Last updated:
October 21, 2020
Years published: 1997, 2001, 2002, 2007, 2020
NORD gratefully acknowledges Henry (Hedi) Zhao, MDCM Candidate, McGill University School of Medicine, and Raoul C.M. Hennekam, MD, PhD, Professor Emeritus of Pediatrics and Translational Genetics, Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands, for assistance in the preparation of this report.
Summary
Ablepharon-macrostomia syndrome (AMS) is a rare genetic disorder characterized by absent or underdeveloped eyelids (ablepharon or microblepharon) and a wide mouth (macrostomia). Characteristics mainly involve the face and skin and rarely involve the internal organs (viscera). Common signs and symptoms in addition to eye and mouth findings include low-set ears with attached earlobes, distortion or fusion of the digits (syndactyly or camptodactyly), bulging cheeks, absent or very small nipples, wrinkled and redundant skin, absent or sparse hair and genital malformations. Other, less frequently reported findings include umbilical abnormalities, growth delay and intellectual disability. AMS has been grouped within the category of diseases called ectodermal dysplasias (genetic disorders that involve defects in the skin, hair, nails, sweat glands, and/or teeth) but because many characteristics involve tissues that are not derived from the ectoderm, it would be better to define AMS as a genuine malformation syndrome. AMS is caused by changes (mutations) in the TWIST2 gene. The pattern of inheritance is autosomal dominant, and most cases arise as spontaneous mutations, so occur sporadically.
Mutations in TWIST2 also cause the Barber Say syndrome and Setleis syndrome, which have very similar features. Indeed, it has been suggested the three disorders in fact form a continuum (De Maria 2016).
Introduction
ABS was originally described in 1977 (McCarthy and West 1977) in two unrelated boys. Advances have been made in the surgical techniques that improve visual function and cosmetic appearance.
AMS is apparent at birth from features of the head and facial (craniofacial) region. The absence of, or underdevelopment of eyelids and a wide mouth are cardinal features. The abnormalities around the eyes, poor eyelid development and absent eyebrows and eyelashes cause the upper and lower lids to turn outwards (ectropion), exposing the inner mucous membranes and prohibiting complete closure of the eyes (lagophthalmos). This results in dry eyes and corneal clouding, which, if left untreated, can lead to light sensitivity (photophobia) and vision loss. Other potential eye issues include inability to produce tears (alacrimia); repeated involuntary eye movements (nystagmus); an unequal, inward deviation of the eyes (strabismus); and/or complete or partial separation of the retina, the nerve-rich membrane lining the inner layer of the back of the eye, from membranes (choroids) in the outer layer (detached retina).
Infants affected with AMS may have additional, characteristic craniofacial features. Prominent features include a wide nasal bridge, long groove between the nose and lips (philtrum), flared nostrils and thick-flared edges of nostrils (alae nasi). The cheeks superolateral to the corners of mouth may bulge; a sign called “cheek pads”. In addition, in some patients, the zygomatic arches of the skull may be absent. Zygomotic arches are the two bony arches spanning from the lower portion of the orbits of the eyes, across the prominence of the cheekbones to the bones forming part of the lower skull. A small chin, low set ears with attached earlobes and impaired hearing can also be present.
The absence of the soft, downy hair at birth that typically covers most of the body (lanugo), sparse scalp hair, redundant and wrinkled skin, small or absent nipples and underdeveloped genitalia can be found. Unusually formed genitalia can include undescended testis (cryptochordism), urethral opening on the underside of the penis (hypospadias), and a small penis in males or small labia minora in females. Sometimes there is an abdominal hernia, so protrusion of portions of the large intestine through an abnormal opening in the abdominal wall which is covered by skin.
At the extremities, it is common to find syndactyly and camptodactyly; the skin over the hands may be abnormally loose, the fingers may be permanently flexed due to tight skin over the finger joints. While physical growth is generally undisturbed, cognitive development may be delayed. It is possible that many of these signs and symptoms do not capture the entirety of the syndrome, as there are relatively few cases and presentations vary in severity from person to person.
AMS is caused by changes (mutations) in the gene called TWIST2. The mutation has often occurred spontaneously in the affected individual (so not inherited from one of the parents) but inheritance from one of the parents in an autosomal dominant pattern has been reported.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Between 1977 and 2020, there have been 16 documented cases of AMS in the literature and a worldwide prevalence of less than <1/1,000,000. No apparent sex or ethnic disparity exists, and males and females present with similar signs and symptoms.
A diagnosis of AMS may be suspected at birth based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic physical findings; typically, a reliable diagnosis is possible on clinical grounds only. Differentiation from BSS and Setleis syndrome may sometimes be difficult. The clinical diagnosis can be confirmed by molecular genetic testing for mutations in TWIST2.
Clinical Testing and Work-Up
Computerized tomography (CT) scanning may be helpful in demonstrating absence of the zygomatic arch, improper union of portions of the upper and lower jawbones (maxillary and mandibular prominences), although this rarely will have consequences for management. Thorough examination and specialized testing may be conducted by eye specialists (ophthalmologists) to appropriately characterize eyelid characteristics, detect any additional or associated eye abnormalities and ensure appropriate preventive steps or treatment.
Treatment
The currently accepted treatment is corrective and reconstructive surgery aimed at preserving vision and reducing visual complications such as corneal clouding (opacification) during the neonatal period. Providing supportive therapy such as lubricant eye drops early on may improve symptoms of eye dryness. Additional surgery at a later age can be aimed at improving function and appearance. Severe ectropion and underdevelopment of eyelids is managed with the transfer of skin flaps to the lid region, thus improving the ability to close the eyes. A possible complication of this procedure is the inability to completely close the eyes (lagophthalmos).
