Introduction

Ablepharon-Macrostomia Syndrome (AMS) is a rare genetic disorder characterized by the absence or underdevelopment of the eyelids (ablepharon or microblepharon) and a wide mouth (macrostomia). AMS is caused by changes (mutations) in the TWIST2 gene, which we will discuss later. It is part of a group of diseases called ectodermal dysplasias, which are genetic disorders that cause defects mostly in the skin, hair, nails, sweat glands, and/or teeth. Although AMS usually affects external organs (mainly the face and skin), it can also impact internal organs.^1,2

Importance of early diagnosis

Impact on patient care 

Knowing when symptoms may have appeared is of vital importance for doctors to find the correct diagnosis. The first symptoms for an initial diagnosis can begin to show during pregnancy or with the newborn baby. However, there is also a possibility that they may manifest in other age ranges. The best approach is to perform a diagnosis at birth that includes a clinical evaluation, a detailed history of the patient and their family, and the identification of characteristic physical findings.^1,2

A vital part of patient care is the psychological treatment for children who suffer from these conditions, as they are often forced to face social pressures and bullying due to their physical appearance. Individuals with this condition have testified to the importance of building self-esteem and having constant support from family members.¹

Management

The most commonly used treatment at an early age consists of corrective and reconstructive surgery aimed primarily at preventing vision loss and reducing visual complications. To avoid symptoms of dry eyes, lubricating drops are often used. Subsequent surgeries in many cases will be more oriented towards improving appearance and function, such as enhancing eyelid closure through the transfer of skin flaps. A potential complication is lagophthalmos, where the eyes cannot close fully. For issues with the fingers, skin, and ears, corrective surgeries are available, though their effectiveness is not well-documented.

Molecular genetics testing is very important for evaluating hereditary disorders. Genotyping can provide crucial data that, in addition to being used for diagnosis, can be used to make a better prognosis and guide treatment selection and response.³

Role of genetic and molecular testing in early diagnosis

A very useful way to confirm this clinical diagnosis can be through molecular genetic testing to detect mutations in the TWIST2 gene.^1,2

Molecular genetics testing is very important for evaluating hereditary disorders. Genotyping can provide crucial data that, in addition to being used for diagnosis, can be used to make a better prognosis and guide treatment selection and response.³

Overview of Ablepharon-Macrostomia Syndrome

Clinical Features

Physical abnormalities 

The clinical features of this syndrome are not yet fully delineated.

Regarding the eyes, apart from malformations and the absence of eyelids, it can also cause the loss of eyelashes and eyebrows. Some deformities of the eyelids can lead to corneal exposure and consequently secondary vision loss.⁴

Other facial malformations include macrostomia, which can be secondary to an abnormal fusion of the lips. Micrognathia, characterized by a small and undersized lower jaw, has also been described and can affect breathing and feeding.^4,5

Associated anomalies 

The outer part of the ears is not fully developed. The nostrils are oriented forward, and the nasal bridge is low. There is no presence of the zygomatic arch, and there is often an absence of nipples, as well as ambiguous genitalia. Hair on the head is very sparse or absent, while skin abnormalities result in very rough, dry, and folded skin. Mild cutaneous syndactyly, camptodactyly, contracted fingers, and shortening of the metacarpals have sometimes been found. Some patients experience hearing problems and growth delays, although cognitive ability is not affected.⁴

Genetic Basis of AMS

Known genetic mutations (e.g., TWIST2 gene)

Specific mutations in the TWIST2 gene domain can be crucial. A lysine substitution in this domain is associated with Ablepharon-Macrostomia Syndrome (AMS) and follows an autosomal dominant pattern. This means that a single altered copy of the gene is sufficient to cause this condition.⁴

Inheritance patterns

It is still not entirely clear whether ablepharon-macrostomia syndrome follows an autosomal dominant or recessive inheritance pattern. The majority of cases occur sporadically (when there are no other cases in the family). However, many experts agree that if inherited, the pattern could be autosomal dominant, meaning that a single altered copy of the gene is sufficient to cause the syndrome. Research is ongoing to confirm the definitive inheritance pattern.^2,4 

Molecular and Genetic Testing Methods

Types of Genetic Testing

Diagnostic testing

These tests are used to detect whether the patient has a specific genetic disorder or disease. The drawback of this test is that, since thousands of diseases can be caused by a single gene, it is sometimes impossible to determine the severity of the disease or the age of onset.⁶

Carrier testing

This test is used to determine if you are a carrier of a specific gene for certain genetic mutations. If done during pregnancy, it can help detect the likelihood of the child having a genetic disorder. ⁷

Prenatal testing

These tests are performed during pregnancy and can confirm if the fetus has any genetic disorders. There are two types of tests: prenatal screening, which indicates the likelihood of the fetus having an aneuploidy or other disorders, and prenatal diagnostic tests, which are conducted on fetal or placental cells to confirm whether the fetus has a disorder or not.⁸

Preimplantation genetic diagnosis (PGD)

