Spondyloepimetaphyseal Dysplasia With Joint Laxity, Type 1, With Or Without Fractures

A number sign (#) is used with this entry because spondyloepimetaphyseal dysplasia with joint laxity type 1 with or without fractures (SEMDJL1) is caused by homozygous or compound heterozygous mutation in the B3GALT6 gene (615291) on chromosome 1p36.

Mutation in the B3GALT6 gene also causes a spondylodysplastic type of Ehlers-Danlos syndrome (EDSSPD2; 615349), which has overlapping features with SEMDJL1.

Description

Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) is characterized by vertebral abnormalities and ligamentous laxity that result in spinal misalignment and progressive severe kyphoscoliosis, thoracic asymmetry, and respiratory compromise resulting in early death. Nonaxial skeletal involvement includes elbow deformities with radial head dislocation, dislocated hips, clubfeet, and tapered fingers with spatulate distal phalanges. Many affected children have an oval face, flat midface, prominent eyes with blue sclerae, and a long philtrum. Palatal abnormalities and congenital heart disease are also observed (summary by Smith et al., 1999). Patients with a similar phenotype and fractures have been described (Malfait et al., 2013).

Genetic Heterogeneity of Spondyloepimetaphyseal Dysplasia with Joint Laxity

Also see SEMDJL2 (603546), caused by mutation in the KIF22 gene (603213) on chromosome 16p11, and SEMDJL3 (618395), caused by mutation in the EXOC6B gene (607880) on chromosome 2p13.

Nomenclature

The International Nosology and Classification of Constitutional Disorder of Bone initially described two disorders of SEMD with dislocation and joint laxity: SEMDJL (Beighton type) and SEMD with multiple dislocations, the Hall or leptodactylic type (Hall et al., 1998). However, in the 2006 revision of Nosology and Classification of Genetic Skeletal Disorders, the Nosology Group of the International Skeletal Dysplasia Society proposed the use of the united term 'joint laxity' instead of the term 'multiple dislocations' (Superti-Furga et al., 2007). These included 2 conditions: SEMDJL-Beighton type (designated SEMDJL1 in OMIM) and SEMDJL-leptodactylic or Hall type (designated SEMDJL2 (603546) in OMIM).

Clinical Features

Beighton and Kozlowski (1980) described a distinctive form of spondyloepimetaphyseal dysplasia with joint laxity and severe scoliosis in patients in South Africa. Beighton et al. (1984) reviewed the findings in their total series of 18 cases, which included 2 girls followed for more than a decade. They showed that 3 affected sibships with a total of 4 affected persons, although ostensibly unrelated, in fact had common antecedents. This and other findings of affected sibs support autosomal recessive inheritance. Cleft palate was present in several. The facies were described as typical: oval face, prominent eyes, long upper lip, small mandible, and blue sclerae. Joint laxity was especially striking in the hands, with foreshortened fingernails and spatulate terminal phalanges. Kyphoscoliosis developed at an early age and was progressive. Clubfoot and dislocated hip were present at birth in several. Some patients died in infancy apparently of cardiac malformation. One child had dislocated lenses.

Farag et al. (1987) described an Arab family with consanguineous parents in which 6 of 9 children had a form of spondyloepimetaphyseal dysplasia resembling that described by Beighton et al. (1984). For example, cleft palate was present in all and a striking facies with long philtrum was described. A striking feature in these cases, however, was dumbbell-shaped long bones resulting from a flaring of the metaphyses. This feature suggested Kniest disease (156550), but because of the different inheritance and some radiologic differences, the authors suggested that the disorder was distinct.

Bradburn and Hall (1995) reported a child of Guatemalan descent with this disorder. The patient had an oval face, prominent eyes, and blue sclerae, as well as high-arched palate, pectus carinatum, severe scoliosis, and hyperextensibility and instability of most joints, with limited extension and supination of the elbows. Radiograms showed severe scoliosis, a 'bat-like' appearance of the iliac bones, dysplastic acetabulum, minimal metaphyseal and epiphyseal abnormalities at the knees, and generalized brachydactyly of the hands and feet. The metacarpals were particularly short with distal enlargement of the metaphyses.

