Otospondylomegaepiphyseal Dysplasia, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that autosomal dominant otospondylomegaepiphyseal dysplasia (OSMEDA), also known as Weissenbacher-Zweymuller syndrome (WZS), is caused by heterozygous mutation in the COL11A2 gene (120290) on chromosome 6p21.

Autosomal recessive otospondylomegaepiphyseal dysplasia (OSMEDB; 215150) is also caused by mutation in the COL11A2 gene.

Description

Otospondylomegaepiphyseal dysplasia (OSMED) is characterized by sensorineural deafness and relatively short extremities with abnormally large knees and elbows but normal total body length. The diagnostic radiologic findings are the enlarged epiphyses combined with a moderate platyspondyly, most marked in the lower thoracic region. There are no ocular abnormalities. Patients have typical facial features, including midface hypoplasia (summary by Giedion et al., 1982). Some patients have osteoarthritis (Brunner et al., 1994).

Nomenclature

Spranger (1998) reviewed the findings of disorders caused by mutation in the COL11A2 gene. He concluded that Weissenbacher-Zweymuller syndrome and nonocular Stickler syndrome are the same disorder and suggested the designation heterozygous OSMED. Pihlajamaa et al. (1998) likewise concluded that WZS and nonocular Stickler syndrome are identical and suggested that they be classified as the heterozygous type of OSMED.

Clinical Features

First described in 1964 as 'Pierre Robin syndrome with fetal chondrodysplasia,' the Weissenbacher-Zweymuller syndrome is characterized by neonatal micrognathia and rhizomelic chondrodysplasia with dumbbell-shaped femora and humeri, and regression of bone changes and normal growth in later years (Weissenbacher and Zweymuller, 1964; Haller et al., 1975). Catch-up growth after 2-3 years is one of the striking features. The patient reported by Weissenbacher and Zweymuller (1964) also had marked snub nose, cleft soft palate, glossoptosis, and hypognathia. Giedion et al. (1982) provided follow-up on this patient (case D), who was then 18 years of age. He had developed sensorineural deafness at age 5. He had no eye abnormalities. Enlarged epiphyses was a prominent radiologic feature. Giedion et al. (1982) reported 3 additional patients with a similar phenotype and proposed that the disorder be called otospondylomegaepiphyseal dysplasia (OSMED). He suggested autosomal recessive inheritance of the disorder because 2 of the patients were sibs.

Brunner et al. (1994) reported a large Dutch kindred in which 16 members had characteristic facial features of Stickler syndrome (see 108300) in combination with hearing impairment. Cleft palate or mild arthropathy occurred in several patients, but ocular signs of Stickler syndrome (high myopia, vitreoretinal degeneration, and retinal detachment) were absent. Four of the affected individuals were born with the Pierre Robin sequence of micrognathia, glossoptosis, and cleft palate. More than half of affected family members reported painful joints, especially of the knees. Degenerative joint disease was documented radiographically in 3 individuals by x-ray of the spine and of the knees. Hearing loss was mostly high-tone perceptive and progressed slowly to involve all frequencies. Shortening of the fourth and fifth metatarsals was present in 2 affected members of the kindred. Both had been born with cleft palate and were considered severely affected. Shortening of the fifth metacarpals was also noted in 1 of them. All affected individuals were of normal stature, except 1 female who was just below the third percentile for height. A mild thorax deformity was noted in 4 cases (pectus excavatum in 2, and pectus carinatum in 2 others).

Sirko-Osadsa et al. (1998) described a family with features of Stickler syndrome but without eye involvement. Affected members of the family had sensorineural hearing loss, cleft palate/uvula, micrognathia, malar flattening, joint pains, and multiple hereditary exostoses.

Vuoristo et al. (2004) described a 3-generation family in which several members were diagnosed with nonocular Stickler syndrome. Sensorineural hearing loss was present in all 3 generations. The propositus was a 4-year-old boy who had Robin sequence at birth. Both the propositus and his father had a flat malar area and nasal bridge, and the nose was upturned. The father had symptoms and radiologic findings of osteoarthritis from the age of 29 years. At age 73 years, the affected grandmother showed extensive osteoarthritic changes in the spine. Her father had undergone hip replacement in mid-adulthood.

Mapping

Studying a large Dutch kindred segregating a nonocular Stickler syndrome phenotype unlinked to COL2A1 (120140), Brunner et al. (1994) found close linkage with polymorphic markers from the 6p22-p21.3 region. The highest lod score was 4.36 without recombination with D6S276. Since the gene encoding the alpha-2 chain of type XI collagen (COL11A2) maps to the same region, Brunner et al. (1994) suggested that mutation in this collagen gene may be the explanation for Stickler syndrome in this and some other families.

Inheritance

Pihlajamaa et al. (1998) proposed that OSMED occurs in both autosomal dominant and autosomal recessive (215150) forms due to heterozygous or homozygous mutations, respectively, in the COL11A2 gene.

Molecular Genetics

In affected members of the large Dutch kindred with a Stickler syndrome-like phenotype reported by Brunner et al. (1994), Vikkula et al. (1995) identified a heterozygous nonsense mutation in the COL11A2 gene (120290.0001).

In affected members of a family with a diagnosis of nonocular Stickler syndrome, Sirko-Osadsa et al. (1998) identified a heterozygous 27-bp deletion within exon 39 of the COL11A2 gene (120290.0003).

In affected members of a 3-generation family with a diagnosis of nonocular Stickler syndrome, Vuoristo et al. (2004) identified a heterozygous nonsense mutation in the COL11A2 gene (120290.0008).

Pihlajamaa et al. (1998) analyzed DNA from the original patient reported by Weissenbacher and Zweymuller (1964) for mutations in 2 candidate genes expressed in cartilage, COL2A1 (120140) and COL11A2 (120290). No mutations were found in the COL2A1 gene but the COL11A2 gene contained a single-base mutation that converted a codon for an obligate glycine to a codon for glutamate at position 955 in the alpha-2 chain (G955E; 120290.0004).