Beukes Hip Dysplasia

A number sign (#) is used with this entry because of evidence that Beukes hip dysplasia (BHD) is caused by heterozygous mutation in the UFSP2 gene (611482) on chromosome 4q35. One such family has been reported.

Description

Beukes hip dysplasia is characterized by severe progressive degenerative osteoarthritis of the hip joint in early adulthood, with underlying dysplasia confined to that region. Affected individuals are of normal stature and have no associated health problems. Symptoms of hip joint discomfort usually develop in infancy or later childhood, but may present as late as the fourth decade. Phenotypic expression is age-related and variable in severity; penetrance is incomplete and has been estimated to be 80%. The earliest primary radiographic features of BHD include bilateral shortening and broadening of the femoral neck, delayed appearance of the secondary ossification center, coxa vara, displacement of the femoral head in the acetabulum, and overgrowth of the greater trochanters. After onset of symptoms, the characteristic signs of osteoarthritis develop, including bone sclerosis, cyst formation, and narrowing of the joint space, with rapid deterioration of the joint (summary by Watson et al., 2015).

Clinical Features

Cilliers and Beighton (1990) identified a 'new' inherited skeletal disorder in 47 patients in 6 generations of an Afrikaner family in South Africa. Hip joint discomfort usually developed during childhood at age less than 2 years, but might develop either later in childhood or, as in one instance, as late as the age of 35 years. After onset of symptoms, the hip joints deteriorated progressively, gait was disturbed, and, by early adulthood, affected individuals were crippled by degenerative arthropathy. General health was good, height was not significantly reduced, and there were no extra-skeletal manifestations. The major changes were in the femoral capital epiphyses, which were severely flattened and irregular. Secondary osteoarthrosis developed at an early age. One member of the kindred had severe kyphoscoliosis necessitating spinal fusion at an young age. By genealogic studies Cilliers and Beighton (1990) traced the family back to a single Dutch immigrant to South Africa who arrived in 1685. Since only members of the Beukes family were identified as suffering from the condition, Cilliers and Beighton (1990) proposed the designation 'Beukes familial hip dysplasia (BFHD).'

Minor changes in the spine suggested to Beighton et al. (1994) that the disorder falls into the general nosologic category of spondyloepiphyseal dysplasia.

Watson et al. (2015) restudied the multigenerational South African family of Dutch origin with BHD that was originally reported by Cilliers and Beighton (1990), extending the pedigree to 8 generations and including family members in Canada, New Zealand, and the United Kingdom. One new member of the pedigree was a 31-year-old man of normal stature who had onset of hip joint discomfort at age 13. Skeletal survey showed no evidence of abnormality other than features of BHD, including shortening and broadening of the femoral neck, coxa vara, and displacement of the femoral head in the acetabulum, as well as associated degenerative osteoarthritis, with narrowing of the joint space, presence of marginal osteophytes, cyst formation, and sclerosis. In keeping with the variable penetrance of the disorder, the progression of disease and radiologic manifestations were less severe than those described for other family members. In addition, the patient's obligate carrier father had only mild joint discomfort at 63 years of age.

Inheritance

The transmission pattern of hip dysplasia in the Afrikaner family reported by Cilliers and Beighton (1990) was consistent with autosomal dominant inheritance, with many instances of male-to-male transmission.

Mapping

By linkage studies in the Afrikaner family originally reported by Cilliers and Beighton (1990), Roby et al. (1999) mapped that BHD locus to an 11-cM region on chromosome 4q35 in which no other forms of autosomal dominant chondrodysplasia with associated osteoarthropathy, such as spondyloepiphyseal dysplasia, multiple epiphyseal dysplasia, and pseudoachondroplasia, had been mapped.

By linkage analysis in the same Afrikaner family, Watson et al. (2008) and Watson et al. (2015) narrowed the BHD locus region on 4q35 from 3.34 Mb to 1.33 Mb. The fine mapping was done by using recombination events and the proximal and distal markers DS4S1535 and rs7663196, respectively (Watson et al., 2015).

Exclusion Studies

In further studies of the Afrikaner family named Beukes, in which 47 members in 6 generations had premature osteoarthropathy of the hip joint, Beighton et al. (1994) excluded the type II collagen gene (COL2A1; 120140) as the site of the mutation.

Molecular Genetics

In 17 affected members of the 8-generation South African family of Dutch origin with hip dysplasia mapping to chromosome 4q35, originally reported by Cilliers and Beighton (1990), Watson et al. (2015) identified a heterozygous missense mutation in the UFSP2 gene (Y290H; 611482.0001). Watson et al. (2008) had previously reported the mutation in this family in an abstract. The mutation was not found in 360 Dutch controls (Watson et al., 2008) or in the dbSNP or Exome Sequencing Project (ESP5400) databases (Watson et al., 2015). Comprehensive exome analysis of the linked allele in 3 distantly related family members confirmed that there were no other candidate disease-causing mutations in linkage disequilibrium with the UFSP2 mutation. There was evidence of nonpenetrance in 1 asymptomatic obligate carrier, and the mutation was also detected in 2 asymptomatic individuals in whom BHD had not been excluded or confirmed due to their young age. Linkage analysis between BHD and the UFSP2 mutation generated a 2-point lod score of 10.4 (theta = 0 and 80% penetrance). In vitro functional assays demonstrated that the BHD mutation abolishes UFSP2-mediated C-terminal cleavage of its substrate, UFM1 (610553).

History

In a stratification analysis of an osteoarthritis genome screen, Loughlin et al. (1999) found a suggestion of linkage centered on 4q12-q21.2 and restricted to female pairs with hip disease. Loughlin et al. (1999) considered it unlikely that this represented the same locus as that identified by Roby et al. (1999) at 4q35.