dysostosis. Roentgenographic studies in all three of these members showed no abnormal findings. The mother has had two spontaneous abortions, occurring in the fourth and sixth months of pregnancy. No other family members are known to be affected with this disorder. Family B The proband, aged 36 years old, is of very short stature, measuring 131 cm (< the 3rd percentile). His height is below that of his parents and sister. Classical physical findings include a brachycephalic skull,

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measuring 54 cm in circumference, with a large open anterior fontanelle. The frontal part of the skull was depressed. There was ocular hypertelorism with bilateral strabismus. Many teeth were missing and he gave a history of poor dentition over a long period of time. Chest examination showed bilateral absence of clavicles with a short and flared rib cage. On standing he displayed kyphoscoliosis with a marked lumbar lordosis. Other physical findings include brachydactyly of hands and feet with bilateral stub thumbs and hypoplasia of all nails, with greater involvement of the toes. Figs. 4A-C illustrate some of the physical findings in this patient. Roentgenographic findings were characteristic for the diagnosis and are listed in Table 1 and illustrated in Figs. 5A-B. The pedigree of this Jewish Iraqi family is shown in Fig. 6. In this case the consanguinity is that of a niece-uncle marriage. The father is 67 years old while the mother is 60 years old. Physical examination of the mother, father and sister revealed that all were of short stature with normal body proportions. None showed any physical findings suggesting the diagnosis of cleidocranial dysostosis and roentgenographic studies in all three individuals were normal. N o other family members were known to be affected with this disorder. Dlscusslon

Since the characteristic features of cleidocranial dysostosis were first described in 1897 by Marie & Sainton, overwhelming evidence points to the fact that the majority of cases are transmitted in an autosomal dominant manner. It has been estimated that about 16 % of the cases occur sporadically (Herndon 1951). In analyzing these sporadic cases Herndon (1951) concluded that they most probably represent new mutations. He further commented that “the tendency of the high mutation rate to in-

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GOODMAN, TADMOR, ZARITSKY, AND BECKER

CLEIDOCRANIAL DYSOSTOSIS

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Table 1 Roentgenographic findings observed in three patients with cleidocranial dysostosis Location

Defect

Skull

Brachycephalic parietal bossing Frontal Incomplete closure of fontanelle Wide persistent sutures Persisting metopic suture Wormian bones Calvarial thickening (occipital) Narrow short sphenoid Large foramen magnum (wide base) Small facial bones Absent paranasal sinuses Hypertelorism Mandibular prognatism

Dentition

+

Embedded teeth Supernumerary teeth Carious deciduous teeth

Chest

Cone-shaped thorax Small scapula

Clavicles

Complete absence

Pelvis

Hypoplasia of iliac wings Wide sacral iliac joint Failure of fusion of symphysis pubis

Spine

Kyphosis Scoliosis Cordosis Spina biflda (cervico-thoracic) Hemivertebrae Posterior wedging of thoracic segment

Long Bones

Broad and short femoral neck Coxa vara

Extremities: Hands

Short distal phalanges Accessory epiphyses at metacarpal base

Feet

Case1 4 years

Case2 8 years

+ + + + + + + + + +

+ + + +

+

+ +

+

-

+ + + + + 0 + + +

+

-

+ + + + + 0 + + + +

Case3

38 years

+ + + + + + + + + + + + + -I-

+ + + + + + -

+ + +

Delay in development of terminal phalanges

Key: (+) = present (-) = absent ( 0 ) = not yet developed

Fig. I. A) Shows the proband (Family A) with narrow shoulders, a protuberant abdomen due to a small chest cage, ocular hypertelorism and a prominent forehead with frontal bossing. His physical development i s reduced for his age. B) Illustrates poor dental development for this 4-year-old child and easy movement of the shoulders due to absence of the clavicles. C) and D) Shows the probands’ brother with short stature for the age of 8 years, along with frontal bossing, ocular hypertelorism, excessive movement of the shoulders and severe lumbar lordosis.

