TWIST2 – Ablepharon Macrostomia Syndrome

Ablepharon macrostomia syndrome (AMS) is a rare congenital ectodermal dysplasia characterized by redundant skin, macrostomia, low‐set ears and ambiguous genitalia. AMS follows an autosomal‐dominant inheritance pattern due to heterozygous mutations in TWIST2 (HGNC:20670) that disrupt the basic helix–loop–helix DNA‐binding domain, leading to craniofacial malformations and occasional visceral anomalies.

Several single‐patient reports expand the phenotypic spectrum. In one case, a 37‐year‐old woman with genetically confirmed AMS developed grade III laryngo‐tracheal stenosis, effectively managed with tracheostomy and corticosteroids (PMID:31462237). Mosaic expression of AMS‐associated TWIST2 mutations has also been observed, correlating with milder eyelid anomalies and underdevelopment of the anterior lamella (PMID:34092176).

A landmark multi‐patient study identified recurrent de novo TWIST2 variants in seven independent AMS probands, all affecting the basic domain (seven unrelated de novo probands) (PMID:26119818). Key coding changes include c.223G>A (p.Glu75Lys) and c.229_234dup (p.Gln77_Arg78dup), which alter DNA‐binding patterns in vitro and segregate with disease.

The variant spectrum in AMS comprises missense and in‐frame duplications within the basic domain: c.223G>A (p.Glu75Lys), c.223G>C (p.Glu75Gln), c.224A>C (p.Glu75Ala) and c.229_234dup (p.Gln77_Arg78dup) (PMID:26119818). No clear founder alleles have been described; all reported variants arose de novo.

Functional assays demonstrate that basic domain substitutions disrupt TWIST2 DNA binding in HeLa cells and induce craniofacial defects in zebrafish models, supporting a dominant‐negative mechanism. Mutant TWIST2 fails to regulate downstream targets of mesenchymal development, concordant with the human phenotype (PMID:26119818).

Overall, the clinical validity of the TWIST2–AMS association is Strong given seven unrelated de novo probands and concordant functional data. Genetic evidence is Moderate (7 de novo variants in unrelated families), and functional evidence is Moderate (in vitro DNA‐binding assays and zebrafish modeling). TWIST2 testing enables diagnosis, guides management of airway anomalies, and informs genetic counseling.

References

• American journal of human genetics • 2015 • Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. PMID:26119818
• BMC pulmonary medicine • 2019 • Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome. PMID:31462237
• Orbit (Amsterdam, Netherlands) • 2022 • Ocular adnexal phenotype and management of a patient with mosaic expression of a mutation in TWIST2. PMID:34092176

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