Alternative titles; symbols
ORPHA: 1427; DO: 0080026;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.32 | Otospondylomegaepiphyseal dysplasia, autosomal recessive | 215150 | Autosomal recessive | 3 | COL11A2 | 120290 |
A number sign (#) is used with this entry because of evidence that autosomal recessive otospondylomegaepiphyseal dysplasia (OSMEDB), also known as Nance-Insley syndrome, is caused by homozygous or compound heterozygous mutation in the COL11A2 gene (120290) on chromosome 6p21.
Autosomal dominant otospondylomegaepiphyseal dysplasia (OSMEDA; 184840) is also caused by mutation in the COL11A2 gene.
Otospondylomegaepiphyseal dysplasia (OSMED) is characterized by sensorineural hearing loss, enlarged epiphyses, disproportionate shortness of the limbs, abnormalities in vertebral bodies, and typical facial features (summary by Harel et al., 2005).
Affected kindreds were reported by Nance and Sweeney (1970) and by Insley and Astley (1974). The adult height of Nance and Sweeney's patient was 51 inches. The nasal bridge was markedly sunken. Superficially the appearance suggested achondroplasia, but clearly it was a different condition. Platyspondyly and progressive fusion of carpal bones were noted. Deafness was progressive and severe. Nance and Sweeney (1970) observed several affected sibs and their female cousins. Insley and Astley (1974) described 2 affected sisters. Miny and Lenz (1985) reported 2 affected sibs in a Turkish family with consanguineous parents. Salinas et al. (1986) also observed parental consanguinity. They described affected brothers and emphasized cleft palate as a feature. The mode of inheritance would seem to differentiate this disorder from the Stickler syndrome (108300). In addition, the epiphyses are abnormally large in this disorder, whereas they are small in Stickler syndrome.
On the basis of 5 new patients from 3 families and an analysis of previously reported cases with a diagnosis of Weissenbacher-Zweymuller syndrome (WZS; see 184850), Chemke et al. (1992) concluded that this is a distinct disorder of delayed skeletal maturation, different from Stickler syndrome, and inherited as an autosomal recessive trait. Myopia and retinal detachment are characteristics of Stickler syndrome that are not found in WZS.
Moore et al. (1989) and Ramer et al. (1993) described monozygotic male twins with skeletal findings typical of WZS, including small size at birth, proximal limb shortness, midface hypoplasia, and myopia. In addition, 1 twin had a parietal-occipital encephalocele, while the other had a meningocele at the same location. One twin had hearing loss and significant delays in development.
Galil et al. (1991) described the physical, motor, cognitive, and academic development of a child with WZS from birth to the age of 8 years and suggested a more favorable prognosis for both physical and psychomotor development than previously reported. Birth length was 44 cm, with rhizomelic shortening of the lower limbs. Facial features included micrognathia with mild glossoptosis, slightly protruding eyes, hypertelorism, depressed nasal bridge, and submucous cleft of the soft palate. The femurs were short, with widening of the metaphyses of the long bones. Coronal cleft of lumbar vertebrae was noted. By age 2 years, only a minor widening of the long bones was still apparent; by age 8 years, there were no abnormal radiographic features. At the age of 8, he was at the 10th percentile for height. Motor development was delayed in the first 18 months because of severe truncal hypotonia and mild hypotonia of the legs. At the age of 5 years, both gross and fine motor performance were within normal limits. Myopia was found at age 2 years and combined sensory and conductive hearing loss at the age of 3. Galil et al. (1991) suggested that WZS is not a dysplasia, but a disease of connective tissue resulting in delayed maturation.
Rosser et al. (1996) found a similar association of skeletal abnormalities, cleft palate, subcutaneous calcifications, and sensorineural deafness in a 15-month-old girl. They proposed the designation Nance-Sweeney chondrodysplasia to describe the condition.
In a Dutch family with OSMED reported by Vikkula et al. (1995), 3 affected sibs had typical features of the disorder but did not have cleft palate, which is present in more than half of the cases of OSMED. The sibs presented in early adulthood with severe degenerative joint disease of the osteoarthritis type affecting predominantly the hips, knees, elbows, and shoulders. The spine was less severely affected, and adult height was only slightly below that of the unaffected sibs. There was increased lumbar lordosis and prominent interphalangeal joints. Short fifth metacarpals were found in all 3. The patients had distinctive facial features: midface hypoplasia with a short upturned nose, prominent eyes, depressed nasal bridge, and prominent supraorbital ridges. Sensorineural hearing loss was present from birth and required the use of hearing aids in all 3. None had myopia or vitreoretinal degeneration.
Temtamy et al. (2006) described a brother and sister with genetically confirmed OSMED. The sibs had disproportionate short stature and short limbs, distinct face with midface hypoplasia, short nose, depressed nasal bridge, long philtrum, and nonprogressive sensorineural deafness. Radiologic examination revealed short long bones and large epiphyses with metaphyseal flaring and mild platyspondyly and coronal clefting. The first-cousin parents were heterozygous for the deletion; the father, who had repeated episodes of unilateral otitis media 2 years previously, was found to have mild unilateral nonprogressive sensorineural hearing loss. A younger brother was unaffected.
In a Dutch family with 3 sibs, the offspring of fourth-cousin parents, who were affected with a syndrome reported as OSMED, Vikkula et al. (1995) demonstrated linkage to the 6p21 region, where the COL11A2 gene (120290) had been mapped.
In 3 affected sibs in a Dutch family with OSMED, Vikkula et al. (1995) identified homozygosity for a missense mutation in the COL11A2 gene (120290.0002) as the cause of the disorder.
