# 186500

MULTIPLE SYNOSTOSES SYNDROME 1; SYNS1


Alternative titles; symbols

SYNOSTOSES, MULTIPLE, WITH BRACHYDACTYLY
SYMPHALANGISM-BRACHYDACTYLY SYNDROME
WL SYNDROME
DEAFNESS-SYMPHALANGISM SYNDROME OF HERRMANN
FACIOAUDIOSYMPHALANGISM SYNDROME


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q22 Multiple synostoses syndrome 1 186500 AD 3 NOG 602991
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Face
- Narrow face
- Short philtrum
Ears
- Progressive conductive deafness
- Stapes ankylosis
Eyes
- Strabismus
Nose
- Hemicylindrical nose
- Hypoplastic alae nasi
- Hypoplastic nasal septum
Mouth
- Thin vermilion border of upper lip
CHEST
Ribs Sternum Clavicles & Scapulae
- Anteriorly positioned shoulders
- Short sternum
- Pectus excavatum
- Prominent costochondral junction
SKELETAL
Spine
- Vertebral anomalies
- Spinal canal stenosis
- Hypoplastic spinal processes (cervical vertebrae)
Limbs
- Short upper arms
- Cubitus valgus
- Dislocated radial head
- Limited forearm pronation/supination
- Short legs
Hands
- Proximal symphalangism (2,3,4)
- Fusion of midphalangeal joints
- Clinodactyly
- Brachydactyly
- Cutaneous syndactyly (2,3,4)
- Carpal fusions
- Hypoplastic/aplastic middle phalanx
- Hypoplastic/aplastic distal phalanx
- Single palmar creases
Feet
- Short feet
- Short halluces
- Tarsal fusions
- Cutaneous 2,3 toe syndactyly
- Absent distal phalanges
- Proximal symphalangism 2,3,4
SKIN, NAILS, & HAIR
Skin
- Absence of skin creases over proximal interphalangeal (PIP) joints
- Absence of skin creases over distal interphalangeal (DIP) joints
- Single palmar creases
Nails
- Aplastic/hypoplastic fingernails
- Aplastic/hypoplastic toenails
MISCELLANEOUS
- Waddling gait
MOLECULAR BASIS
- Caused by mutation in the noggin gene (NOG, 602991.0003)

TEXT

A number sign (#) is used with this entry because of evidence that multiple synostoses syndrome-1 (SYNS1) is caused by heterozygous mutation in the NOG gene (602991) on chromosome 17q22.


Description

Multiple synostoses syndrome is characterized by multiple joint fusions, usually commencing in the hands, conductive deafness, and characteristic facial features, including a broad, tubular-shaped nose and a thin upper vermilion. Other features include brachydactyly, hypoplastic or absent middle phalanges, radial head dislocation, and pectus carinatum (summary by Takahashi et al., 2001).

Genetic Heterogeneity of Multiple Synostoses Syndrome

Other forms of multiple synostoses syndrome include SYNS2 (610017), caused by mutation in the GDF5 gene (601146) on chromosome 20q11; SYNS3 (612961), caused by mutation in the FGF9 gene (600921) on chromosome 13q12; and SYNS4 (617898), caused by mutation in the GDF6 gene (601147) on chromosome 8q22.


Clinical Features

Fuhrmann et al. (1966) described mother and son with bilateral dysplasia and synostosis of the elbow joint, synostoses in the fingers, wrist and foot, and short middle phalanges and metacarpals. The combination was described previously in father and daughter and father and son by other authors.