Corrective surgery can also be pursued for the fingers, skin, or ears, but there is minimal evidence to support this. These surgical procedures include local flaps, face-lift procedures, forehead lifting, Botox injections, fat grafting, orthognathic surgery and nasal reconstruction with rib cartilage grafts (De Maria 2016). These procedures may be riskier in younger individuals because craniofacial growth may be impaired.
Psychosocial support for children with AMS is also important as they grow and face the societal pressures related to physical appearance. Receiving care from a well-informed team of healthcare providers may be beneficial, as they are able to offer care for both the medical and psychosocial aspects of the condition. Testimonies from individuals with AMS report positive experiences from corrective surgery and emphasize the importance of building self-esteem and having continued support from family members. Despite the challenges that are posed by this condition, patients report that they are aware it is mainly external and does not affect their intellectual and physical abilities or their capacity to pursue their ambitions (De Maria 2017).
Genetic counseling is recommended for affected individuals and their families to understand the genetics and natural history of AMS, and to provide psychosocial support.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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For information about clinical trials sponsored by private sources, contact:
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For information about clinical trials conducted in Europe, contact:
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TEXTBOOKS
Hennekam RC, Allanson J, Krantz I. Gorlin’s Syndromes of the Head and Neck. 5th ed. Oxford University Press, London, UK; 2010:744-45.
JOURNAL ARTICLES
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 Plast Reconstr Surg. 2020;36(1):21-25.
Hollanders K, Casteels I, Vandelanotte S, et al. Use of the masquerade flap in ablepharon-macrostomia syndrome: a case report. Cornea. 2018;37(7):929-932.
De Maria B, de Jager T, Sarubbi C, et al. Barber-Say syndrome and ablepharon-macrostomia syndrome: a patient’s view. Mol Syndromol. 2017;8(4):172-178.
De Maria B, Mazzanti L, Roche N, Hennekam RC. Barber-say syndrome and ablepharon-macrostomia syndrome: an overview. Am J Med Genet A. 2016;170(8):1989-2001.
Marchegiani S, Davis T, Tessadori F, et al. Recurrent mutations in the basic domain of twist2 cause ablepharon macrostomia and barber-say syndromes. Am J Hum Genet. 2015;97(1):99-110.
Rohena L, Kuehn D, Marchegiani S, Higginson JD. Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome. Am J Med Genet A. 2011;155A(4):850-854.
Stevens CA. Ablepharon-macrostomia syndrome. Am J Med Gen. 2002;107:30-37.
Ferraz VE, Melo DG, Hansing SE, Cruz AA, Pina-Neto JM. Ablepharon-macrostomia syndrome: first report of familial occurrence. Am J Med Genet. 2000;94:281-83.
Cruz AA, Souza CA, Ferraz VE, Monteiro CA, Martins FA. Familial occurrence of ablepharon macrostomia syndrome: eyelid structure and surgical considerations. Arch Ophthalmol. 2000;118:428-30.
Dinulos MB, Pagon RA. Autosomal dominant inheritance of barber-say syndrome. Am J Med Genet. 1999;86:54-56.
Mazzanti L, Bergamaschi R, Neri I, Perri A, Patrizi A, Cacciari E, Forabosco A. Barber-Say Syndrome: report of a new case. Am J Med Genet. 1998;78:188-91.
Pellegrino JE, Schnur RE, Boghosian-Sell L, et al. Ablepharon macrostomia syndrome with associated cutis laxa: possible localization to 18q. Hum Genet. 1996;97:532-36.
Cruz AA, Guimaraes FC, Obeid HN, Ferraz VE, Noce TR, Martinez FE. Congenital shortening of the anterior lamella of all eyelids: the so-called ablepharon macrostomia syndrome. Ophthal Plast Reconstr Surg. 1995;11:284-87.
Martinez Santana S, Perez Alvarez F, Frias JL, Martinez-Frias ML. Hypertrichosis, atrophic skin, ectropion, and macrostomia (barber-say syndrome): report of a new case. Am J Med Genet. 1993;47:20-23.
Price NJ, Pugh RE, Farndon PA, Willshaw HE. Ablepharon macrostomia syndrome. Br J Ophthalmol. 1991;75:317-19.
David A, Gordeeff A, Badoual J, Delaire J. Macrostomia, ectropion, atrophic skin, hypertrichosis: another observation. Am J Med Genet. 1991;39:112-15.
Cesarino EJ, Pinheiro M, Freire-Maia N, Meira-Silva MC. Lid agenesis-macrostomia-psychomotor retardation-forehead hypertrichosis–a new syndrome? Am J Med Genet. 1988;31:299-304.
Jackson IT, Shaw KE, del Pinal Matorras F. A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence. Br J Plast Surg. 1988;41:410-16.
Hornblass A, Reifler DM. Ablepharon macrostomia syndrome. Am J Ophthalmol. 1985;99:552-56.
McCarthy GT, West CM. Ablepharon macrostomia syndrome. Dev Med Child Neurol. 1977; 19:659-63.
INTERNET
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 200110; Updated September 25, 2015. Available at: https://omim.org/entry/200110?search=200110&highlight=200110 Accessed August 19, 2020.
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 209885; Updated August 10, 2015. https://omim.org/entry/209885 Accessed August 19, 2020.
Ablepharon macrostomia syndrome. Orphanet. Updated November 2014. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=1247&Disease_Disease_Search_diseaseGroup=Ablepharon-macrostomia-syndrome&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Ablepharon-macrostomia-syndrome&title=Ablepharon%20macrostomia%20syndrome&search=Disease_Search_Simple Accessed August 19, 2020.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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