Dermatologic Manifestations of Waardenburg Syndrome 

Updated: Feb 08, 2019
Author: Lyubomir A Dourmishev, MD, PhD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Waardenburg syndrome is a rare disease characterized by deafness in association with pigmentary anomalies and defects of neural crest-derived tissues.

Hammerschlag, in 1907, and Urbantschitsch, in 1910, both mentioned heterochromia iridium and partial albinism as occurring as complications of deafmutism. In 1916, van der Hoeve described a dystopia canthi medialis lateroversa in a pair of monozygotic twin girls with deafmutism. In 1951, Waardenburg[1] defined the syndrome with the following 6 main features:

  • Lateral displacement of the medial canthi combined with dystopia of the lacrimal puncta and blepharophimosis

  • Prominent broad nasal root

  • Hypertrichosis of the medial part of the eyebrows

  • White forelock

  • Heterochromia iridis

  • Deafmutism

In 1947, Klein reported a case of a 10-year-old girl with deafmutism, partial albinism of the skin and hair, hypochromia iridis, blepharophimosis with hypertelorism and absence of the nasofrontal angle, hypertrichosis of the eyebrows, and multiple associated abnormalities (myo-osteo-articulare dysplasia).

Pathophysiology

Waardenburg syndrome is a rare disease with an autosomal dominant mode of inheritance. Several hypotheses, including the following, have been advanced to explain all the clinical features of the syndrome:

  • The deficient neural crest theory, suggesting a developmental abnormality of the neural crest as a cause of the disease: The association of Waardenburg syndrome and congenital aganglionic megacolon supports this hypothesis.

  • Waardenburg syndrome as a part of the first arch syndrome

  • A relationship of Waardenburg syndrome with status dysraphicus

  • The intrauterine necrosis theory

None of these possibilities explains all the features of Waardenburg syndrome. Inherited causes account for approximately 50% of individuals seen for childhood (prelingual) hearing loss, of which 70% are due to mutations in numerous single genes that impair auditory function alone (nonsyndromic). The remainder are associated with other developmental anomalies termed syndromic deafness.

Genes responsible for syndromic forms of hearing loss in Waardenburg syndrome include PAX3 on band 2q37, observed in types I and III, and MITF mapped on 3p12-p 14.1 for type II.[2, 3, 4] Waardenburg syndrome is autosomal dominant for most persons with types I, II, or III. Waardenburg syndrome type IV is autosomal recessive with variable penetrance and is due to SOX10 or endothelin-B receptor (EDNRB) gene mutations, which appear to correlate with the intestinal and/or neurological symptoms manifested in patients.[5, 6, 7, 8, 9, 10, 11]

Sznajer et al[12] described a novel SOX10 splice site mutation (c.698-2A > C) that resulted in severe type 4 Waardenburg syndrome without Hirschsprung disease. The child presented with vivid blue eye, mental retardation, synophrys, deafness, bilateral complete semicircular canals, and peripheral neuropathy.

Etiology

Waardenburg syndrome is a rare disease with an autosomal dominant mode of inheritance.

Epidemiology

Frequency

The frequency of Waardenburg syndrome is estimated to be 1 case per 212,000 persons in the general population of the Netherlands, but owing to a low penetrance of about 20%, the frequency of the entire syndrome (with or without deafness) is probably approximately 1 case per 42,000 persons. In Kenya, the estimated frequency is 1 case per 20,000 persons. The syndrome has been observed in 0.9-2.8% of persons with deafmutism.[13]

Race

Waardenburg syndrome affects people of all races worldwide.

Sex

The disease affects both sexes equally. No sex differences among persons with congenital deafmutism have been found.

Age

As an inheritable disease, Waardenburg syndrome can be recognized immediately or soon after birth. Some dermatologic features (eg, poliosis) change with age.

Prognosis

Children with Waardenburg syndrome have a normal life expectancy. Morbidity is related to deafness and to defects of neural crest-derived tissues, including mental retardation, seizures, psychiatric disorders, skeletal anomalies, and eye disorders (including cataracts).

 

Presentation

History

Characteristic morphologic features of Waardenburg syndrome can be recognized immediately or soon after birth. Features typically include white forelock, broad nasal root, and hypopigmented irides. Parents notice that the child does not react to sounds.

Physical Examination

Not every case expresses all clinical manifestations of the complete Waardenburg syndrome, and forme fruste conditions are commonly observed. Based on clinical and genetic criteria, 4 types of Waardenburg syndrome are recognized. All forms show marked variability, even within families. See the images below.