Maroteaux et al. (1972) described this syndrome in 7 persons in 1 family. A broad hemicylindrical nose without alar flare was noted. Other features were proximal symphalangism, carpal and tarsal fusion, subluxation of the radial heads, short first metacarpal bone, hypoplasia or aplasia of various digital phalanges and corresponding nails, and progressive conduction deafness. Herrmann (1974) described a kindred in which a woman was affected with an unusual hand formation, which they designated 'WL syndrome;' she transmitted the syndrome to 5 children by 2 different husbands (presumably with surnames beginning with W and L). All 6 affected persons had hypoplasia or absence of nails, proximal interphalangeal flexion creases and middle phalanges, as well as short, broad metacarpals, and all but 1, a 12-month-old boy, had proximal symphalangism radiographically. In addition, the patients had conductive deafness as well as dislocation of the radial heads and abnormal toes. The deafness is probably due to anomalies of the auditory ossicles as in other symphalangism syndromes. Lehmann et al. (2007) suggested that the disorder in the kindred reported by Herrmann (1974) and in some of the patients reported by Maroteaux et al. (1972) may have been the same as the disorder Lehmann et al. (2007) showed to be due to mutation in the NOGGIN gene (602991) and designated by them brachydactyly type B2 (BDB2; 611377).

Higashi and Inoue (1983) reported a Japanese family with symphalangism. These authors emphasized peculiarities of the facies, particularly broad nose. Pectus carinatum was conspicuous.

Konigsmark and Gorlin (1976) reported a case. Hurvitz et al. (1985) described a case and suggested the designation facioaudiosymphalangism syndrome. See 113450 for description of a syndrome of brachydactyly with distal symphalangism.

Da-Silva et al. (1984) described a large Brazilian kindred with 28 cases of the multiple synostosis syndrome in an autosomal dominant pattern. The main anomalies were symphalangism and carpal and tarsal synostosis. Some had synostosis involving other bones, absence of phalanges and nails, short metacarpals, hypoplastic alae of the nose, etc.

Gaal et al. (1987) reported a large Hawaiian family with multiple synostoses. Proximal symphalangism was a feature of the syndrome in this family, and the fifth proximal interphalangeal joint was usually the first to be affected. The disorder in the family could be traced to the first known affected individual, a Cherokee Indian who arrived in the Hawaiian Islands in the 1870s. Affected individuals demonstrated the cardinal features of the syndrome, including a broad, tubular-shaped (hemicylindrical) nose with lack of alar flare, otosclerotic deafness, and multiple progressive joint fusions commencing in the hand. All affected individuals examined had some degree of hearing impairment, ranging from mild to severe. Symphalangism was the most consistent finding. The joint fusions were progressive, commencing in the fifth proximal interphalangeal joint in early childhood (or at birth in some individuals) and progressing in an ulnar-to-radial and proximal-to-distal direction. Most of the affected adults were unable to make a fist. With increasing age, ankylosis of other joints, including the cervical vertebrae, hips, and humeroradial joints, developed. Although humeral, radial, and tarsal involvement had been noted in previous reports, little had been written regarding vertebral involvement. In the Hawaiian family, the cervical vertebral fusions commenced in early childhood and ultimately produced significant limitation of neck flexion and extension.

Edwards et al. (2000) reported a male with multiple synostoses syndrome with neurologic complications caused by cervical spinal canal stenosis, not previously described in this syndrome. The authors recommended that individuals with this condition should have a neurologic examination, and that restriction of activities with risk of injury to the neck or spine may be necessary if there are signs of vertebral malformation or neurologic complications.


Inheritance

The transmission pattern of SYNS1 in the family reported by Gaal et al. (1987) and Gong et al. (1999) was consistent with autosomal dominant inheritance.


Mapping

In the large Hawaiian family originally reported by Gaal et al. (1987), Krakow et al. (1998) demonstrated linkage of the multiple synostoses syndrome to chromosome 17q21-q22. The authors tested linkage to 17q because proximal symphalangism (SYM1; 185800) had been mapped to that region in studies of the classic pedigree first reported by Harvey Cushing (1916).


Molecular Genetics

In affected members of the large Hawaiian family with dominantly inherited multiple synostoses syndrome originally reported by Gaal et al. (1987), Gong et al. (1999) identified a heterozygous mutation (602991.0003) in the NOG gene. Furthermore, they demonstrated mutations in the same gene in 5 unrelated families with proximal symphalangism (SYM1; see 185800) and in a de novo case of that disorder. Thus, multiple synostoses syndrome and proximal symphalangism are allelic disorders.

