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The mutated TWIST2 gene produces an altered transcription factor that interferes with the copying of DNA.
The mutated TWIST2 gene produces an altered transcription factor that interferes with the copying of DNA.

Ablepharon-Macrostomia Syndrome

Clinical Characteristics

Ocular Features

The clinical features of this syndrome remain to be fully delineated.  Important ocular anomalies include malformations and sometimes absence of the upper and lower eyelids.  The eyelashes and eyebrows may be sparse or even missing.  The lid fissures, if present, may be shortened.  Deformities of the eyelids can lead to corneal exposure and secondary vision loss. 

Systemic Features

Other facial malformations include macrostomia which may be secondary to aberrant lip fusion.  Micrognathia has been described.  The external ears are often rudimentary, sometimes described as rosebuds.  The nasal bridge is low and the nostrils anteverted.  The zygomatic arches may be absent.  The nipples are often missing as well.  Scalp hair is sparse or even absent while the skin is dry, coarse, and often has redundant folds (cutis laxa).  Mild skin syndactyly, camptodactyly, finger contractures, and shortening of metacarpals have been noted.  The genitalia are often ambiguous and some patients have had ventral hernias.  Hearing loss can be a feature.  Growth retardation has been seen but developmental delays if present are mild.  Intelligence can be normal. 


The majority of sibships suggest autosomal recessive inheritance although autosomal dominant inheritance has been proposed for several. One male child has been reported to have a partial deletion of chromosome 18 but other complex rearrangements were also present.

An amino acid substitution (lysine) in the basic domain of the TWIST2 gene has been found in seven families in which ablepharon-macrostomia followed an autosomal dominant pattern.  Mutations in the same TWIST2 domain but leading to substitutions of glutamine or alanine amino acids is responsible for the Barber-Say phenotype (209885).

Mutations in the TWIST2 gene may also be responsible for Setleis syndrome (227260). 

Treatment Options

Cosmetic surgery can correct at least some of the malformations. Vigorous effort may be required to maintain corneal surface wetting. 


Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, Huang H, Valkanas E, Pusey B, Schanze D, Venselaar H, Vulto-van Silfhout AT, Wolfe LA, Tifft CJ, Zerfas PM, Zambruno G, Kariminejad A, Sabbagh-Kermani F, Lee J, Tsokos MG, Lee CC, Ferraz V, da Silva EM, Stevens CA, Roche N, Bartsch O, Farndon P, Bermejo-Sanchez E, Brooks BP, Maduro V, Dallapiccola B, Ramos FJ, Chung HY, Le Caignec C, Martins F, Jacyk WK, Mazzanti L, Brunner HG, Bakkers J, Lin S, Malicdan MC, Boerkoel CF, Gahl WA, de Vries BB, van Haelst MM, Zenker M, Markello TC. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. Am J Hum Genet. 2015 Jul 2;97(1):99-110.

PubMed ID: 

Rohena L, Kuehn D, Marchegiani S, Higginson JD. Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome. Am J Med Genet A. 2011 Apr;155(4):850-4.

PubMed ID: 

Stevens CA, Sargent LA. Ablepharon-macrostomia syndrome. Am J Med Genet. 2002 Jan 1;107(1):30-7.

PubMed ID: 

Cruz AA, Souza CA, Ferraz VE, Monteiro CA, Martins FA. Familial occurrence of ablepharon macrostomia syndrome: eyelid structure and surgical considerations. Arch Ophthalmol. 2000 Mar;118(3):428-30.

PubMed ID: 

Ferraz VE, Melo DG, Hansing SE, Cruz AA, Pina-Neto JM. Ablepharon-macrostomia syndrome: first report of familial occurrence. Am J Med Genet. 2000 Oct 2;94(4):281-3.

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