Waardenburg syndrome is a genetically heterogeneous hereditary disease characterized by a complex of anomalies and malformations caused by a violation of the formation of neural crest structures in the embryonic period. Symptoms of this condition are displacement of the lateral angle of both eyes, a wide bridge of the nose (“Greek profile”), pigmented abnormalities of the skin, hair and iris, hearing loss. Diagnosis of Waardenburg syndrome is based on the data of the patient’s current status, audiometric and ophthalmological studies, the study of hereditary history and molecular genetic analyses. There is no specific treatment for this condition, therapeutic measures are aimed at eliminating and alleviating the symptoms of pathology.
Waardenburg syndrome is a hereditary disease from the group of neurocrystopathies – pathologies caused by a violation of the embryonic development of the structures of the so–called neural crest. For the first time, the symptom complex characteristic of this disease was described by the Dutch ophthalmologist P. Waardenburg in 1951. In subsequent years, advances in the field of genetics made it possible to determine the causes of Waardenburg syndrome and the variability of the clinical course of this pathology.
The mechanism of inheritance of this disease is different due to genetic heterogeneity – most often there is an autosomal dominant type with incomplete penetrance, but autosomal recessive varieties are also described. The occurrence of Waardenburg syndrome of all types is approximately 1 case per 40,000 newborns, in the southern regions of Australia the frequency is slightly higher, which allows us to make an assumption about the occurrence of pathology in this region. According to medical statistics, this disease is caused by 2 to 5% of all cases of hereditary hearing loss and deafness. The sexual distribution of Waardenburg syndrome has no peculiarities, boys and girls are affected with the same frequency.
Classification and causes
Currently, four clinical types of Waardenburg syndrome have been identified, some of them are divided into subclasses depending on the gene whose mutations led to the development of the disease. The common cause of all forms of pathology is a violation of the formation of neural crest structures in the embryonic period – this leads to facial malformations, pigmented abnormalities, hearing disorders and sometimes vision. Dysembriogenesis in Waardenburg syndrome is caused by defects in genes, in most cases encoding transcription factor proteins, that is, responsible for the expression of other genes.
Waardenburg syndrome type 1 (WS1) is the most common variant of pathology with an autosomal dominant type of inheritance, but with different expressiveness. It is caused by mutations in the PAX3 gene located on the 2nd chromosome. The product of its expression is a transcription factor, presumably controlling the processes of cell migration in the neural crest and affecting the expression of the MITF gene. In addition to Waardenburg syndrome type 1, mutations in the PAX3 gene lead to type 3 of a similar disease (WS3), and its involvement in the development of rhabdosarcoma has also been proven.
Waardenburg syndrome type 2 (WS2) causes about 20-25% of all cases of this pathology, has at least four subclasses (a, b, c, d), but the most studied are WS2a and WS2d. The first is caused by defects in the MITF gene localized on the 3rd chromosome, it encodes a transcription factor that activates the tyrosinase gene, a key enzyme in the development of melanocytes. Waardenburg syndrome WS2d is caused by mutations of the SNAI2 gene located on the 8th chromosome, it also encodes one of the factors of transcription activation. The functions of the genes that cause WS2b and WS2c are currently unclear, it is only known that they are located on the 1st and 8th chromosomes, respectively.
Waardenburg syndrome type 3 (WS3, Klein-Waardenburg syndrome, named after the Swiss doctor D. Klein) is the most severe variant of this condition. It is caused by mutations of the PAX3 gene (which is the cause of WS1), however, defective forms of the gene in patients are in a homozygous state or there is a nonsense mutation.
Waardenburg syndrome type 4 (WS4, Waardenburg-Schach syndrome) is, unlike other types of the disease, a pathology with an autosomal recessive inheritance mechanism. It has three varieties (a, b, c) caused by mutations of various genes. WS4a is caused by a mutation of the EDNRB gene, which is localized on the 13th chromosome and encodes the sequence of the complex protein B-endothelin. Waardenburg syndrome WS4b is similar in molecular pathogenesis to the previous variant, since it is caused by defects in the EDN3 gene – it is located on the 20th chromosome and encodes the B-endothelin ligand. In contrast, WS4c is caused by a mutation of the SOX10 gene, a representative of an extensive group of regulatory genes. It is located on the 22nd chromosome.
