Ablepharon macrostomia syndrome is a rare ectodermal dysplasia first reported in 1977. It is characterized by restricted eyelid formation, enlarged mouth (macrostomia), small ears (microtia), loose skin, sparse hair, genitourinary abnormalities, and growth deficiency.
The term “ablepharon” is technically a misnomer. In this syndrome, eyelid development is not completely absent but “restricted,” with a mucocutaneous junction remaining at the upper and lower eyelid margins. Hornblass and Reifler (1985) proposed that the eyelid findings in this syndrome should be considered microblepharon [3].
Only about 20 cases have been reported in the literature. Ocular and oral symptoms are evident at birth and may be detected by prenatal ultrasound. Cognitive function and life expectancy are usually not affected, but untreated keratopathy can lead to lifelong visual impairment.
Most cases occur due to sporadic mutations. However, autosomal dominant inheritance has also been reported, with confirmed cases of transmission between father and daughter.
Ablepharon-macrostomia syndrome is evident from birth. The main subjective problems are as follows.
Clinical findings of ablepharon macrostomia syndrome are divided into ocular findings and systemic findings.
Ocular Findings
Eyelid hypoplasia: Eyelid tissue is present but severely underdeveloped. Eyebrows and eyelashes are absent.
Corneal opacity: A major ocular complication reported in many cases.
Corneal erosion: Occurs due to lack of eyelid protection.
Cryptophthalmos: Observed in many cases.
Myopia: Reported in many cases.
Systemic Findings
Macrostomia: The mouth angle is significantly enlarged. This is a characteristic facial finding of this syndrome.
Microtia: Accompanied by abnormal development of the outer ear.
Cutis laxa: The skin throughout the body becomes loose and redundant.
Sparse or absent hair: Scalp hair is thin or missing.
Genitourinary abnormalities: Abnormal development of the genitalia is observed.
Other systemic findings include syndactyly, camptodactyly, growth restriction, and mild developmental delay. In adults, absence of the zygomatic arch, micrognathia, and hypoplasia of the nasal alae, cheeks, and breasts have been reported.
It depends on the degree of corneal opacity and corneal erosion. If corneal protection and eyelid reconstruction are performed early, useful vision can be maintained, but delayed intervention may lead to lifelong visual impairment. Some cases have residual high astigmatism.
Ablepharon-macrostomia syndrome is caused by mutations in the TWIST2 gene. This gene is also involved in Barber-Say syndrome and Setleis syndrome.
Most cases result from sporadic mutations. Autosomal dominant inheritance has also been reported. Marchegiani et al. identified a heterozygous missense mutation (E75K) in the TWIST2 gene in a father-daughter pair with ablepharon-macrostomia syndrome, and the same mutation was subsequently confirmed in eight additional patients with ablepharon-macrostomia syndrome [1].
This mutation alters the DNA-binding activity of the TWIST2 protein. It is thought to produce both dominant-negative and gain-of-function effects through transcriptional changes in multiple genes.
Barber-Say syndrome is caused by point mutations (glutamate to glutamine or alanine) in the same TWIST2 gene locus [1]. It shares macrostomia and eyelid developmental abnormalities, but the clinical presentation differs in the following ways [2].
| Feature | Ablepharon-macrostomia syndrome | Barber-Say syndrome |
|---|---|---|
| Skin | Lax | Atrophic |
| Body hair | Sparse/absent | Hypertrichosis |
| Eyelid | Hypoplasia | Ectropion |
The difference in phenotype between the two syndromes is thought to be due to transcriptional changes associated with slight differences in DNA binding.
The diagnosis of ablepharon macrostomia syndrome is based on characteristic clinical findings. The combination of eyelid hypoplasia, macrostomia, microtia, and loose skin is evident from birth and may be noted on prenatal ultrasound.
Ablepharon-macrostomia syndrome is clinically diagnosed based on a combination of the following findings.
Definitive diagnosis is possible by mutation analysis of the TWIST2 gene. The missense mutation E75K is known as a representative mutation.
Barber-Say syndrome is the most important differential diagnosis. It is caused by mutations in the same TWIST2 gene, but differs from ablepharon macrostomia syndrome in that it is characterized by ectropion, hypertrichosis, and atrophic skin. Differentiation from other diseases presenting with congenital eyelid morphological abnormalities, such as blepharophimosis syndrome and Goldenhar syndrome, is also important.
Prenatal ultrasound may reveal abnormalities of the eyelids or mouth. Mutation analysis of the TWIST2 gene is useful for confirmation.
The priority in treating ablepharon macrostomia syndrome is corneal protection. Management follows a stepwise approach.
The following conservative treatments are started immediately after birth:
In severe cases with persistent corneal epithelial defects, temporary tarsorrhaphy may also be considered. The goal is to cover the cornea while maintaining an opening of 2–3 mm, rather than complete eyelid closure.
This is a radical treatment to prevent long-term corneal damage and scarring.
Historically, the following methods have been used.
Among these, eyelid lengthening with skin grafting onto the tarsoconjunctival surface is considered to yield the best results. Cruz et al. reported that in patients who underwent eyelid lengthening by posterior advancement of the levator aponeurosis and skin grafting onto the tarsoconjunctival and Müller muscle layer, corneal transparency and useful visual acuity were maintained during long-term follow-up of 10 to 15 years [4].
After eyelid reconstruction, continuous monitoring for the following complications is necessary.
Even with early intervention, strong astigmatism or a small, curved cornea may persist.
Initially, conservative corneal protection is performed, and surgery is generally considered after 2–3 years of age unless corneal epithelial damage is severe. However, the timing is determined individually based on the degree of corneal damage and systemic condition.
TWIST2 is a transcription factor expressed in the craniofacial region. It plays an important role in mesenchymal tissue differentiation and cartilage formation during embryonic development.
Mutations in the TWIST2 gene lead to changes in tissue development. This results in characteristic morphological abnormalities such as eyelid hypoplasia and macrostomia.
Electron microscopy of a father and daughter with ablepharon macrostomia syndrome revealed the following findings.
The degree of change in DNA binding activity varies depending on the mutation site of the TWIST2 protein. In ablepharon macrostomia syndrome, a missense mutation E75K (glutamic acid to lysine) has been identified, which exerts both dominant-negative and gain-of-function effects. In contrast, Barber-Say syndrome involves different amino acid substitutions (glutamic acid to glutamine or alanine) in the same region. It is inferred that this slight difference in binding activity determines the distinct phenotypes of the two syndromes.
