Arthro-dento-osteo dysplasia (Hajdu-Cheney syndrome)

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  • Z. Kinderheilk. 114, 93 110 (1973) 9 by Springer-Verlag 1973

    Arthro-Dento-Osteo Dysplasia (Uajdu-Cheney Syndrome)*

    Review of a Genetic "Acro-Osteolysis" Syndrome

    Jfirgen Herrmann

    University of Wisconsin Center for HteMth Sciences - - Medical School, Madison, Wisconsin 53706, USA

    Frederick T. Zugibe

    Department of Pathology, Columbia University, New York, N.Y., USA

    Enid F. Gilbert and John M. Opitz

    University of Wisconsin Center for ttealth Sciences Medical School, Madison, Wisconsin 53706, USA

    Received December 6, 1972

    Abstract. From one personal patient and thirteen reported in the literature, arthro-dente-osteo dysplasia (ADOD) is defined as a heritable connective tissue disorder with the main clinical manifestations of laxity of joints, early loss of teeth, and multiple osteolytic lesions, including acro-osteolysis, on roentgenographic examination. These lesions are likely to represent "pseudo-osteolysis" with faulty primary bone formation rather than true osteolysis of previously normal bone.

    ADOD is an example of relational pleiotropism with most elhlical manifestations representing secondary effects and deformities. The cranial sutures frequently re- main uncalcified and contain multiple Wormian bones. Secondary deformities may be progressive and affect primarily the skull, spine, fingers and fingernails. Patho- logic fractures are clinically the most important manifestation of ADOD.

    In one family the mother and four of her six children were affected. The other nine ease reports describe sporadic instances. ADOD is presumed to be caused by an autosomal dominant gene, the sporadic cases representing new mutations.

    Key words: Connective tissue dysplasia - - Generalized skeletal dysplasia - - Osteolysis - - Aero-osteolysis - - Joint laxity - - Loss of teeth - - Autosomal dominant inheritance Relational pleiotropism.

    Introduction

    Acro-osteolysis is primari ly a roentgenologie concept and term apphed to apparently osteolytie lesions of hands and feet, particularly the distal phalanges. In the context of this paper true acro-osteolysis refers to decreased bone density and apparent loss of substance in bones known or presumed to have been previously normal. Circumseript, local lesions may be due to physical or ehemicM injuries (burns, electric shock, frostbite,

    * Studies supported by PHS/NIH Grants GM 15422 and 1 K04 I-ID-18982. This paper is contributed in part as paper number 1566 of the University of Wisconsin Genetics Laboratory.

    7 Z. K inderhe i l k . , ]~d. 11~

  • 94 J. I-Ierrmann et al. : Arthro-Dento-Osteo Dysplasia

    polyvinylchloride exposure), denervation, infections and tumors. Sym- metric, non-specific acro-osteolytic lesions in hands and feet occur in systemic disorders such as epidermolysis bullosa, seleroderma, hyper- parathyroidism and others. The pathogenetie relationship of the aero- osteolytic manifestations to the underlying cause is not equally well understood in all conditions.

    I t is becoming evident that apparent acro-osteolysis is not always true osteolysis with pathologically increased bone destruction. Genetic forms of aero-osteolysis appear particularly likely to include conditions of decreased and/or faulty primary bone formation with roentgenographic lesions appearing as "acro-osteolysis". Examples of such "pseudo- osteolysis" are progeria [15] and pycnodysostosis [18] and the van Bogaert-Hozay syndrome [16]. In these conditions the roentgenographic lesions are symmetrical, and patients have other "osteolytic" lesions in addition to those in the distal phalanges. The lesions may be apparently progressive. However, in this case progression occurs in a skeleton that

    already is abnormal. There probably is a distinct relationship between the primary abnormality and the rate and kind of progression. Progeria, pycnodysostosis and the van Bogaert-Hozay syndrome are caused by the homozygous state of three different autosomal recessive mutant genes.

    A further "pseudo-osteolysis" syndrome has been reported under different names [2--4, 7, 9, 10, 14, 17], and consists of joint laxity, early loss of teeth, osteo- porosis and progressive deformities of the skull, spine and digits. A patient with this rare condition was re- ported recently in detail [19] and is cited briefly in this paper. An analysis of the phenotypic spectrum and of the genetics is based on the present ease and those reported in the literature.

