Waardenburg Syndrome (WS) is divided into four distinct clinical subtypes, one of them being Klein-Waardenburg Syndrome (type 3), which is described as an extreme variant of the classical WS type 1 [1] [2] [3]. Across all WS types, however, symptoms stem from the absence of melanocytes from the skin, eyes, hair and stria vascularis of the cochlea [1] [3]. Congenital sensorineural hearing loss - typically non-progressive, either unilateral or bilateral, and dystopia canthorum (fusion of medial eyelids and the appearance of a blepharophimosis) are observed in the majority of WS type 1 patients [1]. Moreover, heterochromia iridis (segmental or total and either unilateral or bilateral), skin and hair hypopigmentation, a white forelock, early graying of the hair (before 30 years of age) and white skin patches (known as congenital leukoderma) on the trunk, limbs or face are other notable signs [1] [2]. To distinguish Klein-Waardenburg syndrome from other WS variants, musculoskeletal abnormalities should be noted in addition to the mentioned symptoms [1] [4] [5]. Namely, carpal bone fusion, syndactyly, and hypoplasia or contractures of the joints or limb muscles (more commonly the arms) are the main characteristics of this subtype [1] [2].

• Miosis

  Seite 358 - Ocular signs of cerebral involvement include the following: nystagmus, unilateral mydriasis, bilateral miosis with slow response to light, paralysis of accommodation, convergence, and 3rd, 4th, and 6th cranial nerve involvement. ‎ [books.google.de]

• Flexion Contracture

  We report on 2 sibs with the Klein-Waardenburg syndrome; they had dystopia canthorum, blepharophimosis, and bilateral flexion contractures of the fingers. The children's father and paternal aunt are also affected. [ncbi.nlm.nih.gov]

  contractures, fusion of the carpal bones, syndactylies. [malacards.org]

  Clinical description WS3 is characterized by the association of limb anomalies (predominantly involving upper limbs, with hypoplasia of the musculoskeletal system, flexion contractures, fusion of the carpal bones, syndactylia) with features of Waardenburg [orpha.net]

• Joint Stiffness

  Affiliated tissues include skin, eye and bone, and related phenotypes are hearing impairment and joint stiffness Disease Ontology : 12 A Waardenburg's syndrome characterized by upper limb anomalies, congenital hearing loss, dystopia canthorum and pigmentation [malacards.org]

• Carpal Bone Fusion

  Namely, carpal bone fusion, syndactyly, and hypoplasia or contractures of the joints or limb muscles (more commonly the arms) are the main characteristics of this subtype. [symptoma.com]

  bone fusion, or syndactyly Type 4 Individuals having a rare combination of pigmentary abnormalities, hearing loss, and Hirschsprung disease Natural History [ edit ] does not affect lifespan or intelligence Testing [ edit ] Clinical Diagnosis An individual [en.wikibooks.org]

• Short Arm

  Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. Therefore, “chromosome 2q35” refers to band 35 on the long arm of chromosome 2. [rarediseases.org]

• Hearing Impairment

  For example, a person with WS may have a white forelock, a patch of white hair near the forehead, and no hearing impairment. Others may have white patches of skin and severe hearing impairment. [healthfully.org]

  Management of Deafness or Hearing Impairment Once diagnosed with Waardenburg syndrome, the child or infant must begin with programs to manage the hearing impairment. [syndromespedia.com]

  About 20 percent of patients also have hearing impairment. WS2 - When other WS symptoms are present without the wide-set eyes, patients are considered to have WS2. Approximately 50 percent of WS2 patients have a hearing impairment or are deaf. [empowher.com]

  Affiliated tissues include skin, eye and bone, and related phenotypes are hearing impairment and joint stiffness Disease Ontology : 12 A Waardenburg's syndrome characterized by upper limb anomalies, congenital hearing loss, dystopia canthorum and pigmentation [malacards.org]

  The syndrome is named for a Dutch eye doctor named Petrus Johannes Waardenburg (1886-1979) who first noticed that people with differently colored eyes often had a hearing impairment. [medicinenet.com]

• Premature Graying of the Hair

  […] corner of the eye displaced to the side (dystopia canthorum) Minor criteria: Patches of light or white skin Eyebrows extending toward middle of face Nose abnormalities Premature graying of the hair (by age 30) Waardenburg syndrome type 2 is defined as [verywell.com]

  Hypopigmented eyes, hair and skin – White pigmentations can be present in the skin, a lock of gray or white hair growing prematurely can be seen, and a pale color of eyes is noted and the color can be different in both eyes. [syndromespedia.com]

  Minor criteria include skin hypopigmentation (congenital leukoderma/ white skin patches), medial eyebrow flare (synophrys), broad nasal root, hypoplasia alae nasi, and premature graying of the hair. [panafrican-med-journal.com]

  Premature graying of scalp hair, eye brows, cilia or body hair has been reported to occur in 7% cases. [12] Partial or complete heterochromia iridis occurs in 21 to 28% of patients with WS, hypoplastic blue iridis occur in 14.9 to 42% of cases. [1] Fundus [bioline.org.br]