Marked facial asymmetry, lagophthalmos, a drooping Marked facial asymmetry, lagophthalmos, a drooping right corner of the mouth. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.
Visage in profile demonstrates absence of nasofron Visage in profile demonstrates absence of nasofrontal angle, eyebrow hypertrichosis, upturned nasal tip, and shortened upper lip with a pronounced cupid's bow. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.
Brother and sister with Waardenburg syndrome. Imag Brother and sister with Waardenburg syndrome. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.

Type I Waardenburg syndrome is characterized by evidence of dystopia canthorum and the full symptomatology of the disease. Individuals with type I Waardenburg syndrome also have a narrow nose, marked hypoplasia of the nasal bone, short philtrum, and short and retropositioned maxilla. A discriminant analysis revealed that the inner intercanthic distance, philtrum length, lower facial height, and nasal bone length were discriminating parameters of Waardenburg syndrome. Convergent strabismus (blepharophimosis) and reduced visibility of the medial sclera is observed. The head circumference, clivus length, and facial depth are smaller in affected individuals with this syndrome.

Individuals with type II Waardenburg syndrome are a heterogeneous group with normally located canthi (without dystopia canthorum). Sensorineural hearing loss (77%) and heterochromia iridium (47%) are the 2 most important diagnostic indicators for this type.[14, 15]  Other clinical manifestations (eg, white forelock, skin patches) are more frequent in type I.

Type III Waardenburg syndrome (Klein-Waardenburg syndrome) is similar to type I but is also characterized by musculoskeletal abnormalities (ie, aplasia of the first 2 ribs, lack of differentiation of the small carpal bones, cystic formation of the sacrum, abnormalities of the arms [eg, amyoplasia and stiffness of the joints, bilateral cutaneous syndactyly]). Some individuals with type III Waardenburg syndrome are homozygotes. Other clinical manifestations of type III syndrome comprise the full symptomatology of the disease plus mental retardation, microcephaly, and severe skeletal anomalies.

Type IV Waardenburg syndrome (Shah-Waardenburg syndrome) is the association of Waardenburg syndrome with congenital aganglionic megacolon (Hirschsprung disease).[16] Hirschsprung disease affects 1 neonate per 5000 births. See Hirschsprung Disease for more information.[17, 18]

Dystopia canthorum is found in 41.2-99% of persons with Waardenburg syndrome.[13]  The distance between the inner angles of the eyelids is accompanied by increased distance between the inferior lacrimal points. Hageman and Delleman divided Waardenburg syndrome into 2 variants: with dystopia canthorum and without.

Congenital deafmutism occurs in 9-62.5% of persons with Waardenburg syndrome. Different combinations of hearing loss occur: unilateral or bilateral, severe or moderate, total or moderate. Fisch separated Waardenburg syndrome into the following distinct types according to audiogram results:

  • Patients with total deafness and little residual hearing at the lower frequency

  • Patients with a moderate degree of deafness with uniform hearing loss in the lower and middle frequency with improvement in the higher frequency

Overall, 100% of patients with hearing loss and Waardenburg syndrome have temporal bone anomalies on at least one measurement of their inner ear and 50% have an enlargement of the vestibular aqueduct at the mid point.[19] As shown by computed tomography, enlargement of the vestibular aqueduct and the upper vestibule, narrowing of the internal auditory canal porus, and hypoplasia of the modiolus are features of Waardenburg syndrome.

Pigmentary abnormalities in Waardenburg syndrome affect skin, hair, and eyes. Cutaneous color abnormalities are observed in 8.3-50% of patients and include the following types of lesions:

  • Achromic spots with sharply defined, irregular borders and with hyperpigmented islands scattered throughout, resembling those of piebaldism

  • Hyperpigmented macules on normally pigmented skin, which have been described as "patchy skin" and giving a "dappled appearance"

Pigmentary disturbances of hairs in Waardenburg syndrome include 2 types of alterations: white forelock and premature graying of scalp hair, eyebrows, cilia, or body hair. The white forelock is observed in 17-58.4% of persons with Waardenburg syndrome and involves the forehead (and both medial eyebrows), the vertex, or another part of scalp. The white forelock may be evident at birth or soon afterward, or it may develop later. Poliosis may persist throughout life or may disappear in the first years of life and reappear later. Chang et al[20] reported 2 members of a family with Waardenburg syndrome who atypically demonstrated spontaneous pigmentation and contraction of congenital leukodermic patches. In place of a white forelock, an artificial color of red, brown, or black hair was observed. Patients with Waardenburg syndrome become prematurely gray in 7% of cases.

Ocular color abnormalities of Waardenburg syndrome include 3 types of disturbances, as follows:

  • Heterochromia (different color) iridis: Heterochromia iridis, partial or complete, was found in 21-28% of patients with Waardenburg syndrome.

  • Bilateral isohypochromia iridis (pale blue eyes): Pale blue eyes in Waardenburg syndrome are observed in 14.9-42% of patients.