This test provides a genetic diagnosis of embryos at the preimplantation stage to detect genetic disorders. It was created for couples whose offspring are at risk of inheriting genetic diseases.⁹

Molecular Techniques

• DNA sequencing (e.g., Sanger sequencing, Next-Generation Sequencing)
• Polymerase Chain Reaction (PCR)
• Microarray Analysis
• Comparative Genomic Hybridization (CGH)

Process of Genetic Testing for AMS

Indications for Testing

Clinical suspicion based on physical features

While clinical diagnosis is very practical for understanding the condition, it is often too subjective. Therefore, in many cases, when the doctor has suspicions, genetic tests are performed to identify the genes responsible for genetic problems.¹⁰

Family history of AMS

It is recommended to start by testing someone with symptoms. If a genetic alteration is detected, the same test can be performed on other family members. Results from the parents can help determine if the disorder was inherited or occurred for the first time in the patient.¹⁰

Sample Collection

Samples usually include blood, saliva, buccal (cheek) swabs, or skin biopsies. The DNA from these samples is compared with a genetic information database to identify any variants in the genes that may explain the symptoms.¹⁰

Laboratory Analysis

DNA extraction

DNA extraction purifies DNA using physical and/or chemical methods. It involves breaking cellular membranes to separate DNA from proteins and other components.¹¹

Specific tests based on suspected mutations

• Single gene testing
• Targeted gene panel testing
• Exome sequencing
• Genome Sequencing

Interpretation of Test Results

Positive Results

When a genetic test is positive, it means that the altered gene has been found and the diagnosis of AMS is confirmed. The change may be de novo (newly occurring) or it may have been inherited. These tests can also shed light on how this condition is transmitted within families, which can be beneficial. Additionally, understanding the cause of the symptoms can provide relief to family members and help them find other families with the same type of disorder.^10,12 

Negative Results

When a genetic test is negative, it means that the altered gene was not found, and the diagnosis of AMS is not confirmed. However, this does not mean that the patient does not have the condition. Sometimes tests can fail, so it is not wrong to perform additional tests just in case.¹⁰ 

There may also be a Variant of Uncertain Significance (VUS). This means that there is a genetic alteration, but there is not enough information to confirm whether it indicates AMS. Testing other family members may help clarify this result. Sometimes a VUS is eventually classified as benign, indicating that the gene function is not clinically significant or pathogenic. It is important not to make a diagnosis based on a VUS.¹⁰ 

Implications of Genetic Testing

Clinical Management

Children diagnosed with Ablepharon-Macrostomia are given a specific treatment plan to address various medical conditions. Doctors may recommend certain plastic surgeries to correct and alleviate body abnormalities. The nature of these surgeries will vary depending on the age and health of the patient. In some cases, there is a minimum age at which children can begin undergoing surgery.¹³

Genetic Counseling

Genetic counselors work with families to assess the potential risk of genetic conditions by analyzing family history and inheritance patterns, as well as calculating recurrence probabilities. They are skilled at presenting complex technical information in a way that families can understand the genetic risks and diagnoses.

Genetic counselors also guide families on how these conditions impact cultural, personal, and familial contexts. They also facilitate access to educational services, support, and advocacy groups.¹⁴

Ethical Considerations

Doctors often handle confidential information by limiting it to the patient and their immediate family. This approach allows them to alert relatives about hereditary risks without breaching patient confidentiality.

The General Medical Council (GMC) maintains that information should be kept confidential but acknowledges some exceptions, such as when failing to disclose might endanger another person. The exact level of risk required to justify such disclosure is not specified, but when patient and family interests conflict, doctors should prioritize the patient's care while adhering to guidelines and national directives for protecting patient confidentiality.¹⁵

Potential for discrimination

Genetic discrimination refers to "treating individuals unfairly based on a characteristic of their genetic code, such as the risk of developing certain genetic disorders." Genetic information itself is valuable and can be used for biomedical research and preventive medicine.

However, doctors must be aware that indiscriminate use of this information can lead to issues of privacy, confidentiality, and consent. A person's access to medical care, employment, and other rights could be negatively affected by such practices.¹⁶

Summary 

Ablepharon-Macrostomia Syndrome (AMS) is a rare genetic disorder caused by mutations in the TWIST2 gene. Its most characteristic anomalies include the absence or underdevelopment of the eyelids and a wide mouth. It also primarily affects the skin, hair, and other facial features.

Genetic testing encompasses diagnostic, carrier, prenatal, and preimplantation genetic diagnosis tests. Results can confirm AMS, show negative diagnoses, or reveal variants of uncertain significance that require further testing.

These tests are crucial for effective clinical management and genetic counseling, assisting families in understanding the associated risks and available options.

FAQS

Who discovered Ablepharon macrostomia syndrome?

It was discovered by McCarthy and West in 1977, and since then only 4 cases have been reported.¹⁷

How common is macrostomia?

It has an incidence rate between 1 in 60,000 and 1 in 300,000 live births.¹⁸