  Her father and her siblings also have a white forelock with premature graying of hair [Figure 1]. [indianjnephrol.org]

• Cranial Nerve Involvement

  Seite 358 - Ocular signs of cerebral involvement include the following: nystagmus, unilateral mydriasis, bilateral miosis with slow response to light, paralysis of accommodation, convergence, and 3rd, 4th, and 6th cranial nerve involvement. ‎ [books.google.de]

To make the diagnosis of Klein-Waardenburg syndrome, physicians must recognize all signs and symptoms of the condition. Therefore, a detailed physical examination must be conducted. In fact, criteria for the diagnosis of WS type 1 are based solely on clinical findings [1] [2], and the additional presence of symptoms characteristic for Klein-Waardenburg syndrome can confirm the diagnosis. Notable features of the remaining WS types, 2 and 4, such as the absence of dystopia canthorum or presence of the appearance of Hirschsprung disease should be detected or excluded during workup [1]. A thorough patient history is an equally important part of the diagnostic workup since an autosomal dominant pattern of inheritance is the underlying mechanism of the disease [1] [5] [3]. However, many individuals with confirmed Klein-Waardenburg syndrome develop mutations in a sporadic fashion [1] [5], which is why genetic testing for identification of specific mutations should be carried out once valid clinical criteria exist. Detection of PAX3 mutations on the distal long arm of chromosome 2 through sequence analysis is considered diagnostic for WS type 1, and consequently, type 3 [1] [2].

Treatment Treatment Options: No ocular treatment is necessary. Patients may benefit from cochlear implants. [disorders.eyes.arizona.edu]

The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment. [orpha.net]

Exams and Tests Tests may include: Audiometry Bowel transit time Colon biopsy Genetic testing Treatment There is no specific treatment. Symptoms will be treated as needed. [pennstatehershey.adam.com]

If hypopigmentation affects more than half the body, depigmentation treatments may help. These treatments bleach all of your skin. They can make lighter patches less obvious. [healthline.com]

Prognosis Due to the very few number of cases described so far, information on prognosis and quality of life is limited. Disease progression is variable, with symptoms being more severe in homozygous than in heterozygous forms. [orpha.net]

Etiology WS3 is caused by heterozygous or homozygous mutations in the PAX3 (2q36.1) gene. Diagnostic methods Diagnosis is made through criteria of the association of WS1 manifestations with limb anomalies. [orpha.net]

Qualifiers English: BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology EH ethnology ET etiology [decs.bvs.br]

Summary Epidemiology Incidence is unknown, but WS3 is the rarest form of all Waardenburg syndrome types. [orpha.net]

Epidemiology Incidence is unknown, but WS3 is the rarest form of all Waardenburg syndrome types. [rarediseases.info.nih.gov]

Chapters on epidemiology, embryology, non-syndromic hearing loss, and syndromic forms of hearing loss have all been updated with particular attention to the vast amount of new information on molecular mechanisms, and chapters on clinical and molecular [books.google.de]

Syndrome 1991-2012 Allowable Qualifiers English: BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology [decs.bvs.br]

The pigmentary system: physiology and pathophysiology. 2006. pp. 541-50. [dermatologyadvisor.com]

Transcriptional regulation of gene expression: mechanisms and pathophysiology. Hum. Mutat. 3, 180–199 (1994). 8 Tassabehji, M. et al. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. [nature.com]

[…] diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology EH ethnology ET etiology GE genetics HI history IM immunology ME metabolism MI microbiology MO mortality NU nursing PS parasitology PA pathology PP physiopathology PC prevention [decs.bvs.br]

Genetic Counseling Waardenburg syndrome can be prevented by genetic counseling. [syndromespedia.com]

Prevention Genetic counseling may be valuable for prospective parents with a family history of Waardenburg syndrome. Alternative Names Klein-Waardenburg syndrome; Waardenburg-Shah syndrome [dxline.info]

The most common treatments for Waardenburg syndrome include: cochlear implants or a hearing aid to treat hearing loss developmental support, such as special schools, for children with severe hearing loss surgery to prevent or remove blockages in the intestines [medicalnewstoday.com]

These symptoms are believed to arise due to the mutation, which prevents the formation of a covalent disulfide bond (S–S bond), resulting in protein instability. The variant p.Ser369Arg is located in exon 7. [nature.com]

1. Read AP, Newton VE. Waardenburg syndrome. J Med Genet. 1997;34(8):656-665.
2. Milunsky JM. Waardenburg Syndrome Type I. 2001 [Updated 2014 Aug 7]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
3. Choi JH, Moon SK, Lee KH, Lew HM, Chang YH. Three cases of Waardenburg syndrome type 2 in a Korean family. Korean J Ophthalmol. 2004;18(2):185-189.
4. Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010;31(4):391-406.
5. Tekin M, Bodurtha JN, Nance WE, Pandya A. Waardenburg syndrome type 3 (Klein-Waardenburg syndrome) segregating with a heterozygous deletion in the paired box domain of PAX3: a simple variant or a true syndrome? Clin Genet. 2001;60(4):301-304.