In affected members of a family with multiple synostosis syndrome, originally reported by Higashi and Inoue (1983), Takahashi et al. (2001) identified heterozygosity for a 1-bp deletion (602991.0011) in the NOG gene.

Van den Ende et al. (2005) reported a 4-generation family with features of the facioaudiosymphalangism syndrome in which a novel missense mutation (602991.0016) in the NOG gene was identified in affected family members. The variable expression and progressive nature of the syndrome was well illustrated in this family.

In an individual with multiple synostoses syndrome, Dawson et al. (2006) identified heterozygosity for a nonsense mutation (602991.0015) in the NOG gene.

Rudnik-Schoneborn et al. (2010) studied a German father and son with facioaudiosymphalangism syndrome, in whom they identified a heterozygous missense mutation (602991.0019) in the NOG gene. In contrast to the typical presentation, the height of the 10-year-old son was above the 97th centile from the age of 3.5 years and he had markers of an activated bone metabolism, with elevated phosphate levels and bone-derived alkaline phosphatase activity. His father, who had never been under medical supervision, was reported to have been one of the tallest boys in childhood and youth until age 15 years, when growth velocity slowed; his adult height was in the 75th centile (185 cm). Rudnik-Schoneborn et al. (2010) proposed that accelerated growth could be part of the facioaudiosymphalangism syndrome caused by NOG mutations, noting that experimental evidence showed that suppression of noggin might accelerate osteogenesis (Wan et al., 2007).


REFERENCES

  1. Cushing, H. Hereditary anchylosis of proximal phalangeal joints (symphalangism). Genetics 1: 90-106, 1916. [PubMed: 17245852, related citations] [Full Text]

  2. da-Silva, E. O., Filho, S. M., de Albuquerque, S. C. Multiple synostosis syndrome: study of a large Brazilian kindred. Am. J. Med. Genet. 18: 237-247, 1984. [PubMed: 6465200, related citations] [Full Text]

  3. Dawson, K., Seeman, P., Sebald, E., King, L., Edwards, M., Williams, J., III, Mundlos, S., Krakow, D. GDF5 is a second locus for multiple-synostosis syndrome. Am. J. Hum. Genet. 78: 708-712, 2006. [PubMed: 16532400, images, related citations] [Full Text]

  4. Edwards, M. J., Rowe, L., Petroff, V. Herrmann multiple stenosis syndrome with neurological complications caused by spinal canal stenosis. Am. J. Med. Genet. 95: 118-122, 2000. [PubMed: 11078560, related citations]

  5. Fuhrmann, W. G., Steffens, C. H., Rompe, U. Dominant erbliche doppelseitige Dysplasie und Synostose des Ellenbogengelenks mit symmetrischer brachymesophalangie und Brachymetakarpie sowie Synostosen im Finger-, Hand-und Fusswurzelbereich. Humangenetik 3: 64-75, 1966. [PubMed: 5986056, related citations] [Full Text]

  6. Gaal, S. A., Doyle, J. R., Larsen, I. J. Symphalangism and its introduction into Hawaii: a pedigree. Hawaii Med. J. 46: 305-307, 1987. [PubMed: 3667255, related citations]

  7. Gong, Y., Krakow, D., Marcelino, J., Wilkin, D., Chitayat, D., Babul-Hirji, R., Hudgins, L., Cremers, C. W., Cremers, F. P. M., Brunner, H. G., Reinker, K., Rimoin, D. L., Cohn, D. H., Goodman, F. R., Reardon, W., Patton, M., Francomano, C. A., Warman, M. L. Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nature Genet. 21: 302-304, 1999. [PubMed: 10080184, related citations] [Full Text]