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GOODMAN, TADMOR, ZARITSKY, AND BECKER

Flg. 2. A) A Towne view of skull of the proband showing a wide open fontanelle and sutures with Wormian bones. B) A chest X-ray of the proband showing complete absence of both clavicles, hypoplasia of the scapulae and flaring of the rib cage. C) Hand X-ray of the proband’s brother showing accessory epiphyses at the metacarpal base and hypoplasia of the medial and distal phalanges. D) The pelvis of the proband’s brother showing hypoplasia of the iliac wings, wide opening of the symphysis pubis, delay in union of the pelvic bones and bilateral coxa vara

crease the gene frequency is apparently opposed by the adverse effect of mating selection, with discrimination against the abnormal phenotype” (Herndon 1951). In analyzing all possible explanations for these single cases Herndon (1951) does raise the question of recessive inheritance. He postulates that the majority of cases could represent the heterozygous state of a dominant mutation, while the apparently sporadic cases may represent the homozygous state of a recessive mutation producing an identical or similar biologic effect.

Herndon then proceeds to comment on the pedigree charts of the 73 families collected from the literature by Lasker (1946). In only five families were the affected individuals confined to one sibship and in none of these was there consanguinity. In only one family that Lasker (1946) collected was there a consanguineous mating and in that family there was obvious dominant transmission. Both Lasker (1946) and Herndon (1951) conclude that the many reports of sporadic cases and those few where the parents are

CLEIDOCRANIAL DYSOSTOSIS

# 00

Normal male, female. 4 males, 2 females.

Consanguinity. Affected male.

1

Deceased.

a

Examined.

fl

Proband.

Fig. 3. Pedigree of Family A.

thought to be normal and have two or more affected offspring can not be explained by recessive inheritance. Current authoritative texts on genetic disorders (Goodman & Gorlin 1970, McKusick 1972, Sorsby 1973), including McKusick’s catalog (1971), also agree that cleidocranial dysostosis is transmitted as an autosomal dominant trait. However, in a recent textbook on radiology of the skull (Newton & Potts 1971), in a chapter on congenital skull dysplasia (Winchester & Grossman 1971), one can find that this disorder is listed as

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an autosomal recessive. Undoubtedly, this is an error in recording since the references they cite speak of autosomal dominant inheritance for this disease. Thus, in a recent radiological review (Jarvis & Keats 1974) of 40 cases of cleidocranial dysostosis, all of which fulfill the criteria for dominant inheritance, the authors in their discussion quote the chapter by Winchester & Grossman (1971) and state that in some cases there may be recessive transmission of the disorder. In conclusion, it could be stated that, to date, no family studies have been published which would suggest an autosoma1 recessive form of cleidocranial dysostosis. From a genetic viewpoint our three patients representing two unrelated families are both offspring of closely consanguineous parents. Though neither family is related to the other, both originate from Iraq. It is important to know that the overall consanguinity rate among the Iraqi Jewish community is approximately 28 % while that of first cousin marriage is 17 % (GoldSchmidt et al. 1960). These rates are quite high when compared to the Ashkenazi Jewish community where the overall consanguinity rate is 2 % and that of first cousin about 1.5 % (Goldschmidt et al. 1960). Though other genetic disorders are specifically known in the Iraqi Jewish community, there is no evidence at present to suggest that cleidocranial dysostosis should be characterized according to such an ethnic distribution (Goodman, in press). Family studies were possible in both sets of parents and all surviving siblings of the probands. A physical examination and extensive roentgenographic studies were done in a11 of the previously mentioned family members and in none were there any findings suggestive of the disorder. One would therefore conclude that the presumed heterozygous carriers (both parents) do not display any physical features of the disorder.

