Spondyloepiphyseal Dysplasia With Congenital Joint Dislocations

A number sign (#) is used with this entry because of evidence that spondyloepiphyseal dysplasia with congenital joint dislocations (SEDCJD) is caused by homozygous or compound heterozygous mutation in the gene encoding carbohydrate sulfotransferase-3 (CHST3; 603799) on chromosome 10q22.

Description

Although patients with mutations in the CHST3 gene may initially be given varying diagnostic labels, they have similar clinical features, including dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The disorder is usually evident at birth, with short stature and multiple joint dislocations or subluxations that dominate the neonatal clinical and radiographic picture, and affected individuals may receive an initial clinical diagnosis of Larsen syndrome (see 245600) or humerospinal dysostosis. During childhood, the dislocations improve, both spontaneously and with surgical treatment, and features of spondyloepiphyseal dysplasia become apparent, leading to arthritis of the hips and spine with intervertebral disc degeneration, rigid kyphoscoliosis, and trunk shortening by late childhood; at this stage, the clinical features are those previously described as the Omani type of SED (summary by Unger et al., 2010).

Clinical Features

Kozlowski et al. (1974) described 2 half sibs with an unusual skeletal dysplasia of which short humerus with distal bifurcation was one of the more striking features. Other features included coronal cleft vertebrae, subluxation in the elbow joints, shortening and hypotubulation of the long bones of the legs, widened iliac bones, and talipes equinovarus. Both children, brother and sister, had congenital heart disease from which 1 died at the age of 7.5 months. Kozlowski et al. (1974) suggested that the disorder was inherited as a 'dominant trait with variable penetrance.' They stressed, however, that it was not certain that the children had different fathers or that the father or fathers were normal.

Cortina et al. (1979) reported a 2-year-old boy with humeral bifurcation, elbow subluxation, and coronal cleft vertebrae. The patient had a cardiac murmur, but cardiac status was not fully investigated.

Hall (1997) reported a 6-month-old boy with short limbs, limited movement at elbow joints, dislocated right knee, and bilateral talipes equinovarus, who also had small thick ears and hypertelorism. Radiography showed short, mildly bowed long bones, slight widening of metaphyses, dislocated right knee, mild platyspondyly with partially fused coronal clefts in the thoracolumbar vertebrae, bifid distal humeri, generalized brachydactyly, and mildly thin ribs. Evaluation of a heart murmur by electrocardiography demonstrated a thickened mitral valve.

Rajab et al. (2004) described what appeared to be a distinct type of spondyloepiphyseal dysplasia (SED) in a large inbred kindred in Oman. They evaluated 8 individuals from 2 consanguineous sibships, 1 male and 7 females between ages 2 and 22 years. The families were thought to be related through distant consanguineous loops. The clinical features included near to normal length at birth, short stature with final adult height of 110 to 139 cm, shortening of the upper segment due to severe progressive kyphoscoliosis, severe arthritic changes with joint dislocations, rhizomelic limbs, genu valgum, cubitus valgus, mild brachydactyly, camptodactyly, microdontia, and normal intelligence. Radiologic studies showed minor metaphyseal changes but major manifestations in the spine and the epiphyses. During the first year of life, the vertebral bodies were of normal height, but the endplates were irregular and the intervertebral space was narrow. With age, the vertebral endplates became increasingly irregular, the intervertebral space diminished further, and individual vertebrae started to fuse, resulting in a severe short-trunk dwarfism with kyphoscoliosis. The epiphyses were small, and precocious osteoarthropathy involving small and large joints was observed; the elbow, wrist, and hip joints were affected starting in infancy and showed restricted movement. Osteoarthropathy and spinal involvement resulted in physical handicap by early adulthood. Rajab et al. (2004) designated this disorder 'spondyloepiphyseal dysplasia, Omani type.'

Megarbane and Ghanem (2004) reported a 5-year-old Lebanese boy with severe pre- and postnatal short stature, disproportionately short limbs, and multiple joint dislocations including left hip, knees, and radial heads. Other features included a frontal cowlick, high-arched palate, flat nape, and pectus excavatum. Radiologically he had anisospondyly with coronal clefts of the thoracolumbar vertebrae, subluxation of the radial heads, bilateral hip dislocation, hypoplastic left capital femoral epiphysis, short femoral necks, diffuse osseous demineralization, and delayed bone age.

Perez-Aytes et al. (2005) reported a case of humerospinal dysostosis in a boy who was born with rhizomelic shortening of limbs and talipes equinovarus. X-ray findings showed short long bones, vertebral coronal clefts, and distal humeral bifurcation. At 2 years of age, he had short stature, a short thorax, limitation of elbow extension, and genua valga. Psychomotor development was within normal limits. Perez-Aytes et al. (2005) also provided follow-up information on the patient reported by Cortina et al. (1979). At 27 years of age, he had undergone multiple orthopedic surgical interventions primarily for leg deformities. He had severe spine deformities, a short thorax, and limited movement of the elbow joints. His intellectual development was normal, and he worked as a computer expert. There was no cardiac involvement in either patient.