Pina-Neto et al. (1996) described a Brazilian case.

Beighton (1994) reported that malalignment of the spine is refractory to treatment. External bracing is usually ineffective and internal fixation is often necessary. Despite these measures, a significant proportion of affected patients develop spinal cord compression and paraplegia. According to Beighton (1994), most patients die in the first or second decade. No affected person over the age of 25 years had been reported.

Smith et al. (1999) reported the physical and radiographic findings in 2 unrelated North American patients with SEMDJL. They noted that diagnosis in infancy may be difficult because many of the typical findings are not apparent early and only evolve over time.

Tsirikos et al. (2003) described a patient with SEMDJL who presented with all the characteristic orthopedic manifestations of the disorder, requiring multiple operative procedures. The 35-year-old patient had the longest reported follow-up and survival into adulthood with a favorable outcome. Tsirikos et al. (2003) described the clinical and radiographic findings that allow an early diagnosis, the precision of which is of vital importance considering the potentially lethal spinal and pulmonary complications in early childhood.

Nakajima et al. (2013) described 8 members of 6 unrelated families (5 Japanese, 1 Singapore Japanese, and 1 Vietnamese) with SEMDJL1. All 8 patients had characteristic skeletal abnormalities of the disorder, including platyspondyly, short ilia, and elbow malalignment. Some also had a range of extraskeletal and connective tissue abnormalities that overlapped with those seen in the progeroid form of Ehlers-Danlos syndrome (see EDSP2, 615349).

Malfait et al. (2013) described affected members of 3 unrelated Iranian families with a severe autosomal recessive disorder characterized by skin fragility, delayed wound healing, joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and a spondyloepimetaphyseal dysplasia with bone fragility, multiple early-onset fractures, and severe kyphoscoliosis. The authors described the disorder as a 'pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder.'

Inheritance

Spondyloepimetaphyseal dysplasia with joint laxity type 1 is an autosomal recessive disorder (Beighton et al. (1983, 1984)).

Torrington and Beighton (1991) found that all of 8 Afrikaans-speaking families with SEMDJL had ancestral links with 2 females who had multiple marriages and cohabitations during the late 17th and early 18th centuries.

Mapping

SEMDJL1 is caused by mutation in the B3GALT6 gene (615291) on chromosome 1p36.

Exclusion Studies

Beighton (1994) noted that significant negative results had been obtained in linkage studies for SEMDJL1 with the candidate loci COL1A1, COL1A2, COL2A1, COL10A1, fibrillin, and elastin.

Molecular Genetics

By next-generation sequencing in 7 individuals, including 2 sibs, with SEMDJL1 from 5 unrelated Japanese families and a Singapore/Japanese family, Nakajima et al. (2013) identified possible mutations in the B3GALT6 gene. By direct sequencing of this gene in these 7 patients and an additional patient with SEMDJL1 from a Vietnamese family, they identified compound heterozygous missense mutations in all but 1 in whom a second mutation was not found (615291.0001-615291.0006). One of the mutations (M1?; 615291.0001) was found in 5 of the 7 families. Functional studies of mutant B3GALT6 proteins showed mislocalization in some and loss of function in all. Biochemical studies using patient lymphoblastoid cells showed a decrease of heparan sulfate and a paradoxical increase of chondroitin sulfate and dermatan sulfate on the cell surface.

By homozygosity mapping and candidate gene sequence analysis in 3 unrelated Iranian families segregating SEMDJL1 with fractures, Malfait et al. (2013) identified homozygous or compound heterozygous mutations in the B3GALT6 gene (615291.0012-615291.0014), which segregated with the disorder in each family. Patient fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming B3GALT6 loss of function. Dermal electron microscopy showed abnormalities in collagen fibril organization. A strong reduction in heparan sulfate level was also observed, indicating that B3GALT6 deficiency alters synthesis of both main types of glycosaminoglycans. An in vitro wound healing assay revealed a significant delay in fibroblasts from 2 index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo.

Associations Pending Confirmation

For discussion of a possible association between a leptodactylic form of SEMD with joint laxity and mutation in the NIN gene, see 608684.0003.