Introduction

Ablepharon-Macrostomia (AMS) is an extremely rare genetic disorder characterised by absent or underdeveloped eyelids (ablepharon) and an unusually wide mouth (macrostomia). Symptoms may appear during pregnancy and following birth and can vary between individuals. There is limited knowledge regarding causation, prognosis, and treatment of the disease.  Researchers have identified the syndrome in some individuals to be caused by mutations in the TWIST2 gene. 

Only 20 patients have been reported as having AMS, with the first case being in 1977.² The rarity of AMS results in a lack of medical care, psychological pressure on the patients, and a level of loneliness,³ highlighting  the importance of gaining a better understanding of AMS. Additionally, mutations in the TWIST2 gene are also present in other syndromes such as Barber-Say, Setleis, and in conditions such as ectodermal dysplasia, so there is a need to generate new differential diagnostic methods.

In this article we will focus on understanding the different clinical features, diagnosis, cause, treatment, and prognosis of AMS, exploring how it can be differentiated from other syndromes with similar symptoms.

Clinical features

Considering AMS manifests differently in individuals, the features medical professionals look for can be characterised  as very frequent, frequent, and occasional.  

Examples of very frequent features

• Ablepharon of eyelids (absent eyelids)
• Wide mouth (macrostomia)
• Failure to develop eyelashes and eyebrows
• Delayed speech development
• Underdevelopment of the zygomatic bone (cheekbones)
• Microtia (underdevelopment of external ear)

Examples of frequent features

• Abnormality of female genitalia
• Ambiguous genitalia (external genitals not clearly defined)
• Upturned nose
• Absent or small nipples
• Underdeveloped breast
• Clouding of the cornea of the eye
• Dry skin
• Wrinkled skin
• Delayed intellectual development
• Hearing impairment
• Microdontia (decreased size of teeth)

Occasionally there are other features such as abnormal hair patterns, skin pigmentation, depressed nasal bridge, and growth delay that may present in individuals with AMS.

Individuals with AMS mature and often experience societal problems connected to their physical appearance; psychosocial assistance or therapy may benefit certain patients affected in this way.

Diagnosis

The clinical evaluation of AMS is mostly based on physical findings, which are mentioned in the clinical features section. Additional clinical testing is usually done to confirm mutations in the TWIST2 gene. According to the National Library of Medicine, genetic testing for this gene is usually done using CRISPR or new-generation sequencing (methods of detecting targeted mutations in a gene). Some disadvantages faced during testing include the prevalence of false positive and false negative results, individuals not being able to fit a particular criteria required for the testing and the expenses and uncertainties involved overall.

Despite the use of genetic testing for diagnosis, it does not provide differential diagnosis, meaning differentiation between various other syndromes with similar clinical manifestations. The phenotypic abnormalities of AMS are closely linked to that of Barber-Say syndrome and Setleis. There is still a need for research into further diagnostic tests and tools to be performed. For example, health professionals usually use imaging techniques such as CT scans and MRIs to confirm abnormalities in AMS, but these scans can show abnormalities that are also present in other diseases; further diagnostic tools are needed to confirm AMS.

Causes and genetics

As mentioned above, the cause of AMS is a mutation in the TWIST2 gene. The TWIST2 gene is responsible for the inhibition of osteoblast (cells that help with bone growth) maturation. A mutation in the expression of the TWIST2 gene induces  a pathway in our body that stimulates cell death, hence why features such as zygomatic bone underdevelopment are common in patients with AMS.⁴

Research indicates that AMS follows an autosomal dominant inheritance pattern. This means that a single dominant copy of the mutated TWIST2 gene can be inherited and passed onto offspring. However, it is important to note that AMS can also manifest sporadically without a familial pattern. That being said, opting for genetic counselling is advisable for couples trying to conceive. Testing could reduce the risk and aid them in comprehending and preparing, both psychologically and medically, for any potential genetic contributions that may lead to offspring with AMS.

Treatment and management

There is currently no cure for AMS, but there are treatments in place that mainly involve surgery. Additionally, a multidisciplinary approach is essential in treating AMS patients as the treatment involves various health professionals from different backgrounds including GPs, social workers, and supportive care.

Surgical interventions are the most essential in the treatment of AMS. They usually occur later in life targeting the correction and improvement of physical appearances and their functionality. These surgeries can be face-lifts, nasal reconstructions, or forehand lifting. Some orthodontic procedures can also be performed to correct the wide mouth feature, and Botox to ease the symptoms.

As more research goes into understanding AMS, more treatment options will be brought forward.

Prognosis

While the physical appearance of individuals with AMS may not be fully correctable, their life expectancy appears to align with that of individuals without the condition. The prognosis of AMS is based on the reported cases only since there are cases where some individuals have no access to better healthcare and therefore have not been diagnosed. Also, no studies show a correlation between AMS, underlying health conditions and opportunistic diseases.

Research and advances

A promising area of research in AMS is gene editing as a way of curing and diagnosing AMS. This research is, however, more theoretical than practical when applied to individuals who have AMS. In unborn individuals, however, gene editing can be done in vitro by adding a model copy of a functional TWIST2 gene or a gene that silences the TWIST2 mutation. Performing IVF as a way of reproduction is also a viable option.

Additionally, foetal surgery (involves surgical procedures on unborn babies) can be done to improve the appearances of AMS patients, especially since foetal bones are not fully developed until about age 25.

The only downside to these advances in the research of AMS is the target to only unborn and foetal offspring. This is logical because little knowledge is known regarding the syndrome. It is important that more cases be reported and AMS patients be encouraged to participate in clinical studies.

Summary

• AMS is caused by a mutation in the TWIST2 gene and there is currently no cure for it.
• Symptoms of AMS vary between individuals but there are common ones like underdevelopment of eyelids and a zygomatic bone.
• Most treatments involve correctional surgery and do not happen until patients are older.
• Current research is focusing on gene editing techniques as well as a possibility of foetal surgery although this goes against ethical morals for some.
• It is important to raise awareness of the syndrome as it has an impact on people's lives.