Ablepharon Macrostomia Syndrome

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Article initiated by:

Allison Umfress, MD, Jullian Valadez

All contributors:

Jullian Valadez, Paul Phelps, MD, FACS, Gangadhara Sundar, MD, Michael T Yen, MD, Allison Umfress, MD, Hans Heymann, MD

Assigned editor:

Hans Heymann, MD

Review:

Assigned status Up to Date

 by Hans Heymann, MD on January 30, 2026.

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Contributing Editors:	add

Ablepharon Macrostomia Syndrome

Background

Ablepharon macrostomia syndrome [AMS] is a rare ectodermal dysplasia first reported in 1977 characterized by limited eyelid formation, widened oral commissure, microtia, redundant skin, sparse hair, genitourinary abnormalities, and poor growth. The initial description was of two male children presenting with lid malformation as well as and oral, auricular, and genital abnormalities. "Ablepharon" is technically a misnomer, given that AMS is defined by the limitation, not complete absence, of eyelid development; affected patients still have lid tissue present with a muco-cutaneous junction at the upper and lower margins. Only about 20 cases have been reported in the literature since the original description.

The ocular and oral manifestations are apparent at birth, and may be seen via prenatal ultrasound. The ocular manifestations in AMS are linked to keratopathy that culminates into lifelong visual impairment without rapid treatment. While cognition and life expectancy are typically unaffected by AMS, intervention from low vision specialists and pediatric ophthalmologists may improve visual prognosis and promote proper language, emotional, and attentional development.

Etiology

AMS is caused by mutations in the TWIST2 gene, which is also implicated in Barber-Say Syndrome and Setleis Syndrome.  Most cases occur via sporadic mutation in the TWIST2 gene. Inheritance in an autosomal dominant pattern is also described.   Marchegiani and coauthors identified heterozygosity for a missense mutation at the TWIST2 gene (E75K) in a father and daughter with AMS that was subsequently identified in eight other individuals with AMS. Mutations in this region of the TWIST2 protein alters DNA-binding activity that can lead to the gain of function symptoms alongside dominant negative symptoms on account of transcriptional changes for several genes.

Notably, Barber-Say Syndrome results from a point mutation at the same locus (glutamine or alanine replacing the Glutamic acid) and may share the features of macrostomia and abnormal eyelid development. Barber-Say Syndrome differs in presentation however in that it has ectropion , hypertrichosis, atrophic skin, ocular telecanthus, and bulbous nasal tip as characteristic features. The shared but distinct phenotypes of these two syndromes are perhaps caused by the transcriptional changes associated with slight changes in DNA binding.

Pathophysiology

TWIST2 is a gene expressed in the craniofacial region that plays a role in mesenchymal tissue differentiation and chondrogenesis during embryonic development. Mutations in gene transcription culminate into altered tissue development resulting in the characteristic lid underdevelopment and enlargement of the mouth. Electron microscopy in a study of a father and daughter with AMS showed abnormal and thin elastic fibers with amorphous deposits along collagen fibers that were oriented abnormally next to areas of microfibrillar proliferation. Subsequent Masson-trichrome staining identified abnormal reticulodermal collagen patterns in the context of normal elastic fiber staining appearance.

Diagnosis

Features

General

• Macrostomia
• Abnormal External Ear development
• Abnormal genital development
• Syndactyly/camptodactyly
• Redundant skin
• Absent or sparse hair
• Growth Restriction
• Mild developmental delay
• Absent Zygomatic Arch, small chin, and ale/malar/breast hypoplasia reported in an adult patient

Ocular findings

• Ablepharon - note: Hornblass and Reifler 1985 suggested that ablepharon finding of AMS to possibly be considered microblepharon, rather than a true absence of eyelids.

• Absent Eyebrows and Eyelashes
• Corneal opacity is frequently reported
• Corneal Erosion Occasionally reported
• Cryptophthalmos frequently reported
• Myopia frequently reported
• Visual impairment frequently reported

Management

Treatment

Corneal preservation is the main focus of AMS management. Initially, aggressive lubrication with artificial tears, lubricating ointment, the use of bubble shields and close monitoring is needed. Feinstein et al. 2015 describe the use of amniotic membrane grafts as a bedside treatment that can be employed prior to more definitive interventions such as eyelid reconstruction and corneal surgery.

Ophthalmic surgery to reconstruct the eyelid tissue may prevent long-term secondary corneal damage and scarring. Techniques historically employed for upper eyelid reconstruction include local flaps, lid-sharing procedures, and masquerade flaps, though lid-lengthening with skin grafting over the palpebral conjunctiva is the intervention with the best-reported outcomes. In a three-year follow-up of patients with lid lengthening via levator aponeurosis recession and permanent lid lengthening with skin grafts over the palpebral conjunctiva/muller muscle plan, Cruz et al. found cornea and useful vision preservation. Management following lid lengthening and grafting entails monitoring post-surgical lagophthalmos, strabismus, and amblyopia. Even with early intervention, patients may have high astigmatic errors and small, curved corneas.