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].

• 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]

• 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]

• 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]

• 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]

  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]

• 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.