# 184840

OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT; OSMEDA


Alternative titles; symbols

OSMED, HETEROZYGOUS
WEISSENBACHER-ZWEYMULLER SYNDROME; WZS
PIERRE ROBIN SYNDROME WITH FETAL CHONDRODYSPLASIA STICKLER SYNDROME, NONOCULAR TYPE, FORMERLY
STICKLER SYNDROME, TYPE III, FORMERLY; STL3, FORMERLY


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
6p21.32 Otospondylomegaepiphyseal dysplasia, autosomal dominant 184840 AD 3 COL11A2 120290
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Face
- Midface hypoplasia
Ears
- Sensorineural hearing loss
Eyes
- No ocular symptoms
Nose
- Anteverted nares
Mouth
- Pierre-Robin sequence
- Cleft palate
SKELETAL
- Epiphyseal dysplasia
Spine
- Mild platyspondyly
Limbs
- Joint pain
- Premature osteoarthritis
- Large epiphyses
MISCELLANEOUS
- Also called 'heterozygous OSMED' and 'autosomal dominant OSMED'
MOLECULAR BASIS
- Caused by mutation in the collagen XI, alpha-2 polypeptide gene (COL11A2, 120290.0001)
Otospondylomegaepiphyseal dysplasia - PS184840 - 2 Entries

TEXT

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).


REFERENCES

  1. Brunner, H. G., van Beersum, S. E. C., Warman, M. L., Olsen, B. R., Ropers, H.-H., Mariman, E. C. M. A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. Hum. Molec. Genet. 3: 1561-1564, 1994. [PubMed: 7833911, related citations] [Full Text]

  2. Giedion, A., Brandner, M., Lecannellier, J., Muhar, U., Prader, A., Sulzer, J., Zweymuller, E. Oto-spondylo-megaepiphyseal dysplasia (OSMED). Helv. Paediat. Acta 37: 361-380, 1982. [PubMed: 7153059, related citations]

  3. Haller, J. O., Berdon, W. E., Robinow, M., Slovis, T. L., Baker, D. H., Johnson, G. F. The Weissenbacher-Zweymuller syndrome of micrognathia and rhizomelic chondrodysplasia at birth with subsequent normal growth. Am. J. Roentgen. Radium Ther. Nucl. Med. 125: 936-943, 1975. [PubMed: 813535, related citations] [Full Text]

  4. 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, related citations] [Full Text]

  5. Sirko-Osadsa, D. A., Murray, M. A., Scott, J. A., Lavery, M. A., Warman, M. L., Robin, N. H. Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha-2(XI) chain of type XI collagen. J. Pediat. 132: 368-371, 1998. [PubMed: 9506662, related citations] [Full Text]

  6. Spranger, J. The type XI collagenopathies. Pediat. Radiol. 28: 745-750, 1998. [PubMed: 9799295, related citations] [Full Text]

  7. 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, related citations] [Full Text]

  8. Vuoristo, M. M., Pappas, J. G., Jansen, V., Ala-Kokko, L. A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome. Am. J. Med. Genet. 130A: 160-164, 2004. [PubMed: 15372529, related citations] [Full Text]

  9. Weissenbacher, G., Zweymuller, E. Gleichzeitiges Vorkommen eines Syndroms von Pierre Robin und einer fetalen Chondrodysplasie. Mschr. Kinderheilk. 112: 315-317, 1964. [PubMed: 14234962, related citations]


Carol A. Bocchini - updated : 07/18/2017
Michael J. Wright - updated : 7/12/1999
Victor A. McKusick - updated : 12/3/1998
Moyra Smith - updated : 10/18/1996
Creation Date:
Victor A. McKusick : 7/13/1993
carol : 06/21/2019
carol : 07/19/2017
carol : 07/18/2017
carol : 07/12/2017
carol : 08/03/2011
carol : 6/16/2000
carol : 4/17/2000
jlewis : 7/19/1999
terry : 7/12/1999
carol : 12/10/1998
terry : 12/3/1998
mark : 10/18/1996
mark : 10/18/1996
mimadm : 5/10/1995
carol : 2/24/1995
terry : 1/31/1995
carol : 7/13/1993