  8. Herrmann, J. Symphalangism and brachydactyly syndrome: report of the WL symphalangism-brachydactyly syndrome: review of literature and classification. Birth Defects Orig. Art. Ser. X(5): 23-53, 1974. [PubMed: 4469994, related citations]

  9. Higashi, K., Inoue, S. Conductive deafness, symphalangism, and facial abnormalities: the WL syndrome in a Japanese family. Am. J. Med. Genet. 16: 105-109, 1983. [PubMed: 6638061, related citations] [Full Text]

  10. Hurvitz, S. A., Goodman, R. M., Hertz, M., Katznelson, M. B.-M., Sack, Y. The facio-audio-symphalangism syndrome: report of a case and review of the literature. Clin. Genet. 28: 61-68, 1985. [PubMed: 4028502, related citations] [Full Text]

  11. Konigsmark, B. W., Gorlin, R. J. Genetic and Metabolic Deafness. Philadelphia: W. B. Saunders (pub.) 1976. Pp. 159-164.

  12. Krakow, D., Reinker, K., Powell, B., Cantor, R., Priore, M. A., Garber, A., Lachman, R. S., Rimoin, D. L., Cohn, D. H. Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22. Am. J. Hum. Genet. 63: 120-124, 1998. [PubMed: 9634519, related citations] [Full Text]

  13. Lehmann, K., Seemann, P., Silan, F., Goecke, T. O., Irgang, S., Kjaer, K. W., Kjaergaard, S., Mahoney, M. J., Morlot, S., Reissner, C., Kerr, B., Wilkie, A. O. M., Mundlos, S. A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am. J. Hum. Genet. 81: 388-396, 2007. [PubMed: 17668388, images, related citations] [Full Text]

  14. Maroteaux, P., Bouvet, J. P., Briard, M. L. La maladie des synostoses multiples. Nouv. Presse Med. 1: 3041-3047, 1972. [PubMed: 4648959, related citations]

  15. Rudnik-Schoneborn, S., Takahashi, T., Busse, S., Schmidt, T., Senderek, J., Eggermann, T., Zerres, K. Facioaudiosymphalangism syndrome and growth acceleration associated with a heterozygous NOG mutation. Am. J. Med. Genet. 152A: 1540-1544, 2010. [PubMed: 20503332, related citations] [Full Text]

  16. Takahashi, T., Takahashi, I., Komatsu, M., Sawaishi, Y., Higashi, K., Nishimura, G., Saito, H., Takada, G. Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin. Genet. 60: 447-451, 2001. [PubMed: 11846737, related citations] [Full Text]

  17. van den Ende, J. J., Mattelaer, P., Declau, F., Vanhoenacker, F., Claes, J., Van Hul, E., Baten, E. The facio-audio-symphalangism syndrome in a four generation family with a nonsense mutation in the NOG-gene. Clin. Dysmorph. 14: 73-80, 2005. [PubMed: 15770128, related citations]

  18. Wan, D. C., Pomerantz, J. H., Brunet, L. J., Kim, J.-B., Chou, Y.-F., Wu, B. M., Harland, R., Blau, H. M., Longaker, M. T. Noggin suppression enhances in vitro osteogenesis and accelerates in vivo bone formation. J. Biol. Chem. 282: 26450-26459, 2007. [PubMed: 17609215, related citations] [Full Text]


Marla J. F. O'Neill - updated : 1/5/2011
Marla J. F. O'Neill - updated : 7/30/2009
Victor A. McKusick - updated : 8/17/2007
Siobhan M. Dolan - updated : 4/20/2006
Victor A. McKusick - updated : 3/15/2006
Sonja A. Rasmussen - updated : 12/12/2000
Victor A. McKusick - updated : 2/23/1999
Victor A. McKusick - updated : 7/20/1998
Creation Date:
Victor A. McKusick : 6/2/1986
alopez : 03/25/2024
carol : 07/18/2018
carol : 07/18/2018
alopez : 02/28/2018
carol : 09/30/2015
wwang : 1/7/2011
terry : 1/5/2011
wwang : 8/12/2009
terry : 7/30/2009
alopez : 8/27/2007
terry : 8/17/2007
carol : 4/24/2006
terry : 4/20/2006
alopez : 3/29/2006
alopez : 3/29/2006
carol : 3/28/2006
alopez : 3/17/2006
terry : 3/15/2006
carol : 5/12/2004
mcapotos : 12/13/2000
mcapotos : 12/12/2000
alopez : 3/1/1999
terry : 2/23/1999
carol : 7/21/1998
terry : 7/20/1998
mimadm : 5/10/1995
supermim : 3/16/1992
supermim : 3/20/1990
carol : 11/27/1989
ddp : 10/27/1989
marie : 3/25/1988