  • Fundus pigmentary alterations: Patients with fundus pigmentary abnormalities may have 2 types of defects: a generalized decrease in retinal pigment (albinotic fundi) and a pigment mottling in the periphery.

 

A characteristic facial appearance of patients with Waardenburg syndrome and facial asymmetry in various levels of manifestation has been observed. Hyperplasia of the root of the nose is reported in 17.6-78% of persons with Waardenburg syndrome. Hypertrichosis of the medial eyebrows is reported in 17.6-69% of persons with Waardenburg syndrome. Patients with Waardenburg syndrome and facial palsy from age 7 years and lingua plicata (2 main features of the classic triad of Melkersson-Rosenthal syndrome) have been observed.[21]

Various other abnormalities have been described, including central nervous system features (eg, mental retardation, seizures, psychic disturbances), renal agenesis,[22]  skeletal and muscular defects (eg, macrocephaly or microcephaly, osseous cysts, syndactyly, spina bifida), skin and hair manifestations (eg, localized hypertrichosis, palmoplantar hyperkeratosis), and eye features (eg, strabismus, cataracts, palpebral ptosis, epicanthus),

A severe type designated anophthalmia-Waardenburg syndrome presents with bilateral anophthalmia, cerebral malformations, epilepsy, limb anomalies, and mental retardation in addition to skin lesions.[23]

 

DDx

Diagnostic Considerations

Woolf syndrome (the association of albinismus circumscriptus and deafmutism without other features of Waardenburg syndrome) consists of separated genetic defects with autosomal dominant inheritance; however, the distinguishing structural ophthalmologic abnormalities of dystopia canthorum, broad nasal root, and synophrys are not found in either piebaldism or Woolf syndrome.

Fisch syndrome is a distinct entity with early graying of the hair and congenital deafness.

Hermansky-Pudlak syndrome is autosomal recessive oculocutaneous albinism and bleeding problems due to an abnormality in platelet aggregation.

Rozycki syndrome is autosomal recessive deafness associated with vitiligo.

Differential Diagnoses

 

Workup

Laboratory Studies

Waardenburg syndrome types 1 and 3 are most commonly associated with point mutations in PAX3, and type 2 is associated with MITF point mutations. Multiplex ligation-dependent probe amplification can be used to detect changes in targeted genes.[24]

Other Tests

Partington used the following three interocular distances for determining the presence of dystopia cantorum (The referent value between distance of the medial canthi of the eyelids and the length between the pupils was 0.6 mm.):

  • Between the inner canthal angles

  • The near papillary distance

  • Between the other canthal angles

Arias and Mota developed the W index, as follows, for the diagnosis of lateral displacement of the inner canthi (A W index of more than 2.07 shows dystopy, while an index of less than 1.87 is normal.):

  • W index = X + Y + alb

  • Where X = [a - {0.21119c + 3.909}]/c and Y = [2a - {0.2497b + 3.909}]/b in mm

  • Distance a is between inner canthi; distance b, between pupils; and distance c, between outer canthi.

Histologic Findings

Histochemical studies in the achromic skin of persons with Waardenburg syndrome show that the melanocytes are absent, or that only a few dihydroxyphenylalanine-positive cells are present.

Ultrastructural observations do not reveal melanocytes, indeterminate dendritic cells, or melanosomes in the keratinocytes of depigmented skin; however, the number of Langerhans cells in the epidermis is normal. The number of melanocytes on the edge of the leukodermas is reduced, and numerous cytoplasmic nuclear abnormalities are noted. Some melanosomes surrounded by a clear halo are found inside of vacuoles. The number of melanocytes in the hypopigmented patches of Waardenburg syndrome is dramatically reduced. These dendritic cells contained poorly melanized melanosomes.

Histopathologic examination of the inner ears of persons with Waardenburg syndrome shows absent organs of Corti, atrophy of the spinal ganglion, and reduced numbers of nerve fibers.

 

Treatment

Medical Care

No effective treatment is available for persons with Waardenburg syndrome. Early diagnosis and improvement of the hearing defect are important for the psychological development of children with this disease and help to reduce the sense of isolation.

Lack of resources in some societies may add to the physical and psychological obstacles faced by persons with Waardenburg syndrome. Tolerance and understanding of persons with Waardenburg syndrome help support their integration into society.

Surgical Care

No effective surgical care is available except cochlear implantation in children with Waardenburg syndrome, which can improve the speech perception ability.[25]

Consultations

Consultations with a geneticist are important since Waardenburg syndrome type I is an autosomal dominant disease and some affected persons have relatives with the same disease. However, even if prenatal test determines the presence of gene pathology, it still cannot predict the severity of its clinical expression.