The clinical picture of Waardenburg syndrome largely depends on the type of disease, while there are some common manifestations for all types. Thus, in pathology of any type, in 99% of cases, patients have a lateral displacement of the outer corner of the eye (telecant), in two-thirds of cases, an expansion of the bridge of the nose is recorded. Approximately half of all persons suffering from Waardenburg syndrome have a white strand of hair above the forehead, heterochromia of the iris, congenital focal leukoderma, hearing loss of varying severity up to deafness. The disease is characterized by high variability of manifestations not only between types, but also between carriers of the same pathological gene – within the same family or even identical twins may have different symptoms.
Waardenburg syndrome type 1 is considered a classic and is characterized by the presence of a telekant, pigmented disorders of the skin, hair and iris, and other facial anomalies typical of this disease. A feature of WS2 of any subclass is the presence of only isolated pigmentation abnormalities and hearing disorders – it is differentiated from the 1st type of pathology by the absence of a shift in the lateral angle of the eye. Type 3 Waardenburg syndrome is clinically more severe, pigmentation disorders, hearing loss and facial malformations are quite pronounced. In addition, this variant of the disease is also characterized by the development of hypoplasia of muscle tissue, mainly on the upper extremities.
Manifestations of type 4 Waardenburg syndrome (Waardenburg-Schach syndrome) include symptoms of Hirschsprung’s disease – disorders of the autonomic innervation of some parts of the gastrointestinal tract. This variant of the disease, in addition to typical pigmentation disorders, sensorineural hearing loss and deafness, is also characterized by abdominal pain, constipation, flatulence, congenital colon enlargement – megacolon. The severity of these manifestations depends on the length of the colon, devoid of submucosal nerve plexus. In addition, some cases of type 4 Waardenburg syndrome are accompanied by disorders of myelination of nerve fibers, mainly peripheral – researchers sometimes distinguish such cases into a separate variety called PCWH syndrome.
The definition of Waardenburg syndrome is made on the basis of the patient’s examination data, the study of his hereditary history, ophthalmological and audiometric studies. The final confirmation of the diagnosis is given by molecular genetic analysis. In addition, for some forms of the disease, additional diagnostic methods such as electromyography (with WS3), biopsy of the colon wall (with WS4) can be used. When examining a patient with Waardenburg syndrome, as a rule, a characteristic appearance of the face is revealed (displacement of the lateral corners of the eyes, a wide bridge of the nose), leukoderma of varying severity, a white tuft of hair over the forehead is very often visible. The irises of the eyes may have a different color (heterochromia) or inserts of a different shade in the form of a sector.
Audiometric studies with Waardenburg syndrome often reveal hearing loss up to complete deafness. Usually, hearing loss in this disease does not tend to progress. In rare cases, Waardenburg syndrome can be accompanied by congenital heart defects, cleft palate and other severe disorders, with type 3 of the disease, hypoplasia of the muscles of the upper extremities is determined. If the presence of WS4 is suspected, contrast radiography of the large intestine is performed, in the presence of enlarged areas, a biopsy of the intestinal wall in their area is performed – in the case of Waardenburg syndrome type 4, the absence of nerve plexuses is detected there. A geneticist can perform molecular genetic diagnostics of almost any form of this disease by sequencing the genes associated with it. It can also determine the carrier of the defective form of the gene in the case of a burdened hereditary history and prenatal diagnosis of Waardenburg syndrome.
There is no specific therapy for this disease today, only symptomatic treatment is used, as well as measures aimed at improving the quality of life of the patient. Hearing loss and deafness in Waardenburg syndrome can be compensated by implantation of a cochlear apparatus, and this should be done as early as possible for the normal development of speech in a child. In the case of the development of certain ophthalmological disorders, correction may be required in the form of wearing glasses or contact lenses. Muscle hypoplasia, characteristic of type 3 Waardenburg syndrome, may decrease with regular exercises in therapeutic gymnastics and the use of physiotherapy procedures. The defeat of the gastrointestinal tract in WS4 is eliminated surgically – by removing pathologically altered areas of the intestine.
Prognosis and prevention
In most cases, the prognosis of Waardenburg syndrome is favorable, since malformations in this disease often do not threaten the patient’s life and do not tend to progress. In rare cases, the presence of additional developmental abnormalities in this pathology (heart defects, intestinal defects, cleavage of the palate, hydrocephalus) may slightly worsen the prognosis. The most important factor in reducing the quality of life of patients with Waardenburg syndrome is hearing loss and deafness, which, with late diagnosis, can lead to impaired speech development. Often, due to a violation of the pigmentation of the eyes and skin, people with this pathology experience sunburn and hypersensitivity to light, which is eliminated by wearing sunglasses and using special creams. Prevention of Waardenburg syndrome is possible only within the framework of medical and genetic counseling of parents before conception and prenatal diagnosis.