# 186500

MULTIPLE SYNOSTOSES SYNDROME 1; SYNS1


Alternative titles; symbols

SYNOSTOSES, MULTIPLE, WITH BRACHYDACTYLY
SYMPHALANGISM-BRACHYDACTYLY SYNDROME
WL SYNDROME
DEAFNESS-SYMPHALANGISM SYNDROME OF HERRMANN
FACIOAUDIOSYMPHALANGISM SYNDROME


ORPHA: 3237;   DO: 0081317;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q22 Multiple synostoses syndrome 1 186500 Autosomal dominant 3 NOG 602991

TEXT

A number sign (#) is used with this entry because of evidence that multiple synostoses syndrome-1 (SYNS1) is caused by heterozygous mutation in the NOG gene (602991) on chromosome 17q22.


Description

Multiple synostoses syndrome is characterized by multiple joint fusions, usually commencing in the hands, conductive deafness, and characteristic facial features, including a broad, tubular-shaped nose and a thin upper vermilion. Other features include brachydactyly, hypoplastic or absent middle phalanges, radial head dislocation, and pectus carinatum (summary by Takahashi et al., 2001).

Genetic Heterogeneity of Multiple Synostoses Syndrome

Other forms of multiple synostoses syndrome include SYNS2 (610017), caused by mutation in the GDF5 gene (601146) on chromosome 20q11; SYNS3 (612961), caused by mutation in the FGF9 gene (600921) on chromosome 13q12; and SYNS4 (617898), caused by mutation in the GDF6 gene (601147) on chromosome 8q22.


Clinical Features

Fuhrmann et al. (1966) described mother and son with bilateral dysplasia and synostosis of the elbow joint, synostoses in the fingers, wrist and foot, and short middle phalanges and metacarpals. The combination was described previously in father and daughter and father and son by other authors.

Maroteaux et al. (1972) described this syndrome in 7 persons in 1 family. A broad hemicylindrical nose without alar flare was noted. Other features were proximal symphalangism, carpal and tarsal fusion, subluxation of the radial heads, short first metacarpal bone, hypoplasia or aplasia of various digital phalanges and corresponding nails, and progressive conduction deafness. Herrmann (1974) described a kindred in which a woman was affected with an unusual hand formation, which they designated 'WL syndrome;' she transmitted the syndrome to 5 children by 2 different husbands (presumably with surnames beginning with W and L). All 6 affected persons had hypoplasia or absence of nails, proximal interphalangeal flexion creases and middle phalanges, as well as short, broad metacarpals, and all but 1, a 12-month-old boy, had proximal symphalangism radiographically. In addition, the patients had conductive deafness as well as dislocation of the radial heads and abnormal toes. The deafness is probably due to anomalies of the auditory ossicles as in other symphalangism syndromes. Lehmann et al. (2007) suggested that the disorder in the kindred reported by Herrmann (1974) and in some of the patients reported by Maroteaux et al. (1972) may have been the same as the disorder Lehmann et al. (2007) showed to be due to mutation in the NOGGIN gene (602991) and designated by them brachydactyly type B2 (BDB2; 611377).

Higashi and Inoue (1983) reported a Japanese family with symphalangism. These authors emphasized peculiarities of the facies, particularly broad nose. Pectus carinatum was conspicuous.

