Ablepharon Macrostomia syndrome is a pretty rare congenital disorder which as a result has not been discussed as much. In this article we will be looking at what Ablepharon Macrostomia syndrome is, and how it is managed/treated before looking at its genetic basis and inheritance patterns. Genetics can be quite tricky to understand but this article aims to explain it in a simplified manner.

Introduction

What is Ablepharon-Macrostomia syndrome?

Ablepharon Macrostomia syndrome (AMS) is a rare disorder where individuals are born without eyelids and with large mouths. They also have no eyebrows or lashes and dry, loose sagging skin. Other features sometimes present in AMS patients include having webbed fingers, irregular nose, abnormally shaped outer ears and absent or extra nipples.¹ 

AMS doesn’t appear to reduce life expectancy or have an impact on the cognitive function of the individual- abnormalities are mainly external.²

Treatment/management

The lack of eyelids and lashes makes it necessary to use ocular lubricants and antibiotics from birth. The babies may also be temporarily kept in moisture chambers with plastic wrappings.¹

The infant would require eye surgery, usually within the first few months after birth, so that they have eyelids.²

Some individuals with AMS may get cosmetic surgery for other facial features in their late teens or during the stages of early adulthood.²

Cause

At first researchers had suggested that AMS was an autosomal recessive condition. This would mean that a child must have inherited the AMS gene from both parents (one from mother, one from father) and would therefore have two copies of the gene. The parents would have 1 normal and 1 AMS gene themselves, so would not have the disorder. However, Ablepharon Macrostomia syndrome is now believed to be autosomal dominant.¹

Genetic basis and inheritance patterns

Autosomal dominant

A condition is considered autosomal dominant when only one copy of the gene is required for the individual to have that condition. At least one of the parents would also have the disorder.

Cases where a parent with AMS has passed the disorder on to their offspring supports the idea that AMS is autosomal dominant.³

Transcription and transcription factors

Humans have one copy of their DNA in each cell. The DNA is enclosed within the nucleus of the cell and cannot get out. This is essential to prevent DNA from becoming damaged. 

However, the information that the DNA provides is essential for making proteins in a process known as protein synthesis, but the part of the cell where protein synthesis occurs is outside the nucleus of the cell. Luckily, we have a clever way in which the information from the DNA is relayed to the part of the cell where protein synthesis occurs that would not involve DNA leaving the nucleus- messenger RNA (mRNA). 

In a process known as transcription, your DNA is used as a template to make mRNA. mRNA contains the genetic information that is needed to code for the proteins and can leave the nucleus, so this is used in protein synthesis to create proteins- DNA never has to leave the nucleus. 

Transcription itself is regulated by a group of proteins known as transcription factors. 

TWIST-2 mutation

TWIST2 are transcription factor. Research has found that Ablepharon Macrostomia syndrome is caused by what is known as a point mutation in one of the amino acids in TWIST2.⁴ 

Amino acids are the single units that make up proteins and there are a total of 22 of these, each with varying structures. A point mutation in a single amino acid results in the replacement of one amino acid with another In AMS, a glutamic acid in the TWIST2 transcription factor is replaced with Lysine,⁴ resulting in a change to the structure of the DNA-binding activity of TWIST2.³ 

Since TWIST2 is responsible for regulating (mesenchymal) stem cell differentiation and plays a key role in the development of chondrogenic (cartilage) and dermal tissues this could explain the abnormal facial features in AMS.³

Summary

So, overall, Ablepharon Macrostomia syndrome is a congenital disorder caused by a point mutation in TWIST2. This means that the transcription factor TWIST2 is not able to properly perform its function, resulting in the characteristic features of AMS. There is currently a lack of research done on this disorder compared to many others due to just how rare it is and initially it was thought to be an autosomal recessive disorder. It has, however, now been established that this is in fact autosomal dominant. More research is still needed to learn more about AMS.