What are the other Names for this Condition? (Also known as/Synonyms) 

• Hirschsprung Disease with Pigmentary Anomaly
• Waardenburg-Hirschsprung Syndrome
• Waardenburg-Shah Syndrome

What is Waardenburg Syndrome Type 4? (Definition/Background Information)

• Waardenburg Syndrome Type 4 (WS4), or Waardenburg-Shah Syndrome, is a genetic condition that can cause hearing loss; changes in coloring (pigmentation) of the hair, skin, and eyes; and Hirschsprung disease, an intestinal disorder that causes severe constipation or blockage of the intestine 
• Waardenburg Syndrome Type 4 is further divided into types 4A, 4B, and 4C based on their genetic cause
  • Waardenburg Syndrome Type 4A is caused by mutations in the EDNRBgene
  • Mutations in EDN3cause Waardenburg Syndrome Type 4B 
  • Mutations inSOX10cause Waardenburg Syndrome Type 4C
• This condition is usually inherited in an autosomal dominant fashion; however, some cases of type 4 appear to have an autosomal recessive pattern of inheritance

(Source: Wardenburg Syndrome Type 4; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Waardenburg Syndrome Type 4? (Age and Sex Distribution)

• Waardenburg Syndrome Type 4 is a rare congenital disorder. The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Waardenburg Syndrome Type 4? (Predisposing Factors)

• A positive family history may be an important risk factor, since Waardenburg Syndrome Type 4 can be inherited

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Waardenburg Syndrome Type 4? (Etiology)

• Waardenburg Syndrome Type 4 is subdivided into 4A, 4B and 4C subtypes, each caused by mutations in different genes
  • Type 4A is caused by mutations in the EDNRBgene
  • Mutations in EDN3cause 4B 
  • Mutations inSOX10cause type 4C
• Waardenburg Syndrome Type 4 is usually inherited in an autosomal dominant fashion; however, some cases of type 4 appear to have an autosomal recessive pattern of inheritance

(Source: Wardenburg Syndrome Type 4; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Waardenburg Syndrome Type 4?

The signs and symptoms of Waardenburg Syndrome Type 4 may vary among affected individuals, and may include the following:

Very frequently present symptoms in 80-99% of the cases:

• Abnormal macular morphology
• Abnormality of vision
• Aganglionic megacolon
• Constipation
• Hearing impairment
• Intestinal obstruction
• Premature graying of hair
• White eyebrow
• White eyelashes
• White forelock

Frequently present symptoms in 30-79% of the cases:

• Olfactory lobe agenesis
• Prominent nasal bridge
• Synophrys
• Underdeveloped nasal alae
• Wide nasal bridge
• Abnormality of retinal pigmentation
• Anosmia
• Lacrimal gland hypoplasia
• Telecanthus

In addition to the above, the following signs and symptoms may be present:

• Ataxia
• Blue irides
• Cryptorchidism
• Heterochromia iridis
• Hypogonadism
• Hypopigmented skin patches
• Leukodystrophy
• Muscular hypotonia
• Nystagmus
• Polyneuropathy
• Sensorineural hearing impairment
• Spastic paraparesis

(Source: Wardenburg Syndrome Type 4; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Waardenburg Syndrome Type 4 Diagnosed?

Waardenburg Syndrome Type 4 is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Waardenburg Syndrome Type 4?

The complications of Waardenburg Syndrome Type 4 may include:

• Problems with movement and gait
• Permanent hearing loss
• Progressive vision impairment
• Possible loss of sensation in different body parts due to neuropathy

• Developing infections owing to being unaware of the injuries, due to loss of sensation

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Waardenburg Syndrome Type 4 Treated?

There is no cure for Waardenburg Syndrome Type 4, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops.

How can Waardenburg Syndrome Type 4 be Prevented?

Currently, Waardenburg Syndrome Type 4 may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Waardenburg Syndrome Type 4? (Outcomes/Resolutions)

• The prognosis of Waardenburg Syndrome Type 4 is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Waardenburg Syndrome Type 4:

Waardenburg Syndrome Type 4 is also known by the following names:

• Shah-Wardenburg Type IV Variant
• Waardenburg-Hirschsprung Disease

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/