Waardenburg syndrome causes hearing loss and changes in pigmentation of the skin, hair, and eyes. People with Waardenburg syndrome usually have two different-colored eyes.

Waardenburg Syndrome

Type 1 Waardenburg syndrome is a rare genetic disorder characterized by hearing loss, changes in pigmentation, and facial abnormalities. It is caused by mutations in the PAX3 gene, which plays a crucial role in the development of cells and tissues. Understanding the symptoms and genetic basis of type 1 Waardenburg syndrome is vital for accurate diagnosis and appropriate management of individuals affected by this condition.

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Ismail Munir

Overview

Waardenburg syndrome (WS) is a rare genetic disorder<a href="#accordion">[1]</a>. It was first described in 1951 by Dutch geneticist and ophthalmologist, Petrus Johannes Waardenburg, after whom this disorder is named<a href="#accordion">[2]</a>. Being a genetic disorder means that this medical condition is passed from one generation to the next, i.e. from parents to their children<a href="#accordion">[1]</a>.

It is associated with hearing loss or deafness since birth (congenital), defects in the pigmentation of the skin, eyes, and hair, and facial abnormalities<a href="#accordion">[3][4]</a>.

WS is classified into 4 different types according to the clinical presentation and genetic mutations that are unique to each type.&nbsp;It is usually diagnosed either at birth or during early childhood. In some cases, however, diagnosis is made at a later age by evaluating the individual for the classic physical features of the disorder; family history and various tests may help confirm the diagnosis<a href="#accordion">[4]</a>.

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WS is estimated to affect 1 in every 40,000 individuals in a population. It is the primary cause for 3% of the congenitally deaf children<a href="#accordion">[4]</a>. Some sources state that 2-5% of congenital hearing loss is due to WS<a href="#accordion">[3]</a>.&nbsp;

Waardenburg syndrome is known to have no gender preponderance since males and females are equally affected. Furthermore, there is no ethnic or racial predilection associated with this disorder<a href="#accordion">[4]</a>.&nbsp;

Among the various types of WS, type 1 and type 2 are found to be the most common types of this syndrome, while type 3 and 4 are rare<a href="#accordion">[3]</a>.

In Pakistan, type 4 WS, which is the rarest form of the disorder, was reported in Rawalpindi in 2017. The patient presented with signs of intestinal obstruction that is characteristic of type 4 WS<a href="#accordion">[5]</a>.

&nbsp;

There are different types of Waardenburg syndrome based on the different genes that are mutated (defective). 6 mutations cause 4 different types of WS<a href="#accordion">[6]</a>, out of which type 1 and type 2 are the most common types. The clinical presentation varies and, oftentimes, the symptoms of the affected parent are different from the ones seen in the affected child<a href="#accordion">[1]</a>.

&nbsp;

<ul>
	<li>
	<h5>Waardenburg Syndrome Type I (Type 1 WS)&nbsp;</h5>
	</li>
</ul>

It is caused by a mutation in the PAX3 gene on chromosome number 2<a href="#accordion">[7]</a>. A chromosome is a thread-like structure in the cell that contains genetic information in the form of genes.&nbsp;

Individuals with type 1 WS have wide spacing between their eyes, a condition that is known as dystopia canthorum since the medial corners of the eyes are laterally displaced<a href="#accordion">[6][8]</a>. Hearing loss is witnessed in 20% of individuals affected with type I WS.&nbsp;

Additionally, these individuals have pigmentation abnormalities such that there are patches of pigmentation (coloration) or loss of pigmentation in the affected region of hair, skin, and eyes. The presence of white patches on the skin due to loss of pigmentation is referred to as leukoderma and the presence of white forelock of hair due to absence of pigment is referred to as poliosis<a href="#accordion">[8]</a>.&nbsp;

&nbsp;

<ul>
	<li>
	<h5>Waardenburg Syndrome Type II (Type 2 WS)&nbsp;</h5>
	</li>
</ul>

It is caused by a mutation in the MITF gene on chromosome number 3<a href="#accordion">[8]</a>. Half of the individuals affected with type 2 WS have defects in hearing. It has been observed that hearing loss is a more common feature of type II as compared to type I. Additionally, the changes in pigmentation of the skin, hair, and eyes are similar to that seen in type I. However, the distinguishing feature of type 2 WS is the absence of wide spacing between the eyes<a href="#accordion">[6]</a>.

