Ablepharon Macrostomia Syndrome

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Article initiated by:

Allison Umfress, MD, Jullian Valadez

All contributors:

Jullian Valadez, Gangadhara Sundar, MD, Michael T Yen, MD, Allison Umfress, MD

Assigned editor:

Allison Umfress, MD, Gangadhara Sundar, MD

Review:

Assigned status Up to Date

 by Gangadhara Sundar, MD on December 13, 2024.

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Ablepharon Macrostomia Syndrome

Background

Ablepharon macrostomia syndrome [AMS] is a rare ectodermal dysplasia that is characterized by the limited eyelid formation, widened oral commissure, microtia, redundant skin, sparse hair, genitourinary abnormalities, and poor growth The syndrome was initially described with two male children presenting with lid folds that had failed to form correctly and oral, auricular, and genital abnormalities. Despite having Ablepharon in the title, AMS is actually characterized by limitation, not absence, of eyelid development since patients still have lid tissue present with a muco-cutaneous junction at the upper and lower margins Since this initial report in 1977, only about 20 cases have been reported in the literature

The ocular and oral manifestations are readily apparent at birth, and sometimes can 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 directly by AMS, medical intervention from low vision specialists and pediatric ophthalmologists is key to preserving vision and promoting proper language, social, emotional, and attentional development.

Etiology

The syndrome 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 but are inherited in an autosomal dominant fashion when there is a family history.   Marchegiani et al. 2015 identified heterozygosity for a missense mutation at the TWIST2 gene (E75K) in a father and daughter with AMS that was identified in 8 other different individuals with AMS. Mutation 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 site (with glutamine or alanine replacing the Glutamic acid) and shares features of macrostomia and abnormal eyelid development but instead has ectropion (instead of ablepharon), hypertrichosis, atrophic skin, ocular telecanthus, and bulbous nasal tip as its characteristic features. The shared but distinct phenotypical features across these two syndromes are underpinned by the likely transcriptional changes associated with slight changes in DNA binding.

Pathophysiology

TWIST2 is a gene that is expressed in the craniofacial region and underpins mesenchymal tissue differentiation and chondrogenesis during embryonic development. Mutations in gene transcription culminate into altered tissue development that results in the characteristic lid underdevelopment and enlargement of the mouth in AMS namesake. 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 micro 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- Hornblass and Reifler 1985 updated the interpretation of AMS to possibly be a case of microblepharon, rather than a true absence of eyelids.

• Absent Eyebrows and Eyelashes
• Corneal opacity is frequently reported
• Corneal Erosion Occasionally reported
• Cryptophtlamos 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 is a key intervention in order to 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, as even patients with early intervention have been reported to have high astigmatic errors and small and curved corneas