Megarbane (2007) reported a 5-year-old Lebanese girl, born of first-cousin parents, who had severe pre- and postnatal short stature, bilateral dislocation of hips, knees, and elbows, and right clubfoot. Skeletal investigation disclosed an anisospondyly, absence of ossification of the odontoid apophysis, incomplete fusion of the neural arches of the cervical vertebrae, abnormal L3 and L4 vertebrae, partial agenesis of the coccyx, abnormal and subluxated radial heads, bilateral dislocation of the hips, dysplastic acetabula, pseudoacetabula, hypoplasia of the femoral heads, short femoral necks, short long bones with thin diaphyses, widening of the medullary canal and thinning of the cortical canal, slightly enlarged metaphysis, and diffuse osseous demineralization. Bone age was delayed. Megarbane (2007) noted similarities to the features of an unrelated 5-year-old Lebanese boy originally reported by Megarbane and Ghanem (2004) and provided follow-up on the boy at 9 years of age. On x-ray, in addition to previously described findings, he had narrow disc spaces at C3-C4 and C4-C5, subluxation of C4-C5, marked lumbar lordosis and dorsal kyphosis, herniation of the discs of the dorsolumbar spine, irregular vertebral endplates of the vertebrae of the thoracolumbar spine, lumbar spina bifida occulta, abnormal carpal bones with extra-carpal bones on the left hand, abnormal tarsal bones, accessory medial cuneiforms, slightly flared metaphyses, and abnormal epiphyses.

Van Roij et al. (2008) studied 2 Turkish sibs, born of second-cousin parents, with progressive spondyloepiphyseal dysplasia from early childhood. The authors stated that several elements of their clinical presentation differed significantly from the original description of the disorder and suggested that the clinical phenotype should be extended to include congenital joint dislocation, clubfoot, ventricular septal defect, deafness, markedly variable metacarpal shortening, and accessory carpal ossification centers.

Tuysuz et al. (2009) reported a 13-year-old girl and her 11.5-year-old brother, born of consanguineous Turkish parents, who had parogressive skeletal dysplasia with severe spinal involvement, short stature, and premature arthrosis and joint contractures, features consistent with the 'Omani type' of spondyloepiphyseal dysplasia. The sibs also displayed mild facial dysmorphism not previously described in Omani SED, including a broad forehead, mild hypertelorism, sparse and high-arched eyebrows, long philtrum, and small cystic ears. Both patients had systolic murmurs; echocardiography revealed mild mitral regurgitation in the sister, and moderate mitral, tricuspid, and aortic regurgitation in her brother. Their 33-year-old paternal uncle, born of consanguineous parents, was also affected and had a similar facial appearance associated with severe short-trunk dwarfism, pectus carinatus, severe kyphoscoliosis, prominence of large joints, and short fourth metacarpals bilaterally. Limited extension of the elbow, hip, and knee joints, precocious osteoarthropathy of the hip joints, genu valgum, hallux valgus, and pes planus were also noted. Evaluation of a systolic murmur by echocardiography revealed moderate mitral, tricuspid, and aortic regurgitation and aortic stenosis. Radiographically the patients had irregularity of vertebral endplates, scoliosis, and narrowing of the intervertebral spaces, which in the uncle had progressed to absence of intervertebral spaces with subsequent fused vertebrae and severe kyphoscoliosis. In addition, the patients had small, irregular epiphyses in the limbs, subluxation of elbow joints, big femoral epiphyses, and irregular, small tibial epiphyses. The hands showed irregular, small, and accessory carpal ossification centers, brachydactyly, and bilateral metacarpal shortening of the third and fourth fingers in the sister and of the fourth finger in the uncle.

Tanteles et al. (2013) reported 2 Somalian half sibs with CHST3-associated chondrodysplasia who demonstrated the intrafamilial variability of the disorder. The proband was a 14-year-old girl who presented at 5.5 years of age with short stature and genua valga. Her mother did not recall congenital joint dislocations. The girl had marked restriction of forearm pronation, fixed flexion deformities at the hips, stiff spine with minimal lumbar flexion, and thoracic kyphosis with mild scoliosis. Her clinical course was characterized by rapid progression of spinal deformities and large joint contractures, and she was using a wheelchair most of the day by age 10. Her 3-year-old maternal half brother presented at birth with bilateral knee dislocation and talipes equinovarus. He had marked lumbar lordosis at age 2 years but no evidence of scoliosis. Both patients exhibited high anterior hairline, thick eyebrows, hypertelorism, and conductive hearing loss; the girl also had mild mitral valve regurgitation.

