Dermatologic Manifestations of Waardenburg Syndrome

Back

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:

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:

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).

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.



View Image

Marked facial asymmetry, lagophthalmos, a drooping right corner of the mouth. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright ....



View Image

Visage in profile demonstrates absence of nasofrontal angle, eyebrow hypertrichosis, upturned nasal tip, and shortened upper lip with a pronounced cup....



View Image

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:

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:

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:

 

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]

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.):

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.):

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.

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.

Author

Lyubomir A Dourmishev, MD, PhD, Associate Professor, Department of Dermatology and Venereology, Medical University of Sofia, Bulgaria

Disclosure: Nothing to disclose.

Coauthor(s)

Camila K Janniger, MD, Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Albert C Yan, MD, Section Chief, Associate Professor, Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

References

  1. Waardenburg PJ. A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet. 1951 Sep. 3(3):195-253. [View Abstract]
  2. Tachibana M. Evidence to suggest that expression of MITF induces melanocyte differentiation and haploinsufficiency of MITF causes Waardenburg syndrome type 2A. Pigment Cell Res. 1997. 10(1-2):25-33. [View Abstract]
  3. Wildhardt G, Zirn B, Graul-Neumann LM, Wechtenbruch J, Suckfüll M, Buske A, et al. Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics. BMJ Open. 2013. 18;3(3):[View Abstract]
  4. Zhang H, Luo H, Chen H, Mei L, He C, Jiang L, et al. Functionalanalysis of MITF gene mutations associated with Waardenburg syndrome type 2. FEBS. 30;586(23). 2012:4126-31. [View Abstract]
  5. Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, et al. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum Mol Genet. 2000 Aug 12. 9(13):1907-17. [View Abstract]
  6. Chan KK, Wong CK, Lui VC, Tam PK, Sham MH. Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation. J Cell Biochem. 2003 Oct 15. 90(3):573-85. [View Abstract]
  7. DeStefano AL, Cupples LA, Arnos KS, Asher JH Jr, Baldwin CT, Blanton S, et al. Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations. Hum Genet. 1998 May. 102(5):499-506. [View Abstract]
  8. Dundar M, Lowther G, Colgan J, et al. A case with Waardenburg syndrome presenting with two separate translocations--one reciprocal and one complex. Clin Dysmorphol. 2001 Jan. 10(1):65-6. [View Abstract]
  9. Morell R, Carey ML, Lalwani AK, Friedman TB, Asher JH Jr. Three mutations in the paired homeodomain of PAX3 that cause Waardenburg syndrome type 1. Hum Hered. 1997 Jan-Feb. 47(1):38-41. [View Abstract]
  10. Jung HJ, Jin SA, Choi SJ, Lee SC, Yun SJ. A de novo SOX10 mutation in apatient with Waardenburg syndrome type IV. J Am Acad Dermatol. 2013. 68(6):[View Abstract]
  11. Oshimo T, Fukai K, Abe Y, Hozumi Y, Yokoi T, Tanaka A, et al. Pediatric case report: clinical profile of a patient with PCWH withp.Q377X nonsense mutation in the SOX10 gene. J Dermatol. 2012. 39(12):1022-5. [View Abstract]
  12. Sznajer Y, Coldea C, Meire F, Delpierre I, Sekhara T, Touraine RL. A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease. Am J Med Genet A. 2008 Apr 15. 146A(8):1038-41. [View Abstract]
  13. Dourmishev AL, Dourmishev LA, Schwartz RA, Janniger CK. Waardenburg syndrome. Int J Dermatol. 1999 Sep. 38(9):656-63. [View Abstract]
  14. Oysu C, Baserer N, Tinaz M. Audiometric manifestations of Waardenburg's syndrome. Ear Nose Throat J. 2000 Sep. 79(9):704-9. [View Abstract]
  15. Tagra S, Talwar AK, Walia RL, Sidhu P. Waardenburg syndrome. Indian J Dermatol Venereol Leprol. 2006 Jul-Aug. 72(4):326. [View Abstract]
  16. Shim WK, Derieg M, Powell BR, Hsia YE. Near-total intestinal aganglionosis in the Waardenburg-Shah syndrome. J Pediatr Surg. 1999 Dec. 34(12):1853-5. [View Abstract]
  17. Moore SW, Johnson AG. Hirschsprung's disease: genetic and functional associations of Down's and Waardenburg syndromes. Semin Pediatr Surg. 1998 Aug. 7(3):156-61. [View Abstract]
  18. Verheij JB, Sival DA, van der Hoeven JH, Vos YJ, Meiners LC, Brouwer OF, et al. Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: a case report and review of the literature. Eur J Paediatr Neurol. 2006. 10(1):11-7. [View Abstract]
  19. Madden C, Halsted MJ, Hopkin RJ, Choo DI, Benton C, Greinwald JH Jr. Temporal bone abnormalities associated with hearing loss in Waardenburg syndrome. Laryngoscope. 2003 Nov. 113(11):2035-41. [View Abstract]
  20. Chang T, Hashimoto K, Bawle EV. Spontaneous contraction of leukodermic patches in Waardenburg syndrome. J Dermatol. 1993 Nov. 20(11):707-11. [View Abstract]
  21. Dourmishev AL, Dourmishev LA, Schwartz RA, Janniger CK. Waardenburg's syndrome with facial palsy and lingua plicata: is that a new type of disease?. Cutis. 1999 Mar. 63(3):139-41. [View Abstract]
  22. Webb KM, Smith AJ, Dansby LM, Diskin CJ. Waardenburg syndrome with familial unilateral renal agenesis: a new syndrome variant?. Ther Apher Dial. 2015 Jun. 19(3):296-8. [View Abstract]
  23. Galasso C, Bombardieri R, Cerminara C, Stranci G, Curatolo P. Anophthalmia-Waardenburg syndrome with expanding phenotype: does neural crest play a role?. J Child Neurol. 2007 Nov. 22(11):1252-5. [View Abstract]
  24. Milunsky JM, Maher TA, Ito M, Milunsky A. The value of MLPA in Waardenburg syndrome. Genet Test. 2007 Summer. 11(2):179-82. [View Abstract]
  25. Broomfield SJ, Bruce IA, Henderson L, Ramsden RT, Green KM. Cochlear implantation in children with syndromic deafness. Int J Pediatr Otorhinolaryngol. 2013 Aug. 77 (8):1312-6. [View Abstract]

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 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. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.

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 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. Image courtesy of Dourmishev LA et al, Cutis 1999; 63:139-40. Copyright 1999, Quadrant Healthcom, Inc.