    Fig. 1. Propositus at age 10 years: shortness of sta- ture, hirsutism; peculiar facial ap- pearance; genua

    valga

    Case Report

    A 10-year-old boy presented because of shortness of stature (< 3rd percentile), peculiar facies, hirsute forehead, long eyebrows and lashes, prominent supraorbital ridges, hyper- telorism, micrognathia, highly arched palate, ~hick tongue, and stenotic ear canals (Fig. 1). Several teeth were loose and some were absent. He had a grade 2/6 systolic murmur along tile left sternal border, and coarse r~les and expiratory wheezes. The liver was palpated 2 cm below the right costal margin and the spleen tip was felt on deep inspiration. Pro- minence of the lumbar spinous processes was noted. The fingers appeared to be shortened, particularly distally, and

  • left right

    left right Fig. 2a and b. Roentgenogram of hands at age 10 (a) and 14 (b) years: "acro-osteo- ]ysis"; non-calcified epiphyseal lines; multiple circumscript radiolucencies in meta- carpals, carpals and forearm bones; plump modelling of fifth metacarpals; campto- dactyly of both index and the left middle fingers at age 14 years. (Courtesy of

    Dr. F. N. Silverman)

    7*

  • 96 J. Herrmann et al. :

    Fig. 3. Roentgenogram of feet at age 14 years: "acro-osteolysis'; plump modelling; transverse liaear radiolueeney in both fifth metatarsals. (Courtesy of Dr. F. N. Silver-

    man)

    dubbing of the fingertips was significant. The skin was coarse and thick. Mild atepie dermatitis was present. The voice was low-pitched and speech was slurred. Neurologic examination was otherwise normal.

    Pregnancy, delivery and development had been normal. Bilateral inguinal herniae and an umbilical hernia were repaired in infancy. Repeated fractures involved the right leg, and the left arm, fifth finger and ankle. At an early age the parents noticed the peculiar facies, hirsutism, loose joints, and recurrence of resph'atory infections. At one time the diagnosis of the Hurler syndrome had been considered. No similarly affected family members are known, and one brother and two sisters are well. The father has clinical symptoms and radiographic signs con- sistent with Marie-Strfimpel disease (Dr. !~. N. Silverman, Cincinnati).

    Laboratory data revealed normal values for urinalysis and hemogram, and for serum levels of potassium, calcium, phosphorus, alkaline phosphatase, fasting blood sugar, immunoglobulins, proteins, and thyroxin. The erythroeyte sedimentation rate was 38 mm/hr. VDI~L was non-reactive. A urinary amino acid determination showed slight increase in beta amino-isobutyric acid. Term amino acid excretion was within normal limits. A 24-hour urine did not contain significantly increased

  • Arthro-Dento-Osteo Dysplasia 97

    Fig. 4. Lateral skull roentgenogram at age 10 years: normal thickness of calvarium with increased translucency; dolichocephaly; multiple Wormian bones; non- calcification of sutures including of the parieto-temporal suture; elongated posterior cranial fossa; enlarged and shallow pituitary fossa; absent frontal sinuses; hypo-

    plastic maxilla and mandible

    amounts of mucopolysaccharides. Liver secured fresh by needle biopsy did not contain histochemically demonstrable soluble acid mucopolysaccharides, and no pathologic changes were noted with hematoxylin and eosin and PAS staining. May- Griinwald-Giemsa stained smears did not demonstrate Reilly bodies in the peripheral lymphocytes. Slit lamp examination did not uncover corneal opacities. Mild to moderate bilateral hearing loss in the lower frequency ranges and a mild perceptive type hearing loss at 8000 Hz was demonstrated. An intelligence quotient of 86 was obtained on the Stanford-Binct test. The chromosomes appeared normal.

    Recently, at the age of 14 years, this patient was studied at the Children's Hospital in Cincinnati, Ohio, under the direction of Drs. Warkany and Silverman.

    Roentgenographic examination at 10 and at 14 years of age reveMed multiple abnormalities. "Acro-osteolytie" lesions in the hands (Fig. 2) and feet (Fig. 3) were striking, but represent only one aspect of a generalized skeletal dysplasia present in this patient. Generalized osteoporosis was marked. There was nonealcification of cranial sutures and epiphyseal lines, and there was no progression of calcification between 10 and 14 years of age. Difference in technique of the skull roentgenograms at 10 and 14 years did not allow for quantitative evaluation of the progression of the skull deformity. However, it was apparent (Figs. 4 and 5) that progressive basilar invagination led to elongation of the posterior cranial fossa, to increasing

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