&nbsp;

<ul>
	<li>
	<h5>Waardenburg Syndrome Type III (Type 3 WS)&nbsp;</h5>
	</li>
</ul>

It is caused by a mutation in the PAX3 gene on chromosome 3<a href="#accordion">[8]</a>. Type 3 WS is also known as Klein-Waardenburg Syndrome and it is quite similar to type 1 and type 2 since it also presents as hearing loss and pigmentation abnormalities in the skin, hair, and eyes. Individuals with WS may also have wide spacing between their eyes accompanied by a broad nose.&nbsp;

However, the feature unique to Klein-Waardenburg syndrome is the presence of anomalies in the upper limbs (hand and arm region). Individuals with type 3 may have abnormalities in their joints or they may experience weakness in the shoulders and arms. Individuals with Type 3 WS may also have flexion contractures (flexed joints that can&#39;t be straightened), fused digits (syndactyly), and a cleft palate. Intellectual disabilities are also observed in type 3 WS<a href="#accordion">[6][8]</a>.

&nbsp;

<ul>
	<li>
	<h5>Waardenburg Syndrome Type IV (Type 4 WS)&nbsp;</h5>
	</li>
</ul>

It is caused by mutations in the SOX10, EDN3, and EDNRB genes. Type 4 WS is also known as Waardenburg-Shah syndrome or Waardenburg-Hirschsprung syndrome. Along with hearing loss and pigmentation changes, Hirschsprung disease is also present in type 4 WS. Hirschsprung disease is a condition in which nerve cells are missing in the muscles in part or whole of the colon (large intestine), thereby, causing constipation<a href="#accordion">[6][8]</a>.&nbsp;

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Signs And Symptoms

Some of the symptoms of Waardenburg syndrome that are quite common and characteristic of the disorder include<a href="#accordion">[1][6][9]</a>:&nbsp;

<ul>
	<li>Pale skin</li>
	<li>Waardenburg eyes that are pale blue in color</li>
	<li>Heterochromia iridis that means different color of the two eyes</li>
	<li>White forelock of hair near the forehead or early graying or the hair</li>
	<li>Change in vision</li>
	<li>Hearing loss that is more common in type 3 WS than others</li>
	<li>Difficulty in completely straightening the joints as usually seen in type 3 WS</li>
	<li>Slight decrease in intellectual ability</li>
	<li><a href="https://www.merisehat.pk/disease/constipation" target="_blank">Constipation </a>as seen in type 4 WS</li>
</ul>

&nbsp;

Following structural abnormalities are common in people with WS<a href="#accordion">[6]</a>:&nbsp;

<ul>
	<li>Having a small colon</li>
	<li>Experiencing difficulty in the production of tears</li>
	<li>Having a cleft palate&nbsp;</li>
	<li>Having a malformed or abnormally shaped uterus&nbsp;</li>
	<li>Having a broad nose&nbsp;</li>
	<li>Having&nbsp;partially albino skin, i.e., having white patches due to loss of melanocytes (cells responsible for pigmentation)&nbsp;</li>
	<li>Having white eyebrows or eyelashes&nbsp;</li>
	<li>Having either a single eyebrow or a unibrow&nbsp;</li>
</ul>

&nbsp;

Following symptoms and signs are based on the type of WS:

&nbsp;

<h5>Type 1 WS<a href="#accordion">[8][10]</a>&nbsp;</h5>

<ul>
	<li>Wide-spaced eyes</li>
	<li>Hearing loss</li>
	<li>Broad root of nose&nbsp;</li>
	<li>Eyebrows meeting in the midline</li>
	<li>White patches on the skin and white forelock of hair</li>
	<li>Pigmentation defects in the eye, such as pale blue eyes or two different colored irises (heterochromia)</li>
</ul>