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GOODMAN, TADMOR, ZARITSKY, AND BECKER

Fig. 4. A and B) Shows the proband (Family B) with a brachycephalic skull, ocular hypertelorism, excessive movement of the shoulders due to absence of the clavicles, kyphoscoliosis and lumbar lordosis. C) illustrates the hypoplasia of the toe nails.

CLEIDOCRANIAL DYSOSTOSIS

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Fig. 5. A) Anterior-posterior view of the skull showing an open anterior fontanelle, marked ocular hypertelorism and supernumerary teeth. 8 ) An X-ray of the spine showing spina bifida of the upper thoracic region with hemivertebrae at T-6 accounting for the severe kyphoscoliosis.

Family history was completely negative in both kindreds for other possibly affected individuals. It is of interest both genetically and clinically that all three patients have a very severe form of the disease. Each is below the third percentile for height and all have extensive and multiple sites of bony involvement. The extent of bony lesions can be noted in Table 1. Although this report is not primarily concerned with the bony manifestations in cleidocranial dysostosis, it is apparent from the literature that virtually the entire osseous system may be involved (Jarvis & Keats 1974). The similarity in clinical findings among our three patients accounting for a specific range of expressivity also speaks for recessive inheritance, in contrast to the wide

degree of expressivity observed in a dominant disorder and characteristically noted in the classical (dominant) form of cleidocranial dysostosis. Two clinical aspects pertaining to Family A should be mentioned. First, though mild mental retardation has occasionally been associated with this disease, severe mental retardation as found in the proband has to the best of our knowledge never been reported. There is the possibility that his mental retardation may not be related to the cleidocranial dysostosis, though no other etiological factor is apparent. Second, in such a family setting where both parents are presumed carriers, the question arises as to whether or not the two spontaneous abortions (Fig. 3) could at all be related to the disease in question. Certainly, much more

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GOODMAN, TADMOR, ZARITSKY, AND BECKER

00 0

4 males, 2 females.

CPO

Consanguinity

Normal male.female.

Affected male

@

Deceased.

0

Examined

8

Proband.

Fig. 6. Pedigree of Family 6.

information is needed before such a relationship could be established. For the sake of completeness, one could argue that these cases represent the dominant form of the disease, each representing a new mutation. However, it would be unlikely for two identical mutations to occur spontaneously in the same generation as occurred in Family A. Furthermore, in the presence of normal parents (clinically and radiographically) who are consanguineous the most likely mode of transmission is that of autosornal recessive inheritance. It is true, however, that the presence of only affected males raises the question of possible X-linked inheritance.

In trying to correlate the basic defect at a genetic level with the subsequent embryological alteration, certain known bits of information become of extreme interest. Various embryological mechanisms are known to account, at least in part, for the organization of cells into tissues and organs of well-defined shape and size. Embryonic induction and morphogenetic movements constitute two well-known mechanisms involved in such a process (Markert & Ursprung 1971). The former brings about specific types of differentiation by extrinsic, diffusible substances, while the latter relocates cells of different developmental fates with respect to each other and thus indirectly permits sequential transient influences to become effective. For example, it is thought that such malformations as spina bifida or cleft palate result from abnormal morphogenetic movements, whereas the absence of kidneys in renal agenesis may result from the failure of an inductive stimulus. From the descriptive information now available on cleidocranial dysostosis, it is apparent that this is a diffuse disease involving the formation and development of cartilage and bone. Viewing the three main anatomical sites of involvement (clavicles, skull and pelvis) from an embryological aspect, the absence or hypolasia of the clavicles could be explained by an alteration in embryonic induction, while failure in closure of the skull sutures and delay in development of the pelvic bones could be due to some missing or altered factor involving morphogenetic movements. Looking at the problem from a genetic viewpoint the recessive form of cleidocranial dysostosis may be due to some inborn error of metabolism. Perhaps the defect involves an altered or missing enzyme which does not allow for the proper formation of bone and cartilage through such mechanisms as embryonic induction or morphogenetic movement. One could further postulate that,

