Ablepharon Macrostomia Syndrome

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Assigned status Up to Date
 by Allison Umfress, MD on August 29, 2023.

Ablepharon Macrostomia Syndrome


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 [1][2][3][4] 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[1]. 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[5] Since this initial report in 1977, only about 20 cases have been reported in the literature [6]

The ocular and oral manifestations are readily apparent at birth, and sometimes can be seen via prenatal ultrasound.[7] 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.[8]


The syndrome is caused by mutations in the TWIST2 gene, which is also implicated in Barber-Say Syndrome and Setleis Syndrome.[9]  Most cases occur via sporadic mutation in the TWIST2 gene but are inherited in an autosomal dominant fashion when there is a family history.[9] [7]  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.[9] 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.[9]

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.[10] The shared but distinct phenotypical features across these two syndromes are underpinned by the likely transcriptional changes associated with slight changes in DNA binding.[10]


            TWIST2 is a gene that is expressed in the craniofacial region and underpins mesenchymal tissue differentiation and chondrogenesis during embryonic development.[9] 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.[9] [7]Subsequent Masson-trichrome micro staining identified abnormal reticulodermal collagen patterns in the context of normal elastic fiber staining appearance.[9]




-Abnormal External Ear development

-Abnormal genital development


-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 [11]

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.[3] [5][12] [13]

-Absent Eyebrows and Eyelashes

-Corneal opacity is frequently reported

-Corneal Erosion Occasionally reported

-Cryptophtlamos frequently reported

-Myopia frequently reported

-Visual impairment frequently reported


           Corneal preservation is the main focus of AMS treatment. Initially, aggressive lubrication with artificial tears, lubricating ointment, the use of bubble shields and close monitoring is needed. Feinstein et al. 2015 describe the usage of amniotic membrane grafting as a bedside treatment that can be employed prior to more definitive interventions such as eyelid reconstruction and corneal surgery.[14]

Ocular 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.[15] 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[15][16]

  1. 1.0 1.1 McCarthy GT, West CM. Ablepheron Macrostomia Syndrome. Developmental Medicine & Child Neurology. 1977;19(5):659-663. doi:10.1111/j.1469-8749.1977.tb07999.x
  2. Brancati F, Mingarelli R, Sarkozy A, Dallapiccola B. Ablepharon-macrostomia syndrome in a 46-year-old woman. American Journal of Medical Genetics Part A. 2004;127A(1):96-98. doi:10.1002/ajmg.a.20658
  3. 3.0 3.1 Hornblass A, Reifler DM. Ablepharon Macrostomia Syndrome. American Journal of Ophthalmology. 1985;99(5):552-556. doi:10.1016/S0002-9394(14)77956-5
  4. Stevens CA, Sargent LA. Ablepharon-macrostomia syndrome. Am J Med Genet. 2002;107(1):30-37. doi:10.1002/ajmg.10123
  5. 5.0 5.1 V. Cruz AA, Guimarães FC, Obeid HN, Ferraz VEF, Noce TR, Martinez FE. Congenital Shortening of the Anterior Lamella of All Eyelids: The So-Called Ablepharon Macrostomia Syndrome. Ophthalmic Plastic & Reconstructive Surgery. 1995;11(4):284.
  6. Alexopoulos D, Matchinski TL. A case of ablepharon macrostomia syndrome requiring multidisciplinary care. Clinical and Experimental Optometry. 2021;104(4):541-543. doi:10.1080/08164622.2021.1878839
  7. 7.0 7.1 7.2 Rohena L, Kuehn D, Marchegiani S, Higginson JD. Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome. Am J Med Genet. 2011;155(4):850-854. doi:10.1002/ajmg.a.33900
  8. Dale N, Sonksen P. Developmental outcome, including setback, in young children with severe visual impairment. Dev Med Child Neurol. 2002;44(9):613-622. doi:10.1017/s0012162201002651
  9. 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Marchegiani S, Davis T, Tessadori F, et al. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. The American Journal of Human Genetics. 2015;97(1):99-110. doi:10.1016/j.ajhg.2015.05.017
  10. 10.0 10.1 Roche N, Houtmeyers P, Janssens S, Blondeel P. Barber-Say syndrome in a father and daughter. Am J Med Genet A. 2010;152A(10):2563-2568. doi:10.1002/ajmg.a.33622
  11. Brancati F, Mingarelli R, Sarkozy A, Dallapiccola B. Ablepharon-macrostomia syndrome in a 46-year-old woman. American Journal of Medical Genetics Part A. 2004;127A(1):96-98. doi:10.1002/ajmg.a.20658
  12. Cruz AAV, Souza CA, Ferraz VEF, Monteiro CAC, Martins FA. Familial Occurrence of Ablepharon Macrostomia Syndrome: Eyelid Structure and Surgical Considerations. Archives of Ophthalmology. 2000;118(3):429-430
  13. Ferraz VEF, Melo DG, Hansing SE, Cruz AAV, Pina-Neto JM. Ablepharon-Macrostomia syndrome: First report of familial occurrence. American Journal of Medical Genetics. 2000;94(4):281-283. doi:10.1002/1096-8628(20001002)94:4<281::AID-AJMG3>3.0.CO;2-S
  14. Feinstein E, Traish AS, Aakalu V, Kassem IS. A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting. Case Rep Ophthalmol. 2015;6(3):366-372. doi:10.1159/000441615
  15. 15.0 15.1 Cruz AAV, Quiroz D, Boza T, Wambier SPF, Akaishi PS. Long-Term Results of the Surgical Management of the Upper Eyelids in “Ablepharon”-Macrostomia Syndrome. Ophthalmic Plastic & Reconstructive Surgery. 2020;36(1):21-25. doi:10.1097/IOP.0000000000001442
  16. Jackson IT, Shaw KE, del Pinal Matorras F. A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence. Br J Plast Surg. 1988;41(4):410-416. doi:10.1016/0007-1226(88)90084-7
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