In 5 consanguineous Italian families, Novelli et al. (2002) demonstrated that individuals with mandibuloacral dysplasia (MADA; 248370) were homozygous for an arg527-to-his (R527H) mutation.
In affected members from 2 pedigrees with MADA, Simha et al. (2003) identified the homozygous R527H mutation.
In a Mexican American boy with MADA born of related parents, Shen et al. (2003) identified homozygosity for the R527H mutation. The authors noted that all the patients reported by Novelli et al. (2002) shared a common disease haplotype, but that the patients reported by Simha et al. (2003) and their Mexican American patient had different haplotypes, indicating independent origins of the mutation. The mutation is located within the C-terminal immunoglobulin-like domain in the center of a beta sheet on the domain surface of the protein.
Lombardi et al. (2007) identified this mutation in compound heterozygosity with another missense mutation (V440M; 150330.0044) in a patient with an apparent MADA phenotype associated with muscular hyposthenia and generalized hypotonia.
Garavelli et al. (2009) reported 2 unrelated patients with early childhood onset of MADA features associated with a homozygous R527H mutation. One presented at age 5 years, 3 months with bulbous distal phalanges of fingers and was observed to have dysmorphic craniofacial features, lipodystrophy type A, and acroosteolysis. The second child, born of consanguineous Pakistani parents, presented at age 4 years, 2 months with a round face, chubby cheeks, thin nose, lipodystrophy type A, and short, broad distal phalanges. Garavelli et al. (2009) emphasized that features of this disorder may become apparent as early as preschool age and that bulbous fingertips may be a clue to the diagnosis.