&nbsp;

<h5>Type 2 WS<a href="#accordion">[10]</a></h5>

<ul>
	<li>Moderate to severe hearing loss</li>
	<li>Similar symptoms as seen in type 1, except that eyes aren&#39;t wide space</li>
</ul>

&nbsp;

<h5>Type 3 WS<a href="#accordion">[6]</a></h5>

<ul>
	<li>Abnormalities in the hands, arms, and shoulders&nbsp;</li>
	<li>Small head or microcephaly</li>
	<li>Change in the shape of skull bones&nbsp;</li>
	<li>Bones of the fingers fused together (syndactyly)&nbsp;</li>
	<li>Intellectual disabilities or developmental delays</li>
</ul>

&nbsp;

<h5>Type 4 WS<a href="#accordion">[10]</a></h5>

<ul>
	<li>Severe <a href="https://www.merisehat.pk/disease/constipation" target="_blank">constipation</a></li>
	<li>Intestinal blockage&nbsp;</li>
</ul>

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Causes

Waardenburg syndrome is a genetic disorder inherited in an autosomal dominant fashion. If the defective gene causing the disease is present in one parent only and if the defective gene is transferred to the child from that parent, then it would be sufficient to cause the disorder. In other words, in autosomal dominant inherited disorders, only one parent needs to transfer the defective or faulty gene for the disease to manifest in a child.&nbsp;

However, type 2 and type 4 WS can also be inherited through an autosomal recessive pattern. This means that the parents may not show signs or symptoms of the disease but they may be carriers and if the child receives 2 copies of faulty genes from each parent, they will have the disease<a href="#accordion">[10]</a>.

In very rare cases, WS can be caused by de novo mutations, which means new mutations arise in the genes that weren&#39;t present in the family earlier<a href="#accordion">[10]</a>.

Six mutations are identified in WS. These mutations involve the genes that are responsible for the development of nerves and this results in a specific type of Waardenburg syndrome &ndash; type 4 in this case since it is associated with loss of nerves in the colon resulting in Hirschsprung disease<a href="#accordion">[6]</a>.

Genes that regulate melanocytes (cells responsible for causing normal pigmentation in the hair, skin, and eyes) are affected. Consequently, this results in anomalies of pigmentation, such as pale skin, hair, and different eye color<a href="#accordion">[6]</a>.&nbsp;

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If there is a significant family history of Waardenburg syndrome, then it is possible to screen the pregnant woman for genetic mutations. However, the severity of WS symptoms cannot be determined by the screening test<a href="#accordion">[6]</a>.&nbsp;&nbsp;

&nbsp;

Diagnosis

WS diagnosis can be through detailed medical and family history, a physical examination after the baby is born, or a physical examination soon after the baby develops a hearing loss.&nbsp;

&nbsp;

There is a major and a minor criterion for diagnosing this syndrome. For instance:

&nbsp;

<ul>
	<li>Type 1 WS is diagnosed when 2 major criteria or 1 major and 2 minor criteria are present&nbsp;</li>
	<li>Type 2 WS is diagnosed when 2 major criteria are present, excluding the symptom of wide-set eyes&nbsp;</li>
</ul>

&nbsp;

Following are the major and minor diagnostic criteria<a href="#accordion">[9]</a>:&nbsp;

&nbsp;

<h5>Major Criteria</h5>

<ol>
	<li>Heterochromia iridis, i.e., both eyes have different colors&nbsp;</li>
	<li>White forelock of hair or any other pigmentation defect in the hair</li>
	<li>Abnormality of the inner corner (canthi) of either one or both eyes&nbsp;</li>
	<li>Having a parent or sibling with WS&nbsp;</li>
</ol>

&nbsp;

<h5>Minor Criteria&nbsp;</h5>

<ol>
	<li>Unibrow, i.e., eyebrows fused together</li>
	<li>White patches of skin since birth&nbsp;</li>
	<li>Incomplete development of nostril</li>
	<li>Broad bridge of the nose</li>
	<li>Gray hair before the age of 30&nbsp;</li>
</ol>

