Barber–Say syndrome

Barber-Say syndrome (BSS) is a very rare congenital disorder associated with excessive hair growth (hypertrichosis), fragile (atrophic) skin, eyelid deformities (ectropion), and an overly broad mouth (macrostomia).

Barber-Say syndrome is phenotypically similar to Ablepharon macrostomia syndrome, which is also associated with dominant mutations in TWIST2.

Signs and symptoms

 * Severe hypertrichosis, especially of the back
 * Skin abnormalities, including hyperlaxity and redundancy
 * Facial dysmorphism, including macrostomia
 * Eyelid deformities
 * Abnormal and low-set ears
 * Bulbous nasal tip with hypoplastic alae nasi
 * Low frontal hairline

Genetics
Multiple cases of parent-to-child transmission suggest that Barber-Say syndrome exhibits autosomal dominant inheritance. Exome sequencing and expression studies have shown that BSS is caused by mutations in the TWIST2 gene that affect a highly conserved residue of TWIST2 (twist-related protein 2). TWIST2 is a basic helix-loop-helix transcription factor that binds to E-box DNA motifs (5'-CANNTG-3') as a heterodimer and inhibits transcriptional activation. Because TWIST2 mediates mesenchymal stem cell differentiation and prevents premature or ectopic osteoblast differentiation, mutations in TWIST2 that disrupt these functions by altering DNA-binding activity could explain many of the phenotypes of BSS.

Epidemiology
The prevalence of Barber Say syndrome is less than 1 in 1,000,000. As of 2017, only 15 cases have been reported in the literature.