Mapping

Using genomewide linkage analysis in the consanguineous Omani kindred with spondyloepiphyseal dysplasia originally described by Rajab et al. (2004), Thiele et al. (2004) mapped the underlying gene to a 4.5-cM interval on chromosome 10q23.

Molecular Genetics

In affected members of the consanguineous Omani kindred with spondyloepiphyseal dysplasia originally described by Rajab et al. (2004), Thiele et al. (2004) identified homozygosity for a missense mutation in the CHST3 gene (R304Q; 608637.0001). They concluded that this form of SED is caused by deficiency in a specific sulfation of chondroitin sulfate side chains.

Hermanns et al. (2008) identified homozygosity or compound heterozygosity for 9 different mutations in the CHST3 gene (see, e.g., 603799.0002-603799.0006) in 6 unrelated patients born with joint dislocations, including 3 patients who carried a diagnosis of recessive Larsen syndrome (245600) and 3 who had been diagnosed with humerospinal dysostosis (HSD); 1 of the latter patients (see 603799.0005) was the boy originally reported by Cortina et al. (1979). None of the patients had the typical flattened facies of Larsen syndrome. Hermanns et al. (2008) stated that the single feature most useful in recognizing CHST3 deficiency seemed to be dysostotic changes in the thoracolumbar spine, namely, widening of the interpedicular distance at L1 on anteroposterior projection and the short and cleft vertebral bodies on lateral projection, which was seen in their patients and was mentioned by both Kozlowski et al. (1974) and Cortina et al. (1979) in their descriptions of HSD; Hermanns et al. (2008) noted that this radiologic feature was also recognizable in Figure 1 of the report on Omani-type SED by Rajab et al. (2004). Given the relatively narrow phenotypic spectrum of these conditions, Hermanns et al. (2008) suggested that the disorders previously designated as Omani-type spondyloepiphyseal dysplasia and humerospinal dysostosis, as well as some patients given a diagnosis of recessive Larsen syndrome, might represent different age-related descriptions of the same condition.

In 2 Turkish sibs with spondyloepiphyseal dysplasia and joint dislocations, born of consanguineous parents, van Roij et al. (2008) identified homozygosity for a missense mutation in the CHST3 gene (L286P; 603799.0007). In contrast to the consistent widening of the interpedicular distance at L1 seen in the patients studied by Hermanns et al. (2008), both sibs had narrowing of the interpedicular distance in the lumbar region.

In 2 sibs with spondyloepiphyseal dysplasia and their affected uncle from a consanguineous Turkish pedigree, Tuysuz et al. (2009) identified homozygosity for a missense mutation in the CHST3 gene (T141M; 603799.0009). In contrast to the multiple congenital joint dislocations reported in other patients with CHST3 mutations, these patients had only elbow joint dysplasia with radial subluxation and limitation of extension. Tuysuz et al. (2009) noted that their patients also had accessory carpal ossification centers and variable metacarpal shortening similar to the Turkish sibs described by van Roij et al. (2008).

Unger et al. (2010) identified homozygous or compound heterozygous mutations in CHST3 in patients with spondyloepiphyseal dysplasia and congenital joint dislocations from 17 families. The patients had presented with various diagnoses, including 15 who had been diagnosed with Larsen syndrome (see, e.g., 603799.0011 and 603799.0012), 2 with chondrodysplasia with multiple dislocations (previously reported by Megarbane and Ghanem, 2004 and Megarbane, 2007; see, e.g., 603799.0002), 1 with humerospinal dysostosis (originally reported by Hall, 1997; see 603799.0010), 1 with Desbuquois syndrome (see 251450), and 1 with spondyloepiphyseal dysplasia. Unger et al. (2010) reviewed the features of these patients and the 6 patients previously found to have mutations in CHST3 by Hermanns et al. (2008), and stated that the clinical and radiographic pattern of joint dislocations, vertebral changes, normal carpal age, lack of facial flattening, and recessive inheritance is characteristic and distinguishes CHST3 deficiency from other disorders with congenital dislocations.

In 2 Somalian half sibs with chondrodysplasia, Tanteles et al. (2013) identified homozygosity for a missense mutation in the CHST3 gene (603799.0013). Their unaffected parents were heterozygous for the mutation; the sibs had different fathers, who both originated from the same village.

History

Distal humeral bifurcation was noted in association with humeroradioulnar synostosis and tridactylous ectrosyndactyly by Gollop and Coates (1983) and Leroy and Speeckaert (1984). This is presumably a separate disorder.