In a brother and sister with OSMED, Temtamy et al. (2006) identified homozygosity for a 1-bp deletion in the COL11A2 gene (120290.0011).
Pihlajamaa et al. (1998) proposed that OSMED occurs in both autosomal dominant and autosomal recessive forms due to heterozygous or homozygous mutations, respectively, in the COL11A2 gene. The recessive form is represented by cases in which Vikkula et al. (1995) demonstrated a COL11A2 mutation (120290.0002) and the cases of Insley and Astley (1974) and others.
Chemke, J., Carmi, R., Bar-Ziv, J. The Weissenbacher-Zweymuller syndrome: a unique syndrome of delayed osseous maturation. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A51 only, 1990.
Chemke, J., Carmi, R., Galil, A., Bar-Ziv, Y., Ben-Ytzhak, I., Zurkowski, L. Weissenbacher-Zweymuller syndrome: a distinct autosomal recessive skeletal dysplasia. Am. J. Med. Genet. 43: 989-995, 1992. [PubMed: 1415350] [Full Text: https://doi.org/10.1002/ajmg.1320430616]
Galil, A., Carmi, R., Goldstein, E., Porter, B., Bar Ziv, J., Chemke, J. Weissenbacher-Zweymuller syndrome: long-term follow-up of growth and psychomotor development. Dev. Med. Child Neurol. 33: 1104-1109, 1991. [PubMed: 1723388] [Full Text: https://doi.org/10.1111/j.1469-8749.1991.tb14834.x]
Harel, T., Rabinowitz, R., Hendler, N., Galil, A., Flusser, H., Chemke, J., Gradstein, L., Lifshitz, T., Ofir, R., Elbedour, K., Birk, O. S. COL11A2 mutation associated with autosomal recessive Weissenbacher-Zweymuller syndrome: molecular and clinical overlap with otospondylomegaepiphyseal dysplasia (OSMED). Am. J. Med. Genet. 132A: 33-35, 2005. [PubMed: 15558753] [Full Text: https://doi.org/10.1002/ajmg.a.30371]
Insley, J., Astley, R. A bone dysplasia with deafness. Brit. J. Radiol. 47: 244-251, 1974. [PubMed: 4830146] [Full Text: https://doi.org/10.1259/0007-1285-47-557-244]
Miny, P., Lenz, W. Autosomal recessive deafness with skeletal dysplasia and facial appearance of Marshall syndrome. Am. J. Med. Genet. 21: 317-324, 1985. [PubMed: 4014313] [Full Text: https://doi.org/10.1002/ajmg.1320210214]
Moore, S. J., Ladda, R. L., Mowrey, P. N., Mascari, M. J., Ramer, J. C. Weissenbacher-Zweymuller syndrome in monozygous twins with neural tube defects and septo-optic dysplasia. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A56 only, 1989.
Nance, W. E., Sweeney, A. A recessively inherited chondrodystrophy. Birth Defects Orig. Art. Ser. VI(4): 25-27, 1970.
Pihlajamaa, T., Prockop, D. J., Faber, J., Winterpacht, A., Zabel, B., Giedion, A., Wiesbauer, P., Spranger, J., Ala-Kokko, L. Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymuller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome). Am. J. Med. Genet. 80: 115-120, 1998. [PubMed: 9805126] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19981102)80:2<115::aid-ajmg5>3.0.co;2-o]
Ramer, J. C., Eggli, K., Rogan, P. K., Ladda, R. L. Identical twins with Weissenbacher-Zweymuller syndrome and neural tube defect. Am. J. Med. Genet. 45: 614-618, 1993. [PubMed: 8456835] [Full Text: https://doi.org/10.1002/ajmg.1320450520]
Rosser, E. M., Hall, C. M., Harper, J., Lacour, M., Baraitser, M. Nance-Sweeney chondrodysplasia--a further case? Clin. Dysmorph. 5: 207-212, 1996. [PubMed: 8818448]
Salinas, C. F., de Botero, D., Isaza, C. Bone dysplasia, deafness and cleft palate syndrome. (Abstract) 7th International Congress of Human Genetics, Berlin 1986. P. 259.
Temtamy, S. A., Mannikko, M., Abdel-Salam, G. M. H., Hassan, N. A., Ala-Kokko, L., Afifi, H. H. Oto-spondylo-megaepiphyseal dysplasia (OSMED): clinical and radiological findings in sibs homozygous for premature stop codon mutation in the COL11A2 gene. Am. J. Med. Genet. 140A: 1189-1195, 2006. [PubMed: 16637051] [Full Text: https://doi.org/10.1002/ajmg.a.31205]
van Steensel, M. A. M., Buma, P., de Waal Malefijt, M. C., van den Hoogen, F. H. J., Brunner, H. G. Oto-spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am. J. Med. Genet. 70: 315-323, 1997. [PubMed: 9188673] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970613)70:3<315::aid-ajmg19>3.3.co;2-y]
Vikkula, M., Mariman, E. C. M., Lui, V. C. H., Zhidkova, N. I., Tiller, G. E., Goldring, M. B., van Beersum, S. E. C., de Waal Malefijt, M. C., van den Hoogen, F. H. J., Ropers, H.-H., Mayne, R., Cheah, K. S. E., Olsen, B. R., Warman, M. L., Brunner, H. G. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 80: 431-437, 1995. [PubMed: 7859284] [Full Text: https://doi.org/10.1016/0092-8674(95)90493-x]