Waardenburg syndrome

Was ist Waardenburg syndrome?

Waardenburg is a group of rare genetic disorders that occurs in around 1 in every 40,000 births.

The syndrome is made up of four genetic disorders, named Type 1-4. Type 1 and 2 are the most common, while type 3 usually causes the most severe symptoms.

Auditory and pigmentary (relating to the skin) abnormalities are the main characteristics of the syndrome. However symptoms of this rare disease may vary considerably between individuals.

Syndrome Synonyms:
Waardenburg syndrome type 2 Waardenburg syndrome, Type 4b, With Hirschsprung Disease Waardenburg syndrome, Type Ivb WS1 WS2

Was Genveränderungen verursachen Waardenburg syndrome?

Mutationen in sechs Genen, einschließlich der Gene SOX10, EDN3 und EDNRB, TYR, SNAI2, WS2C, MITF, WS2B, verursachen das Syndromes.

Die Krankheit ist eine vererbbare Erkrankung. Die Typen 1 und 3 werden in einem autosomal dominanten Muster vererbt. Die Typen 2 und 4 Mai werden entweder autosomal dominant oder rezessiv vererbt.

Im Fall einer autosomal dominanten Vererbung ist nur ein Elternteil der Träger der Genmutation, und sie haben eine 50% ige Chance, sie an jedes ihrer Kinder weiterzugeben. Syndrome, die in einer autosomal dominanten Vererbung vererbt werden, werden durch nur eine Kopie der Genmutation verursacht.

Autosomal-rezessive Vererbung bedeutet, dass eine betroffene Person von jedem ihrer Elternteile eine Kopie eines mutierten Gens erhält, wodurch sie zwei Kopien eines mutierten Gens erhält. Eltern, die nur eine Kopie der Genmutation tragen, zeigen im Allgemeinen keine Symptome, haben jedoch eine 25% ige Chance, die Kopien der Genmutationen an jedes ihrer Kinder weiterzugeben.

Was sind die wichtigsten symptome von Waardenburg syndrome?

The main symptoms of the syndrome may vary in their severity between individuals and according to the type of the condition developed.

Hearing loss, changes to the color of the eyes, skin, hair and shape of the face are common symptoms between individuals with the syndrome. These changes may include spots in the eyes, and premature greying of hair.

Other potential physical characteristics of the syndrome include problems with producing tears, a small colon, an abnormally shaped uterus, cleft palate, partial albino skin, white eyelashes or eyebrows, a wide nose and a unibrow.

Possible clinical traits/features:
Aganglionic megacolon, Blue irides, Heterogeneous, White forelock, Premature graying of hair, White eyebrow, White eyelashes, Autosomal dominant inheritance, Autosomal recessive inheritance, Sensorineural hearing impairment, Hypopigmented skin patches, Heterochromia iridis

Wie wird jemand getestet? Waardenburg syndrome?

Die ersten Tests für Waardenburg syndrome kann mit einem Gesichtsanalyse-Screening beginnen, durch die FDNA Telehealth Telegenetik-Plattform, die die Schlüsselmarker der syndrom und skizzieren Sie die Notwendigkeit weiterer Tests. Es folgt ein Beratungsgespräch mit einem genetischen Berater und dann einem Genetiker. 

Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.

Medizinische Informationen zu Waardenburg syndrome

This autosomal dominant condition is characterized by abnormalities of skin and hair pigmentation, as well as sensorineural hearing loss. Waardenburg syndrome type 1 manifests with a white forelock, sometimes with more extensive depigmentation of the skin (even circumscribed depigmentation), sensorineural deafness, dystopia canthorum (an increased distance between the inner canthi), heterochromia of the irides, synophrys, and a high nasal bridge. Some patients have premature greying of the hair, true hypertelorism (10%), cleft lip and palate (2-3%), Hirschsprung's disease, and a congenital heart defect (usually a VSD). Generalized freckling, mainly in Asian populations, can be a feature of those with MITF mutations (Leger et al., 2012). Strabismus might also be a feature.