Konigsmark and Gorlin (1976) reported a case. Hurvitz et al. (1985) described a case and suggested the designation facioaudiosymphalangism syndrome. See 113450 for description of a syndrome of brachydactyly with distal symphalangism.

Da-Silva et al. (1984) described a large Brazilian kindred with 28 cases of the multiple synostosis syndrome in an autosomal dominant pattern. The main anomalies were symphalangism and carpal and tarsal synostosis. Some had synostosis involving other bones, absence of phalanges and nails, short metacarpals, hypoplastic alae of the nose, etc.

Gaal et al. (1987) reported a large Hawaiian family with multiple synostoses. Proximal symphalangism was a feature of the syndrome in this family, and the fifth proximal interphalangeal joint was usually the first to be affected. The disorder in the family could be traced to the first known affected individual, a Cherokee Indian who arrived in the Hawaiian Islands in the 1870s. Affected individuals demonstrated the cardinal features of the syndrome, including a broad, tubular-shaped (hemicylindrical) nose with lack of alar flare, otosclerotic deafness, and multiple progressive joint fusions commencing in the hand. All affected individuals examined had some degree of hearing impairment, ranging from mild to severe. Symphalangism was the most consistent finding. The joint fusions were progressive, commencing in the fifth proximal interphalangeal joint in early childhood (or at birth in some individuals) and progressing in an ulnar-to-radial and proximal-to-distal direction. Most of the affected adults were unable to make a fist. With increasing age, ankylosis of other joints, including the cervical vertebrae, hips, and humeroradial joints, developed. Although humeral, radial, and tarsal involvement had been noted in previous reports, little had been written regarding vertebral involvement. In the Hawaiian family, the cervical vertebral fusions commenced in early childhood and ultimately produced significant limitation of neck flexion and extension.

Edwards et al. (2000) reported a male with multiple synostoses syndrome with neurologic complications caused by cervical spinal canal stenosis, not previously described in this syndrome. The authors recommended that individuals with this condition should have a neurologic examination, and that restriction of activities with risk of injury to the neck or spine may be necessary if there are signs of vertebral malformation or neurologic complications.


Inheritance

The transmission pattern of SYNS1 in the family reported by Gaal et al. (1987) and Gong et al. (1999) was consistent with autosomal dominant inheritance.


Mapping

In the large Hawaiian family originally reported by Gaal et al. (1987), Krakow et al. (1998) demonstrated linkage of the multiple synostoses syndrome to chromosome 17q21-q22. The authors tested linkage to 17q because proximal symphalangism (SYM1; 185800) had been mapped to that region in studies of the classic pedigree first reported by Harvey Cushing (1916).


Molecular Genetics

In affected members of the large Hawaiian family with dominantly inherited multiple synostoses syndrome originally reported by Gaal et al. (1987), Gong et al. (1999) identified a heterozygous mutation (602991.0003) in the NOG gene. Furthermore, they demonstrated mutations in the same gene in 5 unrelated families with proximal symphalangism (SYM1; see 185800) and in a de novo case of that disorder. Thus, multiple synostoses syndrome and proximal symphalangism are allelic disorders.

In affected members of a family with multiple synostosis syndrome, originally reported by Higashi and Inoue (1983), Takahashi et al. (2001) identified heterozygosity for a 1-bp deletion (602991.0011) in the NOG gene.

Van den Ende et al. (2005) reported a 4-generation family with features of the facioaudiosymphalangism syndrome in which a novel missense mutation (602991.0016) in the NOG gene was identified in affected family members. The variable expression and progressive nature of the syndrome was well illustrated in this family.

In an individual with multiple synostoses syndrome, Dawson et al. (2006) identified heterozygosity for a nonsense mutation (602991.0015) in the NOG gene.

