AAS is a disorder characterized by facial, genital and skeletal anomalies. Affected individuals often suffer from developmental delay, short stature, hypertelorism, shawl scrotum, and brachydactyly. Other variable facial features may include a widow’s peak in their hairline, a small, short nose with a wide nasal bridge and anteverted nostrils, a round face, ptosis and slanted eyes, a wide philtrum and ears that fold down at the top. Skeletal anomalies consist of short, broad hands and feet, clinodactyly, mild syndactyly, single transverse palmar crease, finger joint hyperextensibility, cervical spine hypermobility, odontoid hypoplasia, and scoliosis. Patients also exhibit delayed puberty, hyperactivity and attention deficit disorder.
AAS is a rare condition with an unknown rate of incidence. As an X-linked recessive disorder, it affects more males than females. The prognosis of AAS is positive and postpubertal males may only have minor remnants of the prepubertal phenotype. Patients may also have mild degrees of mental slowness and reduced fertility. The disorder has a highly variable presentation and symptoms often overlap with other conditions. Hence genetic testing of the FGD1 gene can help confirm the diagnosis of AAS. There is currently no cure for the disorder and treatment is limited to supportive and symptomatic management. Patients may require orthodontic treatment for misaligned teeth, hernia repair surgery or orchidopexy for undescended testicles.
AAS follows an X-linked recessive pattern of inheritance and is caused by mutations in the FGD1 gene. This gene encodes a guanine nucleotide exchange factor responsible for activating the Rho GTPase CDC42. FGD1 regulates secretory membrane trafficking and extracellular matrix remodeling, playing an important role in skeletal development and morphogenesis. Around 20 variants in the gene have been associated with AAS, including missense mutations, insertions, deletions, inversions and duplications. Of these, missense point mutations occurring in the catalytic central domains are the most common.
Hamzeh et al. (2017) described a consanguineous Emirati family with two AAS affected members. The proband was a 7-year-old male suffering from developmental and speech delay, obesity, short stature, aggressive and hyperactive behavior, pectus carinatum with excavatum, brachydactyly, bilateral fifth finger clinodactyly, interdigital webbing of the toes, single palmar creases and sleep disturbance. He also had a left undescended testis for which orchidopexy was scheduled. His 3-year-old brother also exhibited short stature, hyperactivity, aggressive behavior, developmental delay, brachydactyly and bilateral fifth finger clinodactyly. Both siblings had the dysmorphic features of broad foreheads with widow’s peaks, bilateral partial ptosis, blepharophimosis, telecanthus, hypertelorism, epicanthic folds, down-slanting palpebral fissures, broad nasal bridges, short noses, anteverted nostrils, short philtrum, malformed ears with thickened helix, and short necks. The patients were both found to carry the novel FGD1 variant c.53del (p.Pro18Argfs*106) in a hemizygous state while their mother was found to be a heterozygous carrier.
To contribute with your findings to the content of this record, please fill the CTGA Database Information Submission Form and email it, along with supportive documents, to firstname.lastname@example.org.