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].

• 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]

• 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

  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]

  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]

• Progressive Hearing Loss

  Four had congenital hearing loss and one had progressive hearing loss. The patient who had progressive hearing loss underwent CI at 6 years 3 months of age. [hindawi.com]

• Premature Graying of the Hair

  graying of the hair (by age 30) Waardenburg syndrome type 2 is defined as having all the features of type 1 except dystopia canthorum. 77% of individuals with type 2 have hearing loss. [verywell.com]

  Signs and Symptoms Deafness (bilateral or unilateral) White patches in the skin Premature graying of the hair Presence of white locks of hair Heterochromia- the color of the eyes do not match Wide set eyes (hypertelorism) A prominent square jaw Eyebrows [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]

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

  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]

• Bright Blue Eyes

  And as I mentioned, some of the other major signs are eyes of two different colors; bright blue eyes; a streak of very white hair--like a skunk stripe--usually located in the center of the forehead; and very white patches of skin on areas that should [speechpathology.com]

• 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]

• Mydriasis

  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]

• 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].

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.