Arias (1971) first suggested heterogeneity and Hageman and Delleman (1977) presented further evidence. In type I there is dystopia canthorum and 25% of patients have deafness; in type II there is no dystopia canthorum and over 50% of patients have deafness (Liu et al., 1995). Type I patients tend to have the distinctive facial features of a high nasal bridge, synophrys, and hypoplasia of the alae nasi. Vichare and Bhargava (1014) reported a case with congenital cataracts, although the unaffected mother was diagnosed in her late 30s with ""presenile"" cataracts.
Goodman et al., (1988) reported a case with absence of the vagina and a hemiuterus. Rare cases have renal anomalies such as multicystic dysplasia, renal duplication, and renal artery anomalies (Ekinci et al., 2005).
da-Silva (1991) provides a good clinical review and Asher and Friedman (1990) a review of animal models. Read and Newton (1997) provided a good review of the molecular and clinical aspects of the condition.
Ayme and Philip (1995) reported a fetus apparently homozygous for type 1 Waardenburg syndrome. There were multiple joint contractures with pterygia. Exencephaly was present, the nose was hypoplastic, the upper lip notched and the neck webbed. Radiographs showed complete disorganisation of the spine.
Genetics/Specific Mutations
Type I has been localized to 2q37 (Foy et al., 1990). Farrer et al., (1992) estimated that approximately 45% of pedigrees in a sample of 41 WS type I and 3 WS type II families were linked to 2q37.
Carezani-Gavin (1992) and Chatkupt et al., (1993) reported type I cases with a meningomyelocele, Splotch mice also have this association.
Tassabehji et al., (1992) and Baldwin et al., (1992) demonstrated mutations in the HuP2 gene (the homologue of mouse Pax-3) in type I cases. This confirmed the homology to the Splotch mutant in the mouse (Moase and Trasler, 1992).
Tassabehji et al., (1993) showed a mutation in the human PAX3 gene in a family with probable type II Waardenburg syndrome.
Tassabehji et al., (1994) point out that PAX3 mutations in human Waardenburg cases, and the Splotch mouse, have close analogies including chromosomal deletions, splice-site mutations and similar amino acid substitutions.
Farrer et al., (1994) showed that type I families, as defined by having significant dystopia canthorum, all mapped to the PAX3 gene without evidence of heterogeneity.
Hughes et al., (1994) mapped the gene for type II Waardenburg syndrome to 3p12-p14, close to the human homologue of the mouse microphthalmia (mi) gene.
Tassabehji et al., (1994) showed that mutations in the human homologue (MITF) of the mouse mi gene caused Waardenburg syndrome type II. This gene codes for a helix-loop-helix-leucine zipper (bHLH-ZIP) protein. Two WS type II families were shown to have mutations affecting splice sites in the MITF gene. It should be noted that not all type II Waardenburg families appear to map to this locus. Van Camp et al., (1995) reported a patient with features of type II Waardenburg syndrome and a deletion of 13q21-q31. A family with features of type II Waardenburg syndrome and Hirschsprung disease, not mapping to chromosome 2 or 3, but not excluded from 13q, was also described. The authors suggested that the endothelin-B receptor gene at 13q22 might be mutated in these cases.
Tassabehji et al., (1995) review the mutational spectrum in both Waardenburg type I and type II. About 20% of type II cases are thought to be caused by mutations in the MITF gene. All type I and type III cases appear to be caused by PAX3 mutations leading to haploinsufficiency.
Reynolds et al., (1996) provide evidence that suggests that an epigenetic locus or loci affects the degree of dystopia canthorum in type I cases. Morell et al., (1997) also provided evidence suggesting that genetic background affects expression of different PAX3 alleles.
DeStefano et al., (1998) provide information about phenotype/genotype correlations with the PAX3 mutations.
Hol et al., (1995) reported a PAX3 mutation in a girl with this association.
Zlotogora et al., (1995) reported a child who was shown to be homozygous for a PAX3 mutation. Both parents had Waardenburg syndrome type I. There was significant dystopia canthorum, partial albinism, and marked contractures and muscle atrophy of the upper limbs, however, there was no neural tube defect. The phenotype resembled severe Klein- Waardenburg syndrome (qv).
Nye et al., (1998) reported two cases with features of Waardenburg associated with neural tube defects who had an interstitial deletion around 2q35.
Pierpont et al., (1995) reported a dominant family where the proband had cleft lip and palate, Hirschsprung disease, and features of type I Waardenburg syndrome. The mother had features of the syndrome and her maternal uncle was reported to have a white forelock and heterochromia iridis. The gene was not apparently linked to PAX3.
Edery et al., (1996), and Hofstra et al., (1996) demonstrated homozygous mutations in the endothelin-3 gene in patients with Waardenburg syndrome associated with Hirschsprung disease.
Occasional families have been reported with the association of ocular albinism. Morell et al., (1997) studied a family with phenotypic features of Waardenburg type 2 where some individuals also have ocular albinism. The individuals with ocular albinism were found to be either heterozygous or homozygous for a polymorphism in the TYR gene leading to reduced tyrosinase activity. There was also a 1 bp deletion in exon 8 of the MITF gene in affected individuals. The authors suggested that this was an example of digenic inheritance.
Carey et al., (1998) reported a case with features of Waardenburg syndrome type 1 together with Septo-optic dysplasia. A mutation in exon 7 of the PAX3 gene was demonstrated. Other members of the family with the same mutation did not have the septo-optic dysplasia.
Sanchez-Martin et al., (2002) studied two unrelated patients with WS2 who had homozygous deletions in the SLUG (SNA12) gene. This gene codes for a zinc-finger transcription factor expressed in migratory neural crest cells. Mutations in SOX10 are also a cause of WS2 (Bondurand et al., 2007). Mutations in KITLG do the same (Seco et al., 2015).
Cortés-González et al. (2016) reported on patients with MITF mutations who had previously undescribed features including bilateral reduced ocular anteroposterior axial length and a high hyperopic refractive error corresponding to posterior microphthalmos.
Baspinar et al., (2006) reported a child with type II who had a cardiomyopathy.
There may be a more severe autosomal recessive type associated with Hirschsprung disease.
Hart et. al., (2017) reviewed the patients with mutations in PAX3 who had neural tube defects (myelomeningocele, spina bifida, sacral dimple, spinal dysraphism in individuals with heterozygous mutations.) Patients with homozygous mutations showed exencephaly, holoprosencephaly, and curved spine.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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