Introduction

X-Linked Ectodermal Dysplasia(XLED) is a rare genetic disorder that is present from birth. It most commonly affects the teeth, skin, hair or sweat glands.¹ However, there are over 150 variants of this disease.² Individuals assigned male at birth(AMAB) typically experience more severe symptoms than those assigned female at birth(AFAB).³ 

Those AFAB tend to exhibit milder symptoms but can still pass the gene on to their children, who may experience worse symptoms. This can affect the number of children AFAB carriers have, as ⅓ of individuals assigned female at birth decide not to have children.⁴ Especially, as the chances of a child being born with XLED are higher, resulting in a higher risk of early death.⁵  

By examining the clinical and genetic features of female carriers of XLED, we can work towards a better understanding of the condition and improve genetic counselling and care. 

Genetics of X-linked ectodermal dysplasia

Inheritance pattern^6,7

We have 23 pairs of chromosomes in our bodies, made up of sex chromosomes and autosomes. These chromosomes come in pairs, and these individual pairs are called alleles. These alleles are either dominant or recessive. 

• Recessive allele: A gene that is present but does not show any characteristics unless it is paired with another recessive allele
• Dominant allele: Whenever present, its characteristics will show
• Sex chromosomes: Control the sex an individual is born as. Individuals born as males have an X and a Y chromosome. Individuals born as females have two X chromosomes
• Autosomes: All other chromosomes that are not linked to the gender you are born as

Any changes to an autosomal gene will affect both females and males the same way. 

As mentioned in the introduction, there are two types of inheritance patterns that lead to the activation of XLED. 

The first is autosomal recessive inheritance. This is where both parents carry the gene for Ectodermal Dysplasia (ED); however, it is not noticeable in either parent as the gene is recessive (non-working). These parents are then known as carriers. This means that when they have children, there is a 1 in 4 chance that the child will have ED, but they must inherit both non-working genes from the parent.

Then there is autosomal dominant inheritance(see figure 2), where the gene for ED is carried on a dominant allele. Meaning whenever it is present, it will show its characteristics, even if one allele does not have a copy of ED. 

Carrier status 

What does X-linked mean?

XLED means that it is carried on the X chromosome. Whether the mother or father has  XLED will also affect the probability of the children inheriting the condition, depending on whether they are assigned female or male at birth. 

How does X-linked recessive inheritance work?

Individuals assigned male at birth

Since individuals AMAB only carry one X chromosome, if they carry the mutation, they will show the condition, as they do not have the other X chromosome to cancel it out. Leading to all daughters being definite carriers of the gene, but sons will not.

Individuals assigned female at birth

Individuals AFAB have two X chromosomes. If only one of these carries the gene mutation for ED, the other, unaffected X chromosome usually masks the effects. As a result, they typically do not show the full symptoms of the condition and are considered carriers. However, there is a 50% chance that the mutated gene will be passed on to their children.

How does X-linked dominant inheritance work?

Individuals assigned male at birth

The same as X-linked recessive inheritance conditions, if an individual assigned male at birth inherits an X chromosome carrying the gene for ED,  they will develop the condition. Affected males will pass their X chromosome to all their daughters, making them carriers of the condition. However, they pass their Y chromosome to their sons, so their sons will not inherit the mutated gene or condition. 

Individuals assigned female at birth

In this case, if a female inherits one X chromosome with the gene for ED, the condition will develop, with the unaffected X chromosome unable to mask it. Therefore, there is a 50% chance that it will be passed on to all children, no matter the gender assigned at birth. 

Affected genes

The main gene affected by XLED is a gene called EDA(Ectodysplasin  A), which is located on the X chromosome.⁹

EDA is a protein in the body used to develop ectodermal tissues such as skin, hair, teeth and sweat glands. When a mutation occurs in this gene, it disrupts its purpose.¹⁰

Clinical features in female carriers

Individuals AFAB tend to have a mild version of XLED symptoms, which normally includes:¹¹

• Hair thinning
• Sweat problems
• Small or missing teeth 
• Decrease in milk production during nursing
• Underdeveloped nipples

Probability of experiencing symptoms if you are a female carrier⁹

• 80% have teeth abnormalities 
• Over 65% have sparse hair
• 25% have heat intolerance 

Diagnosis and genetic testing

Sweat testing¹²

Sweat testing is done through the use of starch-iodine powder applied to the skin. It then reveals all the pores of the area where the powder was applied. Individuals assigned female at birth who are carriers of XLED will have pores that are unevenly dispersed (even missing in some areas). 

Genetic testing¹³

Normally, a blood, saliva or cheek sample is taken and sent to a lab where direct or indirect testing will be done.

Direct molecular testing (mutation analysis) 

These samples are taken to a lab where they search for the mutation responsible. If a change is found, then family members can also get tested for it. 

Indirect molecular testing (linkage analysis)

If more than one person is affected within a family, then an indirect test is done. The test tracks certain markers in the X chromosome and how it has been passed down in the family. However, it does not directly find the mutation. The results are given as a probability. 

Management and support for female carriers

Normally, for treatment, there is a multidisciplinary group:

1. Teeth

An Orthodontist, an endodontist, and a prosthodontist. Normally, a treatment plan with 5 stages is created for an individual.¹⁴

2. Hair

3%  minoxidil has been used to encourage hair growth, and occasionally, some people tend to use wigs.¹⁵

3. Skin

Emollients are used for dry skin. 

4. Temperature maintenance

Body temperature must be monitored when exposed to heat. Making sure the individual has frequent consumption of water and is wearing a cooling vest.

Future research and clinical implications

Future research should include¹⁶

• Currently, there is no way of doing prenatal testing of maternal blood without it being invasive, which female carriers tend to do if they are aware that they carry the gene
• Tooth germ screening, which is commonly done on individuals with XLED, is done on fetuses in pregnant women; the effects are unknown

Clinical implications include

• Reproductive decision making
  • Studies have shown that female carriers with XLED tend to prevent pregnancy due to the risk of passing on the gene¹⁶
• Early identification of at-risk  infants
  • Knowing whether a pregnant individual, AFAB, is a carrier early on can be important if a male fetus is born. This is because neonatal and pediatric care must be provided straight away, as they are more at risk of death during infancy if the gene is passed on¹⁷
• Support and education
  • Female carriers tend to observe the social exclusion that their male relatives face, especially due to the physical features¹⁸
  • A lot of mothers who are carriers feel guilty for transmitting this to their sons

Summary

Female carriers of XLED typically show mild and variable symptoms because one of their X chromosomes does not carry the mutated gene. However, they have the same chance of passing the affected gene to their children as individuals assigned male at birth who are affected by XLED, often with much more severe symptoms. 

There is a significant risk that children, particularly sons, born to female carriers may inherit the condition and experience serious health complications, including the potential for early death. This risk can make reproductive decision-making especially challenging for female carriers.

Currently, there are limited non-invasive methods available during pregnancy to determine whether a fetus has inherited XLED. Invasive prenatal screening methods that could provide more definitive answers are often not considered safe for all pregnant individuals. This lack of accessible and reliable testing options adds further emotional and ethical difficulties to family planning.

As a result, many female carriers face difficult choices and may struggle with feelings of guilt, especially if their children are born with severe forms of the condition.