American Journal of Medical Genetics 49308-312 (1994)

Brachyolmia: An Autosomal Dominant Form

Jessica Gardner and Peter Beighton MRC Unit for Medical Genetics, Department of Human Genetics, University of Cape Town, Medical School, Observatory 7925, South Africa

We have investigated a mother and son of South African Xhosa stock who presented with short-trunk dwarfism and kyphoscolio- sis. Radiographs show the marked platyspon- dyly and vertebral irregularity characteristic of brachyolmia. Our patients provide further evidence for the existence of an autosomal dominant form and supports the theory of heterogeneity in this rare group of genetic skeletal disorders. Molecular investigations in this South African family are currently un- derway but at present the basic defect of bra- chyolmia remains unknown. Q 1994 Wiley-Liss, Inc.

KEY WORDS: collagen, genetic, skeletal, spine

INTRODUCTION Brachyolmia is a heterogeneous group of rare genetic

disorders which manifest as short-trunk dwarfism. Ra- diological changes are essentially limited to the spine where there is generalized platyspondyly. In addition, in some instances, minor abnormalities may be present in the metaphyses of the long bones, especially in the femoral necks.

At least 2 types of autosomal recessive brachyolmia have been delineated and an autosomal dominant form has been described [Shohat et al., 19891. We have inves- tigated a mother and son with short-trunk dwarfism and severe vertebral abnormalities in whom the diag- nosis of autosomal dominant brachyolmia seems likely. The clinical and radiological manifestations in these persons differed to some extent from those previously documented in autosomal dominant brachyolmia and it is possible that there is even further heterogeneity in the disorder. Our findings are presented and discussed in this paper.

Received for publication May 11,1993; revision received August 12, 1993.

Address reprint requests to Professor P. Beighton, Department of Human Genetics, University of Cape Town, Medical School, Observatory 7925, Fkpublic of South Africa.

CLINICAL REPORTS The affected persons whom we investigated were OM,

a woman of Xhosa stock, born in 1962 and her son, LM, born in 1986 (Figs. 1 and 2). They lived in a remote rural region of the Transkei, South Africa and travelled to Cape Town seeking medical attention for their progressive spi- nal deformities. The mother was the youngest of 10 sibs; these persons, together with their own offspring and non- consanguineous parents, all had normal stature.

The mother, OM, developed a kyphoscoliosis in early childhood. Growth was impaired and she was always much smaller than her peers. Her health was good until 8 months before her visit to Cape Town, when she had developed lumbar back pain with mild weakness and paresthesia in her legs.

On examination in 1993 she was found to have short- trunk dwarfism with a marked mid-thoracic gibbus. She had a short neck and barrel chest, and her arms and legs appeared disproportionately long with respect to her trunk (height 125 cm, <3rd centile, upper segment 52 em, lower segment 75 cm, a rm span 164 cm). She had objective evidence of spinal cord compression, no- tably mild weakness of lower limbs, impaired sensa- tion, and brisk reflexes. There was no sphincter distur- bance and her intellect, eyes, and other bodily systems were normal.

The son, LM, born in 1986, was delivered by Cae- sarian section because of cephalopelvic disproportion. At birth he weighed 4.2 kg but his length was not re- corded. His early development was uneventful and his mother first noticed his spinal deformity at age one year. This abnormality progressed to an obvious ky- phoscoliosis associated with short stature. He remained asymptomatic and his general health was unimpaired. When examined in Cape Town in 1993, he was found to be dwarfed with a short trunk, wide chest, and a marked lower thoracic kyphoscoliosis (height 109 cm, upper seg- ment 52 cm, lower segment 57 cm, span 112 cm, head circumference 57.5 cm). There were no limb or gait ab- normalities and no localizing neurological signs. His intelligence was normal and he had no minor facial anomalies. His eyes were clinically normal and there was no evidence of any visceral ramifications.

Radiographic Findings The spinal radiographs ofbothmother and son showed

kyphoscoliosis and universal platyspondyly with marked

0 1994 Wiley-Liss, Inc.

