Ablepharon-Macrostomia Syndrome (AMS): Causes, Symptoms, Complications, And Treatment

AMS can be described as a rare genetic disorder that can be characterized by ablepharon or microblepharon ( absent or underdeveloped eyelids) along with macrostomia (wide mouth). The key characteristics of the syndrome are that it mainly involves the abnormalities of the face and skin and rarely involves viscera or internal organs. This is because, AMS belongs to a group of diseases that are known as ectodermal dysplasias as it majorly involves abnormalities in the area of skin, sweat glands, hair, nails, and/or teeth.

What makes it distinctive from other ectodermal dysplasias does not involve all the characteristics and that is why it is considered a genuine malformation syndrome. Furthermore, AMS is caused due to TWIST2 gene mutations with autosomal dominant gene making its occurrence spontaneous and sporadically amongst its patients. But, mutations in TWIST2 not only cause ASM but also causes Barber Say syndrome and Setleis syndrome so it's important to get it tested before drawing any conclusions.

As mentioned above, the root cause of Ablepharon-Macrostomia Syndrome is the abnormal mutation of the TWIST2 gene. Since the effects of this condition occurred spontaneously, the affected individual does not inherit the mutation from both of the parents but one of the parents who has mutated the TWIST2 gene in an autosomal dominant pattern. Although in order to get affected by the mutation, the abnormal gene should come from the dominant parent.

This condition is known as a dominant genetic disorder where one of the parents ( the dominant one) inherits a non-working copy of the gene ( also called the silent carrier of the disease). The risk is equally the same for males and females and the probability of passing the non-working gene to your offspring is almost 50% in each pregnancy.

The gene gets its name on the basis of the activity and function that it performs in the human body. This gene encodes over a 160 amino acid protein which can be subcategorized into 2 nuclear localizations named helix-loop-helix (bHLH) domain and a C-terminal.

TWIST2 gene plays an important role in the formation of early bone development and aids in the positive regulator of osteoblast differentiation. Mutation in the gene affects the formation of normal corneal keratocyte proliferation and eyelid morphogenesis. The inability of TWIST2 will lead to early cessation of the proliferation of corneal stromal progenitors making your corneal thinner than required resulting in immature development of stromal keratocytes for the production of the corneal matrix.

TWIST2 is also involved in mesodermal patterning and the production of multiple cell lineages which include cartilage, muscle, adipogenic, osteogenic, and myeloid cells which mainly trigger disorders like Barber-Say syndrome, Setleis syndrome, and Ablepharon-Macrostomia Syndrome.

Since ASMD is a dominant genetic disease, the mutation of the gene which causes the disorder has to be inherited from one of the parents. Even though your parents don't have the default genetic trait, it can transfer from any of their family members.

The design of the genetic pattern of a human is a combination of genetics inherited by the parents, that is it can be possessed by either one from the father's side or the mother's side. Dominant genetic disorders such as AMS developed only when a person received a TWIST2 mutated gene from one of the parents. The chances can vary from case to case, like:

• If one of the parents has a faulty gene and another has a normal copy of a gene, the offspring might get a faulty gene.
• If both of your parents have faulty genes, there is a 50% chance that you have the genetic mutation.
• If one of the grandparents along with your parents has been a carrier of the faulty gene, there is a 50% chance that you might get affected.
• If any of the parents don't have any genetic mutation, and never have been a carrier of the mutation, there is a 25% chance that you might have it. It is quite rare but few cases have been detected.

Autosomal dominant is a pattern of inheritance where affected individuals possess one copy of a mutant gene (autosomal chromosomes) and one copy of the normal gene. An individual with autosomal dominant diseases has a 50-50 chance of passing the mutant gene to their offspring.

On the other hand, the autosomal recessive disease is a pattern of inheritance where the affected individual possesses two copies of the mutant gene. This disorder is only passed when both of the parents have the same genetic mutation. This can also happen if one copy of the gene is dominant and one copy is recessive.

The chances of getting affected by the genetic mutation can be different, for example, there is a 25% chance that a child may turn out to be normal with no mutation whatsoever or become get affected with two recessive genes, but in this case, there is a 50% chance that the offspring will become a carrier of the disease with no such medical condition.

Common signs of Ablepharon-Macrostomia Syndrome can show its effect anytime throughout your life and that may include:

• Low-set ears with attached earlobes.
• Camptodactyly ( fusion of fingers).
• Camptodactyly ( distortion of fingers).
• Bulging cheeks.
• Small or no nipples.
• Redundant and wrinkled skin.
• Sparse or no hair.
• Genital malformations.
• Underdevelopment or absence of eyelids, eyebrows, and eyelashes.
• Wide mouth.