# 184840

OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT; OSMEDA


Alternative titles; symbols

OSMED, HETEROZYGOUS
WEISSENBACHER-ZWEYMULLER SYNDROME; WZS
PIERRE ROBIN SYNDROME WITH FETAL CHONDRODYSPLASIA STICKLER SYNDROME, NONOCULAR TYPE, FORMERLY
STICKLER SYNDROME, TYPE III, FORMERLY; STL3, FORMERLY


ORPHA: 166100, 3450;   DO: 0080677;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
6p21.32 Otospondylomegaepiphyseal dysplasia, autosomal dominant 184840 Autosomal dominant 3 COL11A2 120290

TEXT

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).


REFERENCES

  1. Brunner, H. G., van Beersum, S. E. C., Warman, M. L., Olsen, B. R., Ropers, H.-H., Mariman, E. C. M. A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. Hum. Molec. Genet. 3: 1561-1564, 1994. [PubMed: 7833911] [Full Text: https://doi.org/10.1093/hmg/3.9.1561]

  2. Giedion, A., Brandner, M., Lecannellier, J., Muhar, U., Prader, A., Sulzer, J., Zweymuller, E. Oto-spondylo-megaepiphyseal dysplasia (OSMED). Helv. Paediat. Acta 37: 361-380, 1982. [PubMed: 7153059]

  3. Haller, J. O., Berdon, W. E., Robinow, M., Slovis, T. L., Baker, D. H., Johnson, G. F. The Weissenbacher-Zweymuller syndrome of micrognathia and rhizomelic chondrodysplasia at birth with subsequent normal growth. Am. J. Roentgen. Radium Ther. Nucl. Med. 125: 936-943, 1975. [PubMed: 813535] [Full Text: https://doi.org/10.2214/ajr.125.4.936]

  4. 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]

  5. Sirko-Osadsa, D. A., Murray, M. A., Scott, J. A., Lavery, M. A., Warman, M. L., Robin, N. H. Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha-2(XI) chain of type XI collagen. J. Pediat. 132: 368-371, 1998. [PubMed: 9506662] [Full Text: https://doi.org/10.1016/s0022-3476(98)70466-4]

  6. Spranger, J. The type XI collagenopathies. Pediat. Radiol. 28: 745-750, 1998. [PubMed: 9799295] [Full Text: https://doi.org/10.1007/s002470050459]

  7. 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]

  8. Vuoristo, M. M., Pappas, J. G., Jansen, V., Ala-Kokko, L. A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome. Am. J. Med. Genet. 130A: 160-164, 2004. [PubMed: 15372529] [Full Text: https://doi.org/10.1002/ajmg.a.30111]

  9. Weissenbacher, G., Zweymuller, E. Gleichzeitiges Vorkommen eines Syndroms von Pierre Robin und einer fetalen Chondrodysplasie. Mschr. Kinderheilk. 112: 315-317, 1964. [PubMed: 14234962]


Contributors:
Carol A. Bocchini - updated : 07/18/2017
Michael J. Wright - updated : 7/12/1999
Victor A. McKusick - updated : 12/3/1998
Moyra Smith - updated : 10/18/1996

Creation Date:
Victor A. McKusick : 7/13/1993

Edit History:
carol : 06/21/2019
carol : 07/19/2017
carol : 07/18/2017
carol : 07/12/2017
carol : 08/03/2011
carol : 6/16/2000
carol : 4/17/2000
jlewis : 7/19/1999
terry : 7/12/1999
carol : 12/10/1998
terry : 12/3/1998
mark : 10/18/1996
mark : 10/18/1996
mimadm : 5/10/1995
carol : 2/24/1995
terry : 1/31/1995
carol : 7/13/1993