CLEIDOCRANIAL DYSOSTOSIS

in the dominant form of the disease, identical defects could be produced a t another genetic level involving either a regulatory or structural gene. Such a genetic defect would more easily explain the wide range of expressivity seen in the common autosoma1 dominant form of the disorder. In summary, we would propose that there are two genetic forms of cleidocranial dysostosis: the much more common form transmitted as a n autosomal dominant with a wide range of expressivity; and a much rarer type inherited as an autosomal recessive with consistently severe manifestations of the disease. Clinically, the recessive type may be characterized by dwarfism and extensive classical bony changes throughout the body. When a n individual is so affected and has normal parents who are consanguineous, such a form of cleidocranial dysostosis should be highly suspected. To carry this recessive form one step further, such a differentiation in types becomes of paramount importance t o the physician involved in genetic counselling. Whereas the risk of reoccurrence in the dominant form is 50 % when one parent is known to be affected, such a risk drops t o 25 % for heterozygous parents of a n affected child. Acknowledgments

We are grateful to Mrs. R. Bender of Mossad Gil for her kind cooperation in helping us to evaluate Family A, t o Prof. Y. Rotem and Dr. M. Frand f o r calling our attention to Case 2, and to Mrs. A. Goodman and Mrs. R. Grossman for their secretarial aid.

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References

Fitchet, S. M. (1929). Cleidocranial dysostosis: hereditary and familial. J . Bone Surg. 11, 838-866.

Goldschmidt, E. A., A. Ronen & I. Ronen (1960). Changing marriage systems in the Jewish communities of Israel. Ann. hum. Genet. 24, 191-204. Goodrnan,R. M. & R. J. Gorlin (1970). The Face in Genetic Disorder. St. Louis, C. V. Mosby Co. p. 44. Goodman, R. M. (1975). Genetic diseases among Jews. Modern Trends in Human Genetics, ed. Emery, A. E. H. London, Butterworth. In press. Herndon, C. N. (1951). Cleidocranial dysostosis. Amer. J . hum. Genet. 3, 314-324. Jarvis, L. J. & T. E. Keats (1974). Cleidocranial dysostosis, a review of 40 new cases. Amer. J. Roentgenol. 121,5-16. Lasker, G. W. (194.6). The inheritance of cleidocranial dysostosis. Hum. Biol. 18, 103-126. Markert, C. L. & H. Ursprung (1971). Developmental Genetics. Englewood Cliffs, N. J. Prentice-Hall. p. 208. Marie, P. & P. Sainton (1897). Observation d'hydrocCphalie hkreditaire (p6re et fils) par vice de developpement du crdne et du cerveau. Bull. me'm. SOC.mCd. h6p. Paris 14, 706. McKusick, V. A. (1971). Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive and X-Linked Phenotypes, 3rd ed. Baltimore, The Johns Hopkins Press. McKusick, V. A. (1972). Heritable Disorders of Connective Tissue. St. Louis, C. V. Mosby co. pp. 777-779. Newton, T. H. & D. G . Potts (eds.) (1971). Radiology of the skull and brain. The Skull, Vol. I, Book 2. St. Louis, C. V. Mosby Co. Sorsby, A. (1973). Clinical Genetics, 2nd ed. London, Butterworth, p. 194. Winchester, P. H. & H. Grossman (1971). Congenital skull dysplasias in radiology of the skull and brain. The Skull, Vol. I, Book 2, ed. Newton, T. H. & D. G. Potts. St. Louis, C. V. Mosby Co. p. 654. Address: R . M . Goodman, M . D . The Chaim Sheba Medical Center Tel-Hashomer Israel

Evidence for an autosomal recessive form of cleidocranial dysostosis.

Three cases of cleidocranial dysostosis from two unrelated consanguineous families are reported. The family setting, the distribution of the affected ...
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