Atelosteogenesis, Type Iii

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 3p14.3.

For a discussion of genetic heterogeneity of atelosteogenesis, see AO1 (108720).

Clinical Features

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.

Molecular Genetics

In 2 unrelated individuals with sporadically occurring AO3, Krakow et al. (2004) identified heterozygosity for 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.