Rudnik-Schoneborn et al. (2010) studied a German father and son with facioaudiosymphalangism syndrome, in whom they identified a heterozygous missense mutation (602991.0019) in the NOG gene. In contrast to the typical presentation, the height of the 10-year-old son was above the 97th centile from the age of 3.5 years and he had markers of an activated bone metabolism, with elevated phosphate levels and bone-derived alkaline phosphatase activity. His father, who had never been under medical supervision, was reported to have been one of the tallest boys in childhood and youth until age 15 years, when growth velocity slowed; his adult height was in the 75th centile (185 cm). Rudnik-Schoneborn et al. (2010) proposed that accelerated growth could be part of the facioaudiosymphalangism syndrome caused by NOG mutations, noting that experimental evidence showed that suppression of noggin might accelerate osteogenesis (Wan et al., 2007).


REFERENCES

  1. Cushing, H. Hereditary anchylosis of proximal phalangeal joints (symphalangism). Genetics 1: 90-106, 1916. [PubMed: 17245852] [Full Text: https://doi.org/10.1093/genetics/1.1.90]

  2. da-Silva, E. O., Filho, S. M., de Albuquerque, S. C. Multiple synostosis syndrome: study of a large Brazilian kindred. Am. J. Med. Genet. 18: 237-247, 1984. [PubMed: 6465200] [Full Text: https://doi.org/10.1002/ajmg.1320180208]

  3. Dawson, K., Seeman, P., Sebald, E., King, L., Edwards, M., Williams, J., III, Mundlos, S., Krakow, D. GDF5 is a second locus for multiple-synostosis syndrome. Am. J. Hum. Genet. 78: 708-712, 2006. [PubMed: 16532400] [Full Text: https://doi.org/10.1086/503204]

  4. Edwards, M. J., Rowe, L., Petroff, V. Herrmann multiple stenosis syndrome with neurological complications caused by spinal canal stenosis. Am. J. Med. Genet. 95: 118-122, 2000. [PubMed: 11078560]

  5. Fuhrmann, W. G., Steffens, C. H., Rompe, U. Dominant erbliche doppelseitige Dysplasie und Synostose des Ellenbogengelenks mit symmetrischer brachymesophalangie und Brachymetakarpie sowie Synostosen im Finger-, Hand-und Fusswurzelbereich. Humangenetik 3: 64-75, 1966. [PubMed: 5986056] [Full Text: https://doi.org/10.1007/BF00273020]

  6. Gaal, S. A., Doyle, J. R., Larsen, I. J. Symphalangism and its introduction into Hawaii: a pedigree. Hawaii Med. J. 46: 305-307, 1987. [PubMed: 3667255]

  7. Gong, Y., Krakow, D., Marcelino, J., Wilkin, D., Chitayat, D., Babul-Hirji, R., Hudgins, L., Cremers, C. W., Cremers, F. P. M., Brunner, H. G., Reinker, K., Rimoin, D. L., Cohn, D. H., Goodman, F. R., Reardon, W., Patton, M., Francomano, C. A., Warman, M. L. Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nature Genet. 21: 302-304, 1999. [PubMed: 10080184] [Full Text: https://doi.org/10.1038/6821]

  8. Herrmann, J. Symphalangism and brachydactyly syndrome: report of the WL symphalangism-brachydactyly syndrome: review of literature and classification. Birth Defects Orig. Art. Ser. X(5): 23-53, 1974. [PubMed: 4469994]

  9. Higashi, K., Inoue, S. Conductive deafness, symphalangism, and facial abnormalities: the WL syndrome in a Japanese family. Am. J. Med. Genet. 16: 105-109, 1983. [PubMed: 6638061] [Full Text: https://doi.org/10.1002/ajmg.1320160116]

  10. Hurvitz, S. A., Goodman, R. M., Hertz, M., Katznelson, M. B.-M., Sack, Y. The facio-audio-symphalangism syndrome: report of a case and review of the literature. Clin. Genet. 28: 61-68, 1985. [PubMed: 4028502] [Full Text: https://doi.org/10.1111/j.1399-0004.1985.tb01219.x]

  11. Konigsmark, B. W., Gorlin, R. J. Genetic and Metabolic Deafness. Philadelphia: W. B. Saunders (pub.) 1976. Pp. 159-164.

