Alternative titles; symbols
SNOMEDCT: 725142004; ORPHA: 56305; DO: 0050648;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p14.3 | Atelosteogenesis, type III | 108721 | Autosomal dominant | 3 | FLNB | 603381 |
A number sign (#) is used with this entry because of evidence that atelosteogenesis type III (AO3) is caused by heterozygous mutation in the FLNB gene (603381), which encodes filamin B, on chromosome 3p14.
For a discussion of genetic heterogeneity of atelosteogenesis, see AO1 (108720).
Atelosteogenesis type III (AO3) is an autosomal dominant skeletal dysplasia with vertebral abnormalities, disharmonious skeletal maturation, poorly modeled long bones, and joint dislocations. Craniofacial abnormalities, vertebral fusions, and carpal, tarsal, and phalangeal abnormalities are present (Krakow et al., 2004). There is considerable phenotypic overlap with AO1 (108720), but patients with AO3 have less delay in normal ossification, with better ossification of vertebrae, fibulae, metacarpals, and phalanges. Infants with AO3 often have respiratory and feeding difficulties, and respiratory complications and cervical spine instability are the apparent causes of death in reported cases (summary by Schultz et al., 1999).
Stern et al. (1990) described 5 examples of a short-limb dwarfism syndrome with manifestations overlapping those of atelosteogenesis and otopalatodigital syndrome type II (304120). They presented clinical, radiographic, genetic, and histologic data that demonstrated differences between these patients and previously reported cases of the other conditions. Like AO1, this new disorder, designated atelosteogenesis type III, has been observed only in isolated cases, suggesting fresh dominant mutation. In 1 of the 5 patients with AO3, there was advanced paternal age consistent with this possibility. On the other hand, Pyeritz (1993) reported a case of affected sibs.
Schultz et al. (1999) reported a mother and son with atelosteogenesis type III. They stated that this was the first report of survival to adulthood, of prenatal diagnosis, and of dominant transmission. The authors reviewed 9 previously published cases to describe the syndrome more completely; they suggested that the physical and radiographic findings of AO3 and Larsen syndrome (150250) are quite similar, and that the disorders are probably allelic.
The heterozygous mutations in the FLNB gene in the patients with AO3 reported by Krakow et al. (2004) occurred de novo.
In 2 unrelated individuals with sporadically occurring AO3, Krakow et al. (2004) identified de novo heterozygous point mutations in the FLNB gene (603381) that predicted single-residue substitutions in the N-terminal actin-binding domain of filamin B (M202V, 603381.0007 and G751R, 603381.0008). They also identified the M202V mutation in a patient with AO1.
Krakow, D., Robertson, S. P., King, L. M., Morgan, T., Sebald, E. T., Bertolotto, C., Wachsmann-Hogiu, S., Acuna, D., Shapiro, S. S., Takafuta, T., Aftimos, S., Kim, C. A., and 13 others. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nature Genet. 36: 405-410, 2004. [PubMed: 14991055] [Full Text: https://doi.org/10.1038/ng1319]
Pyeritz, R. E. Personal Communication. Baltimore, Md. 5/5/1993.
Schultz, C., Langer, L. O., Laxova, R., Pauli, R. M. Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission. Am. J. Med. Genet. 83: 28-42, 1999. [PubMed: 10076882] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990305)83:1<28::aid-ajmg7>3.0.co;2-g]
Stern, H. J., Graham, J. M., Jr., Lachman, R. S., Horton, W., Bernini, P. M., Spiegel, P. K., Bodurtha, J., Ives, E. J., Bocian, M., Rimoin, D. L. Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II. Am. J. Med. Genet. 36: 183-195, 1990. [PubMed: 2368807] [Full Text: https://doi.org/10.1002/ajmg.1320360212]