Ablepharon Macrostomia Syndrome

Ablepharon macrostomia syndrome (AMS) is an extremely rare autosomal dominant genetic disorder marked by unusual phenotypic features that predominantly affect the head, face, skull, skin, fingers, and genitals. AMS typically leads to abnormal ectoderm-derived structures. The most notable abnormalities include underdevelopment (microblepharon) or absence of eyelids, indicating the ablepharon aspect of the condition, and a wide, fish-like mouth, known as macrostomia.

Recently, researchers and surgeons have questioned the term "Ablepharon" due to new findings and histological evidence showing some eyelid tissue is consistently present. Infants with AMS may also exhibit malformations of the abdominal wall and nipples. Children with AMS might face challenges with learning development, language difficulties, and intellectual disabilities.

AMS results from mutations in the TWIST2 gene, among others, and shares phenotypic abnormalities with Barber–Say syndrome.

Signs and symptoms

AMS is generally marked by unusual appearances of the skin, eyes, fingers, genitals, head, and face. Infants with AMS may have thin, redundantly wrinkled skin and excessive facial creases; wide-set eyes with missing or severely underdeveloped eyelids and down-turned lower eyelids; and a wide, fish-like mouth that might be fused at the corners. Other facial and head features include a broad nasal bridge, wide, flared nostrils, and thick, flared alae nasi (edges of the nostrils).

Abnormalities are also evident in the hands and fingers, as infants with AMS may have webbed fingers with limited flexibility. They may also have small, rudimentary ears set atypically low on the skull. The absence of the zygomatic bone is possible. The skin may be dry and coarse, excessively wrinkled around the face, loose around the hands, but tight around the finger joints, leading to reduced finger function.

Causes

Similar to Barber–Say syndrome, AMS is caused by mutations in the TWIST2 gene affecting a highly conserved residue of TWIST2 (twist-related protein 2). TWIST2 is a basic helix-loop-helix transcription factor that binds to E-box DNA motifs (5'-CANNTG-3') as a heterodimer and inhibits transcriptional activation. TWIST2 regulates mesenchymal stem cell differentiation and prevents premature or ectopic osteoblast differentiation. Mutations in TWIST2 that disturb these functions by altering DNA-binding activity could explain many AMS phenotypes. Current research highlights the substitution of the wild-type amino acid for Lysine at TWIST2 residue 75 as a key genetic cause of AMS.

AMS is inherited in an autosomal dominant pattern, where an affected individual needs only one copy of the mutant allele to express the disease.

Mechanism

The mesenchyme is a mesodermal embryonic tissue capable of developing into various tissues based on the embryo's needs. It can develop into blood, cartilage, and membranes. In a typical patient, TWIST2 is highly expressed during embryonic development, especially in craniofacial development and chondrogenisis. TWIST2 prevents premature maturation of chondrogenic cells and osteoblasts, which form cartilage and bone, respectively. The dominant mutation in TWIST2 causes chondrogenic and osteoblastic cells to mature prematurely, leading to the primary craniofacial deformities seen in AMS patients.

Diagnosis

Ablepharon macrostomia syndrome can be diagnosed at birth through identification of characteristic physical findings, clinical evaluation, and specialized imaging techniques such as CT scans.

Treatment

Primary treatment focuses on alleviating immediate symptoms, such as using eye lubrication to relieve pain and dryness; antibiotics may also be prescribed to prevent infections and inflammation. Surgical measures can be taken, and a plastic surgeon can correct the lack of eyelids through reconstructive surgery. Eyelid surgery is considered a surgical emergency during the neonatal period, as eyelids are crucial for lubricating and protecting the cornea and maintaining optimal visual and facial aesthetics. Current eyelid reconstruction approaches involve recessing the levator aponeurosis, widening the shortened septum seen in these patients' eyelids, and descending the lid margin over the fissure before using subsequent skin grafts.

Surgery to correct malformations of the mouth, ears, genitals, fingers, and skin can also be performed as needed. A maxillofacial surgeon can correct macrostomia, the wide, fish-like mouth. Skin treatments include creams to alleviate dryness and coarseness; in some cases, botulinum toxin and skin grafts have been used to improve overall appearance. It is highly recommended that patients seek help from pediatric psychologists throughout the treatment process.

Prognosis

While AMS has no cure, treatment plans from doctors can enhance development, overall quality of life, and physical appearance. Physical appearance cannot be fully corrected to the "norm," but the life expectancy of AMS patients is normal.