  12. Krakow, D., Reinker, K., Powell, B., Cantor, R., Priore, M. A., Garber, A., Lachman, R. S., Rimoin, D. L., Cohn, D. H. Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22. Am. J. Hum. Genet. 63: 120-124, 1998. [PubMed: 9634519] [Full Text: https://doi.org/10.1086/301921]

  13. Lehmann, K., Seemann, P., Silan, F., Goecke, T. O., Irgang, S., Kjaer, K. W., Kjaergaard, S., Mahoney, M. J., Morlot, S., Reissner, C., Kerr, B., Wilkie, A. O. M., Mundlos, S. A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am. J. Hum. Genet. 81: 388-396, 2007. [PubMed: 17668388] [Full Text: https://doi.org/10.1086/519697]

  14. Maroteaux, P., Bouvet, J. P., Briard, M. L. La maladie des synostoses multiples. Nouv. Presse Med. 1: 3041-3047, 1972. [PubMed: 4648959]

  15. Rudnik-Schoneborn, S., Takahashi, T., Busse, S., Schmidt, T., Senderek, J., Eggermann, T., Zerres, K. Facioaudiosymphalangism syndrome and growth acceleration associated with a heterozygous NOG mutation. Am. J. Med. Genet. 152A: 1540-1544, 2010. [PubMed: 20503332] [Full Text: https://doi.org/10.1002/ajmg.a.33387]

  16. Takahashi, T., Takahashi, I., Komatsu, M., Sawaishi, Y., Higashi, K., Nishimura, G., Saito, H., Takada, G. Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin. Genet. 60: 447-451, 2001. [PubMed: 11846737] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.600607.x]

  17. van den Ende, J. J., Mattelaer, P., Declau, F., Vanhoenacker, F., Claes, J., Van Hul, E., Baten, E. The facio-audio-symphalangism syndrome in a four generation family with a nonsense mutation in the NOG-gene. Clin. Dysmorph. 14: 73-80, 2005. [PubMed: 15770128]

  18. Wan, D. C., Pomerantz, J. H., Brunet, L. J., Kim, J.-B., Chou, Y.-F., Wu, B. M., Harland, R., Blau, H. M., Longaker, M. T. Noggin suppression enhances in vitro osteogenesis and accelerates in vivo bone formation. J. Biol. Chem. 282: 26450-26459, 2007. [PubMed: 17609215] [Full Text: https://doi.org/10.1074/jbc.M703282200]


Contributors:
Marla J. F. O'Neill - updated : 1/5/2011
Marla J. F. O'Neill - updated : 7/30/2009
Victor A. McKusick - updated : 8/17/2007
Siobhan M. Dolan - updated : 4/20/2006
Victor A. McKusick - updated : 3/15/2006
Sonja A. Rasmussen - updated : 12/12/2000
Victor A. McKusick - updated : 2/23/1999
Victor A. McKusick - updated : 7/20/1998

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
alopez : 03/25/2024
carol : 07/18/2018
carol : 07/18/2018
alopez : 02/28/2018
carol : 09/30/2015
wwang : 1/7/2011
terry : 1/5/2011
wwang : 8/12/2009
terry : 7/30/2009
alopez : 8/27/2007
terry : 8/17/2007
carol : 4/24/2006
terry : 4/20/2006
alopez : 3/29/2006
alopez : 3/29/2006
carol : 3/28/2006
alopez : 3/17/2006
terry : 3/15/2006
carol : 5/12/2004
mcapotos : 12/13/2000
mcapotos : 12/12/2000
alopez : 3/1/1999
terry : 2/23/1999
carol : 7/21/1998
terry : 7/20/1998
mimadm : 5/10/1995
supermim : 3/16/1992
supermim : 3/20/1990
carol : 11/27/1989
ddp : 10/27/1989
marie : 3/25/1988