An overview of ablepharon-macrostomia syndrome

Ablepharon-Macrostomia Syndrome (AMS) is an extremely rare genetic disorder that is characterised by a mutation of the TWIST2 gene, which can cause abnormal formation of the skin, face, teeth, and genitalia, as well as cognitive and behavioural deficits. This disease is autosomal dominant, meaning a mutation in one parent of the dominant gene is enough for it to be expressed in offspring, even when the parent with the mutation does not show symptoms themselves. The TWIST2 gene is responsible for coding 160 different amino acids in the body, and its mutation has been linked to a number of diseases such as AMS, Barber-Say Syndrome (BSS) and Setleis Syndrome, which all have similar symptoms. As the TWIST2 gene is responsible for the development of bones and tissues prominently in the face and skin, a mutation to this gene in early development results in a variety of physical symptoms, but the cognitive and behavioural symptoms that have been associated with certain patients are still an active area of research. The question of whether these symptoms are a direct link to AMS or whether these symptoms occur because of the presence of another disease accompanied by AMS is a question still being asked by medical professionals. 

Cognitive symptoms of AMS

Whilst the physical symptoms of AMS have been recorded in detail by multiple professionals in the 16 current patients that have been diagnosed with this rare disease, cognitive symptoms have been less consistent within these patients, which leaves room for further research to be conducted. Out of 16 patients that were reviewed in the study conducted by De Maria et al. in 2016, only 6 patients with AMS showed cognitive delay. Two patients in McCarthy and West’s study in 1977 showed delayed expressive language development, which may be caused by neurological symptoms of the disease or dental abnormalities associated with the malformation of the skull in AMS. However, the review by Rohena et al in 2011 found a case of AMS where the patient had less severe physical symptoms as well as no signs of cognitive decline. Cognitive impairment can also be affected by other symptoms of the disease.  Poor vision and loss of hearing are common aspects of AMS and can impact performance in education and affect everyday life.

Behavioural aspects of AMS

As with cognitive aspects of AMS, behavioural development in the 16 patients who have been diagnosed with this disease has been inconsistent, with some clinical reviews finding developmental delay in children, whereas other patients seem to show normal behavioural development. The study by Hornblass and Reifler in 1985 suggested that there were some developmental delays in the AMS patients, but they still had some control over their bodies, such as being able to sit unassisted and follow objects with limited gaze fixation as well as grasp objects. However, the review by Ferraz et al. (2000 found no developmental delay in the patient with no sign of cognitive impairment, suggesting that AMS is mostly seen without cognitive or behavioural deficits in patients. As with cognitive impairments, behaviour may be affected by certain physical characteristics of the disease. Limb malformation, such as clubbed feet or loss of fingers, may impact the patients’ abilities to develop normal behaviours such as a speech impediment or limited grasping of objects with hands. This suggests that physical attributes of the disease and their severity may also impact the patient in other areas.

Summary

AMS is a rare genetic disorder that affects the development of facial structures, limbs, skin and hair growth, as well as possible stunted growth. The disease is suggested to be autosomal dominant, as only one parent carrier is required to produce offspring that show symptoms of the disease. AMS was found to be caused primarily by the mutation of the TWIST2 gene that causes malformation of mesodermal development within embryonic stages. Whilst the physical signs of this disease can be quite extreme and unique to this disease, there has been mixed evidence as to the cognitive and behavioural aspects of this disease, partly due to the small number of patients confirmed to have the disease. A third of all patients reviewed have shown signs of developmental delay, ranging from limited control of fine movements to speech disorders, as well as some patients have shown cognitive delay. However, two-thirds of patients reviewed have shown no such symptoms to suggest that cognitive or behavioural development is affected by the disease, and so this is still a topic of investigation within the medical sphere, which will develop as more patients arise in the medical community.

FAQs

What are the symptoms of AMS?

The symptoms of AMS are sometimes hard to differentiate from other TWIST2 mutation diseases, such as BSS, but can include features such as:

• Malformation or missing eyelids, eyelashes or eyebrows
• Wide mouth with missing or malformed lips
• Wrinkled skin on the face or body
• Lack of hair on the body
• Lack of or deformed nipples 
• Low set ears
• Fusion or distortion of fingers
• Detached retina 
• Broad nasal ridge
• Malformation of genitalia