&nbsp;

A Waardenburg (W) index is used to access dystopia canthi (lateral displacement of the inner corners of the eyes). A W index of more than 1.95 is significant for the presence of dystopia canthi<a href="#accordion">[4]</a>.&nbsp;

&nbsp;

The following tests are done to confirm the diagnosis<a href="#accordion">[10]</a>:

<ul>
	<li>A genetic test</li>
	<li>An eye examination&nbsp;</li>
	<li>An auditory (hearing) test</li>
	<li>Imaging tests for either the hands, arms, or intestines based on the type of WS suspected&nbsp;</li>
</ul>

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Treatment

There is no known treatment that currently exists. However, individuals with this disorder do have a normal life expectancy and their abnormalities persist throughout their life. Treatment is aimed at managing the symptoms and improving the quality of life of the affected individuals. This includes<a href="#accordion">[6][8]</a>:

&nbsp;

<ul>
	<li>Hearing aids or cochlear implants for correction of deafness.&nbsp;</li>
	<li>Surgery to remove the affected area of the large intestine involved in Hirschsprung disease.&nbsp;</li>
	<li>Sun protection (e.g., sunscreen) to protect areas of unpigmented patches of skin from sun damage.&nbsp;</li>
	<li>A colostomy bag which supports the intestines in case of blockages as seen in type 4 WS.&nbsp;</li>
	<li>Special schools to support children with hearing loss.&nbsp;</li>
	<li>Surgery to correct facial defects, such as cleft lip and palate.&nbsp;</li>
	<li>Cosmetic surgery to correct the pigmentation defects in the hair and skin by dying the white patches of hair and covering the white areas of skin with makeup.</li>
</ul>

<div>&nbsp;</div>

Following complications can result in individuals with Waardenburg syndrome<a href="#accordion">[1]</a>:

<ul>
	<li>Hearing loss</li>
	<li>Severe <a href="https://www.merisehat.pk/disease/constipation" target="_blank">constipation&nbsp;</a></li>
	<li>Self-esteem issues&nbsp;</li>
	<li>Intellectual disabilities&nbsp;</li>
</ul>

<div>&nbsp;</div>

Having a family history of Waardenburg syndrome is the most important risk factor. However, some types of WS may present as new mutations arising de novo, hence, a family history is not needed for them to develop.&nbsp;&nbsp;

&nbsp;

Unfortunately, there are no strategies to prevent Waardenburg syndrome since it is a genetic disorder. However, an individual at risk of having a child with Waardenburg syndrome can go for genetic counseling and consult with their healthcare provider who will suggest genetic testing to screen for the mutations that are characteristic of this disorder<a href="#accordion">[10]</a>.

&nbsp;

Waardenburg syndrome presents with diverse clinical findings. In a recent case report, a 43-year-old man was initially diagnosed as a case of Juvenile open angle glaucoma, a condition in which the intraocular pressure (pressure inside the eyes) increases. Later, it was found that he had WS based on the genetic findings and clinical picture. Genetic testing revealed mutations in the EDNRB gene, therefore, the patient had type 4 WS. Open angle glaucoma is a clinical feature that was not previously associated with WS and this case in particular highlighted the diversity of the clinical presentation of this genetic disorder<a href="#accordion">[11]</a>.&nbsp;

&nbsp;

Key Points

<ul>
	<li>Waardenburg syndrome (WS) is a rare genetic disorder that is transmitted in an autosomal dominant fashion.</li>
	<li>6 mutations lead to 4 types of WS with some clinical features common to all.</li>
	<li>Individuals with WS may have pigmentation defects in the face, hair, and eyes. Also, hearing loss may or may not be present.</li>
	<li>Diagnosis is primarily done through clinical presentation and genetic testing. Further diagnostic tests, like audiometry and eye examination, can also be carried out for assessing severity.&nbsp;</li>
	<li>Currently, no treatment is available for WS since it is a genetic disorder. However, supportive treatment is possible through implantation of hearing aids, etc.&nbsp;</li>
</ul>

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