Introduction
Ablepharon-Macrostomia Syndrome (AMS) is a rare hereditary disorder, with only 20 reported cases as of 2020.1 The disease is characterized by absent or underdeveloped eyelids - (ablepharon) and an abnormally wide, large mouth (macrostomia).2 AMS affects several parts of the body, with the symptoms mainly involving the face, skin, and genitals. The condition is inherited via an autosomal dominant inheritance pattern3 - this means only one copy of the causative faulty gene needs to be inherited for one to develop the disease.
What causes Ablepharon-Macrostomia Syndrome?
AMS is caused by mutations in the gene that encodes the TWIST2 protein.8 This protein binds to DNA and allows for proper development of various tissues, playing a significant role in the differentiation and proliferation of cells.7 Mutations in this gene are the cause of the developmental defects in craniofacial, skin and genitals. Several different mutations of the TWIST2 gene have been reported,9 and these mutations are heritable from generation to generation.
Symptoms and Features of Ablepharon Macrostomia Syndrome4,5,6
Facial Deformities
- Eyes
- Ablepharon - Absence or extreme underdevelopment of the eyelids - typically underdeveloped eyelids present as short
- Hypertelorism - abnormally enlarged distance between the eyes
- Corneal opacity - when the cornea is damaged, it may become opaque
- Visual impairment
- Nose
- Abnormal thick and flared ala nasi (the area encircling the nostrils)
- Tend to have broad ridge and tip
- Mouth and Teeth
- Macrostomia - Abnormally wide and large mouth
- This may affect feeding, speech, and other oral functions
- Mouth may also appear fish-like
- Teeth may be widely spaced, small, and delayed in growth
- Macrostomia - Abnormally wide and large mouth
- Cheekbones may be underdeveloped and may protrude lateral of mouth
- Ears
- Small, malformed ears
- Impaired hearing and hearing loss
Skin Deformities
- Skin is typically redundant, which means the skin is loose and sagging due to a lack of elasticity
- Skin is wrinkling, thin and dry
- In some, there may also be patches of hyperpigmentation in the skin
Genital Abnormalities
- Folds of the pubic area (labia majora) and scrotum are underdeveloped
- Small penis, hypospadias (whereby the urethra is abnormal) and abnormally-positioned testicles in males
- The inner lips of the vagina (labia minora) is small and underdeveloped in females
Other abnormalities associated with AMS
- Absence or sparse hair, particularly in the scalp
- Absent eyebrows and eyelashes
- Absent or underdeveloped/faint nipples
- Developmental delays and growth impairments
- Umbilical abnormalities at pregnancy or birth – the umbilical cord may be too long or too short, not well connected to the placenta, or knotted
Conclusion
Ablepharon-Macrostomia Syndrome (AMS) is a rare genetic disease, characterised by distinctive abnormalities in the facial features such as absent/underdeveloped eyelids and abnormally wide mouth, in addition to skin and genital deformities. Given the rarity of the disease, little is known about the underlying mechanisms of the disease - it is believed that AMS is caused by mutations in the TWIST2 gene, leading to a wide array of symptoms that differ from patient to patient. Continued research and awareness is incredibly important to improved understanding and management of AMS.
References
- Kor-anantakul P, Suphapeetiporn K, Jaruratanasirikul S. Ablepharon macrostomia syndrome in a Thai patient: case report and literature review. Asian Biomedicine [Internet]. 2020 [cited 2024 Jul 23]; 14(2):83–8. Available from: https://sciendo.com/article/10.1515/abm-2020-0012.
- Larumbe J, Villalta P, Velez I. Clinical Variant of Ablepharon Macrostomia Syndrome. Case Rep Dermatol Med [Internet]. 2011 [cited 2024 Jul 23]; 2011:593045. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504267/.
- Rohena L, Kuehn D, Marchegiani S, Higginson JD. Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome. Am J Med Genet [Internet]. 2011 [cited 2024 Jul 23]; 155(4):850–4. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.33900.
- De Maria B, Mazzanti L, Roche N, Hennekam RC. Barber–Say syndrome and Ablepharon–Macrostomia syndrome: An overview. American J of Med Genetics Pt A [Internet]. 2016 [cited 2024 Aug 2]; 170(8):1989–2001. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.37757.
- Stevens CA, Sargent LA. Ablepharon‐macrostomia syndrome. Am J Med Genet [Internet]. 2002 [cited 2024 Aug 2]; 107(1):30–7. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.10123.
- Kallish S, McDonald‐McGinn DM, Van Haelst MM, Bartlett SP, Katowitz JA, Zackai EH. Ablepharon–Macrostomia syndrome—Extension of the phenotype. American J of Med Genetics Pt A [Internet]. 2011 [cited 2024 Aug 2]; 155(12):3060–2. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.34287.
- TWIST2 twist family bHLH transcription factor 2 [Homo sapiens (human)] - Gene - NCBI [Internet]. [cited 2024 Aug 2]. Available from: https://www.ncbi.nlm.nih.gov/gene/117581.
- Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, et al. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. Am J Hum Genet [Internet]. 2015 [cited 2024 Aug 2]; 97(1):99–110. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572501/.
- Nwaneli E, Chukwuka J, Uju C, Epundu C. Ablepharon macrostomia syndrome: Absent prepuce in the first case report in West Africa. Niger Postgrad Med J [Internet]. 2021 [cited 2024 Aug 2]; 28(4):298. Available from: https://journals.lww.com/10.4103/npmj.npmj_318_20.