Further complications from the initial symptoms may include:

• Ectropion - the inward turning of upper or lower eyelids.
• Lagophthalmos - exposure of inner mucous membranes making it difficult for eyes to shut.
• Photophobia - sensitivity to light.
• Syndactyly - Abnormal loose skin over the hands.
• Alacrimia - inability to produce tears.
• Nystagmus - involuntary and repeated eye movements.
• Strabismus - inward unequal deviation of the eyes.
• Partial or complete separation of the retina.
• Detached retina.
• Vision loss.

Infants affected by Ablepharon-Macrostomia Syndrome may show additional signs like:

• Wide nasal bridge.
• Small chin.
• Low set ears with attached earlobes.
• Flared nostrils.
• Impaired hearing.
• Philtrum -long groove between the nose and lips.
• Alae nasi - thick-flared edges of nostrils.
• Cheek pads like appearance due to bulging cheeks superolateral in the corners of the mouth.
• Absence of zygomatic arches in the skull.
• Lanugo - Absence of the soft, downy hair.
• Redundant and wrinkled skin.
• Sparse scalp hair.
• Absent nipples.
• Abdominal hernia.
• Underdeveloped or unusual genitalia formation (cryptorchidism and hypospadias).
• Small penis in males and small labia minora in females.

Apart from physical abnormalities, ASM often causes delayed cognitive development which might not be seen at the initial stages but as the diagnosis goes further, it will come into detection.

Due to its multipurpose function in the encoding process of bones and skin cells, the mutation in the TWIST2 gene not only develop Ablepharon-Macrostomia Syndrome but has the potential to develop other medical conditions like:

• Barber-Say syndrome (BSS): It is a very rare condition that can be described as excessive hair growth or hypertrichosis in an abnormal way followed by atrophic (papery thin and fragile skin), ectropion (outward turned eyelids), and macrostomia (a large mouth). What makes BSS from AMS is the presence of a different set of symptoms like:
  • Excessive hair growth
  • Narrow ear canals
  • Less marked eye findings
  • Normal hands and genitalia
• Setleis syndrome: Also known as focal facial dermal dysplasia 3, can be described as a distinctive skin abnormality that affects the facial area since the time of birth. Most of the cases that came into existence were of infants with bitemporal (multiple, scar-like, circular depressions on both temples).

  Setleis syndrome exhibits identical symptoms to AMS and BSS, but the only characteristic that makes it different from the other two is the intensity of the symptoms. The projection will be slightly milder with (entropion) inward folding eyelids, absence of cheek pads, and bitemporal narrowing.

The medical diagnosis of Ablepharon-Macrostomia Syndrome can be detected from birth via clinical evaluation, family medical history, and physical examination through sampling and testing. It is difficult to identify differences between BSS and AMS through regular testing, so molecular genetic testing for mutations in TWIST2 is required.

Apart from the molecular testing here is a list of testings that are been conducted to diagnose the cases of AMS:

• Computerized tomography (CT) scanning - detects skeletal abnormalities like maxillary and mandibular prominences and absence of the zygomatic arch.
• Eye testing to determine the overall development and related damage caused due to abnormalities of eyelids.

The core of the treatment is mainly focused on the affecting symptoms. AMS directly affects the presence of healthy eyelids, so the treatment medical professionals prefer is corrective and reconstructive surgery. These surgeries will be aimed at preserving and reducing any visual complications such as corneal clouding (opacification) that has been commonly witnessed during the neonatal period.

Additional surgeries and medical procedures will be conducted at a later age amining the more improved function and appearance. One of the most complicated symptoms that affect AMS patients is lagophthalmos (inability to close the eyelids). So to manage ectropion and underdevelopment of eyelids a surgery will be conducted to transfer the skin flaps to the lid region.

Further corrective surgeries can be done to correct the discomfort of fingers, skin, or ears. Providing supportive therapy such as lubricant eye drops early on may improve symptoms of eye dryness. These may include:

• Local flaps correction.
• Face-lift procedures.
• Forehead lifting.
• Botox injections.
• Fat grafting.
• Orthognathic surgery.
• Nasal reconstruction with rib cartilage grafts.

These procedures are not openly recommended to every patient, especially to young ones as they may risk craniofacial growth.

Genetic counseling will also be recommended for patients and their families to build an understanding of the genetic inheritance and medical history of the family with AMS. Not only for the patient but for the guardians and other family members psychosocial support has been recommended for overall healthcare.

Psychosocial support for children with AMS is also recommended as it is important as they grow and face the social pressures and societal stigmas of the ideal human body. These may be related to the overall physical appearance of the patient. A team of well-informed healthcare professionals may be provided to the patient and their family, to help them cope with both the medical and psychosocial aspects of the condition.

Summary: AMS can be described as a rare genetic disorder that can be characterized by absent or underdeveloped eyelids along with a wide mouth followed by low-set ears with attached earlobes, wrinkled skin, etc. Caused by a mutation in the TWIST2 gene mutations, the side effects of this condition are severe and spontaneous in nature.