Ablepharon-Macrostomia syndrome

What is Ablepharon-Macrostomia syndrome?

This rare disease is a very rare genetic condition.

Symptoms of the syndrome largely affect the head and face but can also affect the skin, fingers, and genitals.

The unique facial features of the syndrome are one of its main identifying symptoms.

This syndrome is also known as:
Ams McCarthy syndrome

What gene change causes Ablepharon-Macrostomia syndrome?

The syndrome is caused by mutations in the TWIST2 gene. It is inherited in an autosomal dominant pattern.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

what are the main symptoms of Ablepharon-Macrostomia syndrome?

Symptoms mainly affect the head and face but also the skin, fingers and genitals.

The unique facial features of the condition include missing or under-developed eyelids, as well as missing eyelashes and eyebrows. A very wide mouth, and under-developed ears are also common to the syndrome. A triangular face, a small misshapen nose, and thin hair may also be present.

Other syndromes may include webbed fingers, thin skin with folds, intestinal hernias and genital abnormalities including underdeveloped nipples and testes.

Possible clinical traits/features:
Umbilical hernia, Ventral hernia, Abnormal hair quantity, Camptodactyly of finger, Delayed speech and language development, Visual impairment, Depressed nasal bridge, Hypoplasia of penis, Underdeveloped nasal alae, Hypoplasia of the zygomatic bone, Opacification of the corneal stroma, Hearing impairment, Cognitive impairment, Myopia, Anteverted nares, Neurological speech impairment, Microdontia, Microtia, third degree, Ablepharon, Abnormality of female external genitalia, Abnormal nasal morphology, Absent eyebrow, Ambiguous genitalia, Abnormality of the mouth, Abnormality of skin pigmentation, Abnormal eyelash morphology, Aplasia/Hypoplasia of the nipples, Aplasia/Hypoplasia of the eyebrow, Breast aplasia, Autosomal recessive inheritance, Thin skin, Thin vermilion border, Wide mouth, Toe syndactyly, Omphalocele, Fine hair, Atresia of the external auditory canal, Absent eyelashes, Cryptorchidism, Cutis laxa, Cryptophthalmos, Corneal erosion, Dry skin

How does someone get tested for Ablepharon-Macrostomia syndrome?

The initial testing for Ablepharon-Macrostomia syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medican information on Ablepharon-Macrostomia syndrome

This syndrome was first described in two infants by McCarthy and West (1977). The facial abnormalities were severe with absent or vestigial eyelids, a small nose with hypoplastic alae nasi and macrostomia. The ears were small and malformed and corneal scarring with visual defects was a major problem. Other abnormalities included ambiguous genitalia and cryptorchidism, absence of lanugo, ventral hernia and enlarged fontanelles. Hornblass and Reifler (1985) described a male infant with the same condition. He was brought up as a female because of ambiguous genitalia; the authors reviewed the clinical and embryological similarities between cryptophthalmos and ablepharon syndromes. Markouizos et al., (1990) described a further female case. The zygoma is characteristically absent.
Pellegrino et al., (1996) reported a convincing case with a complex chromosomal rearrangement including chromosome 18. There appeared to be a deletion of 18q3->ter and an inversion of 18q12.3->18q21.2. The authors review the similarity with Barber-Say syndrome.
Sibs have now been reported (Cruz et al.,2000). Ferraz et al., (2000) reported that a half-sister of the case reported by Cruz et al., (1995) was also affected. The common father had mild features of the condition. Further support for AD inheritance was provided by Rohena et al., (2011) who reported a child with a convincingly affected father. Amor and Savarirayan (2001) reported a boy with possible mild features of the condition. He was hypoptonic and had seizures. MRI scan showed hypoplasia of the corpus callosum, mild prominence of the lateral ventricles and possible heterotopic grey matter related to the left lateral ventricle.
Stevens and Sargent (2002) report 4 further cases, including a 10-year follow-up of one case previously reported only in an abstract (Markouizos et al., 1990). Hair growth was sparse in adulthood and hearing loss was a problem. The adult females had very small breasts and absent body hair. There was mild short stature. In their literature review these authors note that two-thirds of patients have mild developmental impairment. Camptodactyly of the fingers also developed. A 46 year-old female was reported by Brancati et al., (2004). Unlike other patients, except the one reported by Ferraz et al., (2000), her hair was thick and coarse, but distribution was normal. With time, her skin had become thin, dry and wrinkled. There was also diffuse lentigenes over her back and neck, and there there large pigmented maculae over her shoulders. Skin over the dorsum of her hands seemed redundant.
Note the sib-pair reported by Cavalcanti et al., (2007). One was phenotypically AMS whereas the other had Fraser syndrome. Both were homozygous for the FRAS1 mutation, and the authors suggest that AMS might be in the phenotypic spectrum of Fraser syndrome. Almost complete (1st toe not completely syndactylous) toe syndactyly was reported by Kallish et al., (2011). A cohort of 11 patients was reported by Schanze et al., (2013). No mutations were found in FRAS1 or FREM2 making this condition distinct from Fraser syndrome.
Mutations have now been found in this syndome and in Barber-Say syndrome in TWIST2 (Marchegiani et al., (2015). The 2 syndromes differ in that in ablepharon-macrostomia in lysine at residue 75 was common, whereas in Barber-Say a glutamine or alanine was the cause.

* This information is courtesy of the L M D.

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