General Discussion

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.

Signs & Symptoms

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.

Causes

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.

Affected Populations

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.

Related Disorders

Barber-Say syndrome (BSS) and Setleis syndrome (also known as focal facial dermal dysplasia 3) fall within the spectrum of disorders resulting from TWIST2 mutations. Key features that differentiate BSS from AMS are presence of excessive hair (hypertrichosis), less marked eye findings, narrow ear canals and relatively normal hands and genitalia. Setleis syndrome presents with some overlap to AMS and BSS but is typically milder and can be differentiated by the finding of inward folding eyelids (entropion), bitemporal narrowing and absence of cheek pads.

Diagnosis

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.

Standard Therapies

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.