Mutations in FGD1 cause Aarskog-Scott syndrome (AAS), an X-linked condition characterized by abnormal facial, skeletal, and genital development due to abnormal embryonic morphogenesis and skeletal formation. Here we report a novel FGD1 mutation in a family with atypical features of AAS, specifically bilateral upper and lower limb congenital joint contractures and cardiac abnormalities. The male proband and his affected maternal uncle are hemizygous for the novel FGD1 mutation p.Arg921X. This variant is the most carboxy-terminal FGD1 mutation identified in a family with AAS and is predicted to truncate the FGD1 protein at the second to last amino acid of the carboxy-terminal pleckstrin homology (PH) domain. Our study emphasizes the importance of the 3' peptide sequence in the structure and/or function of the FGD1 protein and further demonstrates the need to screen patients with X-linked congenital joint contractures for FGD1 mutations.
Keywords: ankyloglossia; bilateral cryptorchidism; clinodactyly of the fifth finger; congenital foot contractures; decreased palmar creases; deep philtrum; downslanted palpebral fissures; flexion contracture; low-set, posteriorly rotated ears; metatarsus adductus; nonrestrictive ventricular septal defect; shawl scrotum; short nose; unilateral ptosis.