Brachyolmia 309

Fig. 1. The affected mother and son; severe, short-trunk dwarfism Fig. 2. The affected mother and son. Both have obvious mid- is evident. thoracic kyphoscoliosis.

flatness ofthe cervical vertebra (Figs. 3-6). In the mid- thoracic regions anterior vertebral wedging was evident in the region of the gibbus. The vertebral bodies had irregular Eoncavities on their superior, inferior and an- terior surraces in parent and child. Nuclear magnetic imaging o F the son’s spine excluded tuberculous involve- ment.

Radiographs of the long bones demonstrated moder- ately severe metaphyseal changes in the upper femora with some shortness of the femoral necks in mother and son (Figs. 7 and 8). Some irregularities of the acetabula were also present. The long bones were otherwise nor- mal, as ww bone age. In distinction to other forms of brachyolm ia, there was no precocious calcification of the falx cereb ri or costal cartilages.

Laboratory Findings Full blood count, ESR, and routine biochemical inves-

tigations yielded normal results for both affected per- sons. Chromosomes were normal (46,XX and 46,XY).

DISCUSSION There has been considerable debate concerning the

syndromic status of brachyolmia. Following an investi- gation of 1 1 affected persons from 6 families and a re- view of the literature, Shohat et al. 119891 proposed the

existence of 3, or possibly 4, forms of brachyolmia. These include the autosomal recessive Hobaek, Toledo and Maroteaux types, together with an autosomal dominant form. These conditions all share the major manifesta- tions of short-trunk dwarfism with predominant ver- tebral involvement. The independent syndromic status of the autosomal recessive (MIM 271530) and the auto- soma1 dominant (MIM 113500) types seems likely but these conditions had not received the confirmatory as- terisk in the tenth edition of McKusick’s “Mendelian Inheritance in Man” [McKusick 19921.

The presence of brachyolmia in multigeneration fami- lies is strongly suggestive of autosomal dominant inher- itance and there is little doubt concerning the autonomy of this entity. Maroteaux [1979] drew attention to this form of the disorder. Shohat et al. 119891 subsequently documented an affected mother and son. Other possible earlier examples of the condition with generation to generation transmission which can be recognized in the literature include reports by Brown and McDonald [1933] (mother and 2 daughters), Lomas and Boyle 119591 (3 generations), and Lenz 119641 (father and son). The syndromic status of autosomal dominant brachy- olmia now seems to be firmly established. The clinical and radiographic manifestations of the affected mother and son reported by Shohat et al. 119891 were very simi-

310 Gardner and Beighton

Fig. 4. LM age 6 years. Lateral radiograph of the lumbar spine showing marked platyspondyly and superior, inferior, and anterior concavity of the vertebral bodies.

Fig. 3. OM age 31 years. Lateral radiograph of the lumbar and lower thoracic spine, showing a gross gibbus. The vertebral bodies are flat with coneavity of their superior, inferior, and anterior surfaces.

Fig. 5. LM age 6 years. Lateral spinal radiograph, coned view, showing anterior and vertebral wedging at the apex of the gihbus.

Brachyolmia 311

lar to those of the persons whom we have studied, al- though the South African patients differed in terms of the severity of their platyspondyly and the shape of their vertebral bodies. At this stage i t is uncertain whether these observations are indicative of further hetero- geneity or merely represent variation of phenotypic ex- pression.

Kozlowski et al. 119821 pointed out that minor meta- physeal changes were invariably present in persons di- agnosed as having brachyolmia, and they contended that this disorder should be regarded as a form of spond- ylometaphyseal dysplasia. Maroteaux and Spranger 119911, in their tentative classification of the spondylo- metaphyseal dysplasias, also commented that their type B2 category was “close to brachyolmy.” While their assertions are probably semantically correct, the fact that significant abnormalities are virtually confined to the spine in the brachyolmias argues for acceptance of the independent identify of this disorder. Indeed, the designation “brachyolmia” is now enshrined in the liter- ature and accepted in general usage. Furthermore, the term “brachyolmia” has been promulgated in the Inter- national Classification of Osteochondrodysplasias [Spranger, 19921 and any attempt a t nosological mod- ification would only engender confusion.

Fig. 6. LM age 6 years. Lateral radiograph of the cervical spine. Flattening of the vertebral bodies is extreme.

Fig. 7. OM age 31 years. Anteroposterior view of the pelvis and hip joints. The femoral necks are very

LM age 6 years. Anteroposterior radiograph of the pelvis and hips. The femoral necks are short

short with a varus deformity.

and their metaphyseal regions are irregular, with areas of patchy lucency and sclerosis. Fig. 8.

The basic defect in the brachyolmias is unknown. In the autosomal recessive Hobaek form, Horton et al.

less, the underlying abnormality in the autosomal dominant form has not vet been elucidated.

[19831 identified enlarged chondrocyte lacunae and ex- cessive collagen aggregation in their histoloeical inves- ACKNOWLEDGMENTS

I -I I

tigation of growth plate material obtained at iliac crest biopsy. There has also been a hint of disordered mu- copolysaccharide metabolism in some persons with au- tosomal recessive types [Toledo et al., 19781; neverthe-

We are grateful to Gillian Shapley for typing the manuscript with her usual efficiency. Our work was supported by grants from the Medical Research Council of South Africa, the Harry Crossley Foundation, the

312 Gardner and Beighton

Mauerberger Foundation, and the University of Cape Town Staff Research Fund.

REFERENCES Brown DO, McDonald C (1933): Three cases of familial osseous dystro-

phy. Aust New Zeal J Surg 3:78-88. Horton WA, Langer LO, Collins DL, Dwyer C (1983): Brachyolmia,

recessive type (Hobaek): A clinical, radiographic and histochemical study. Am J Med Genet 16:201-211.

Kozlowski K, Beemer FA, Bens G, Dijkstra PF, Iannaccone G, Emons D, Lopez-Ruiz P, Masel J, van Nieuwenhuizen 0, Rodriguez-Barrio- nuevo C (1982): Spondylo-metaphyseal dysplasia: Report of 7 cases and essay ofclassification. In: Papadatos CJ and Bartsocas CS (eds): “Skeletal Dysplasia.” New York: Alan R Liss, pp 89-101.

Lenz W (1964): Anomalien des Wachstums und der Korperform. In Becker PE (ed): “Hamangenetik. Ein kurzes Handbuch in Funf Banden,”Vol2. Stuttgart: Georg Thieme Verlag, pp 88-89 (Fig. 30).

Lomas JJP, Boyle AC (1959): Osteo-chondrodystrophy (Morquio’s dis- ease) in three generations. Lancet 2:430- 432.

Maroteaux P (1979): “Bone Diseases of Children.” Philadelphia: Lippincott, pp 81-82.

Maroteaux P, Spranger J 11991): The spondylometaphyseal dysplasias. A tentative classification. Pediatr Radio1 21:293-297.

McKusick VA (19921: “Mendelian Inheritance in Man: Catalogues of Autosomal Dominant, Autosomal Recessive and X-Linked Phe- notypes,” 10th ed. Baltimore: Johns Hopkins University Press.

Shohat M, Lachman R, Gruber HE, Rimoin D (1989): Brachyolmia: Radiographic and genetic evidence of heterogeneity. Am J Med Genet 33:209-219.

Spranger J (1992): International classification of osteochondro- dysplasias. Eur J Pediatr 151:407-415.

Toledo SPA, Mourao PAS, Lamego C, Alves CAR, Dietrich CP, Assis LM, Mattar E (1978): Recessively inherited, late onset spondylar dysplasia and peripheral corneal opacity with anomalies in urinary mucopolysaccharides: A possible error of chondroitin-6-sulphate synthesis. Am J Med Genet 2385-395.