Waardenburg syndrome is a deafness disorder with associated pigmentary abnormalities. The syndrome affects one out of 270,000 births per year and accounts for approximately 2% of all congenital deafness cases. It is transmitted in an autosomal dominant fashion and characterized by symptoms including inner canthi displacement, iride heterochromia, white forelock and some level of sensorineural deafness, poliosis and piebaldism (Faivre & Vekemans, 2005a; Faivre & Vekemans, 2005b; Faivre & Vekemans, 2005c; Pardono, 2006; Zlotogora, 1995). Disease expression is considered as very variable since even monozygotic twins manifest different symptoms.
Apart from the above conditions commonly observed in patients having Waardenburg syndrome, the following characteristics were also reported: facial palsy, incomplete anodontia, lingua plicata and myelomeningocele. There are four known types of Waardenburg syndrome, distinguishable by major characteristics and varying levels of expression of common symptoms. These are Waardenburg syndromes I, II, III (Klein – WS) and IV (Shah – WS). Waardenburg syndrome type I is characterized by lateral displacement of the inner canthi whereas Waardenburg syndrome type II presents normally located inner canthi.
Waardenburg syndrome type III covers extreme cases with arm deformities while Waardenburg syndrome type IV includes patients lacking colonic ganglia (Read & Newton, 1997). Waardenburg Syndrome I. Apart from the lateral displacement of the inner canthi, several symptoms are also associated with WS I which are synophrys, white forelock, white skin patches and nasal root hyperplasia. Rare related disorders include elevation of the scapula or Sprengel anomaly, spina bifida, cleft lip or palate, cardiac deformity and vestibular dysfunction (Faivre & Vekemans, 2005a).
This syndrome type arises due to the absence of pigmentary cells called melanocytes normally found in skin, hair, eyes and ears – more particularly the stria vascularis ductus cochlearis which is the stratified epithelial lining of the ligamentum spirale cochleae upper segment. In other words, the deafness is a result of lack of melanocytes in the ear due to the blockage or failure of normal migration of crest-derived cells to this region (Pardono, 2006; Read & Newton, 1997). This condition or phenotype is a product of an heterozygous mutation of the PAX3 gene found in the 2q37 chromosome.
WS I is inherited in an autosomal dominant fashion with a wide inter- and intra-familial expressivity. Symptoms vary from the basic dystopia of the inner canthi to the complete features listed above (Faivre & Vekemans, 2005a). Prenatal diagnosis is feasible when the mutation is established in the family although there are no prevention or treatment interventions available. Management includes use of hearing aids the deafness and other strategies for different abnormalities (Zlotogora, 1995; Read & Newton, 1997). Waardenburg Syndrome II. There are two synonyms or subtypes of WS II: type IIA and IIB.
This syndrome is a complex mix of disease features that is distinguished from WS I through the absence of the symptom of dystopia canthorum while in order for a family to be considered as affected with this disease, there must be a history of congenital deafness or pigmentation abnormalities (Faivre & Vekemans, 2005b). Although deafness is also present in WS I, this is more pronounced or severe in WS II. Another more frequent condition is heterochromia of the iris. However, in terms of incidence, WS I was observed to be more frequent than WS II.
Of those afflicted by the disease, almost three-fourths have neurosensory deafness, around half have eye pigmentation anomalies, about a third have white forelocks and premature graying of the hair. A number of patients also present with skin depigmentation but no facial dysmorphism is reported in WS II patients (Pardono, 2006; Read & Newton, 1997). Waardenburg Syndrome II also correlates with the aberrations in the pigmentation cells or melanocytes in the skin, hair, eyes and ears. Whereas WS I is brought about by mutations in the PAX3 gene, WSII was found to be a result of a MITF gene mutation.
MITF stands for the micropthalmia-associated transcription factor important in the development of and migration of melanocytes from the neural crest. Recent studies also attribute this disease to mutations in the following genes: the endotheline (EDN3) gene, the endothelin-B receptor (EDNRB) and the SLUG gene (Faivre & Vekemans, 2005b). Waardenburg Syndrome II is inherited in an autosomal dominant pattern with fluctuating inter- and intra-familial expressivity. The same management strategies for WS I are also recommended for WS II patients (Zlotogora, 1995; Read & Newton, 1997). Waardenburg Syndrome III.
WS III is also referred to as Waardenburg – Klein syndrome or Waardenburg syndrome with limbs anomalies. It is considered as an extreme severity and rarity manifestation of Waardenburg syndrome I. Moreover, musculoskeletal abnormalities figure prominently in this symptom type, in addition to the heightened features also seen in WS I (Faivre & Vekemans, 2005c). Limbs anomalies take in the form of musculoskeletal system hypoplasia, contracture flexion, carpal bone fusion and syndactyly. In addition to these are the usual pigmentation abnormalities, displacement of the canthi and deafness.
However, WS III is less frequent than WS I and WS II (Pardono, 2006; Read & Newton, 1997). Waardenburg syndrome III is caused by an abnormality in the pigmentation cells called melanocytes in the hair, skin, eyes and ears. This results from a heterozygous mutation in the PAX3 gene located in the 2q37 chromosome. This mutation is inherited in an autosomal dominant fashion featuring a wide range of expressivity inside and outside families. The same management strategies as in WS I and WS II are recommended for WS III patients.
These are physiotherapy of affected limbs and hearing aid for deafness as well as skin and eye protection (Faivre & Vekemans, 2005c). Waardenburg Syndrome IV. WS IV is also sometimes referred to as Shah – Waardenburg syndrome, Waardenburg – Hirschsprung disease, Waardenburg Syndrome Variant or Hirschsprung disease with pigmentary anomaly. It is a multigenic neurocristopathy characterized by distal gastrointestinal tract aganglionosis. Symptoms include deafness, white forelock, dystopia canthorum, heterochromia of the irides and correlation with Hirschsprung disease (Pardono, 2006).
WS IV is caused by homozygous mutations of the endotheline (EDN3) gene, the endothelin-B receptor (EDNRB) and the SLUG gene. This condition is transmitted in autosomal recessive pattern of inheritance unlike the other three syndrome types which are all transmitted in autosomal dominant way (Read & Newton, 1997). Waardenburg syndrome and Hirschsprung disease are associated due to their common progenitors in the form of the neural crest cells that migrate as cranial neural crest cells to the visceral ganglia in the formation of the gastrointestinal tract (Pardono, 2006).
Mechanisms Involving Waardenburg Syndrome Gene and Gene Products As described in the previous section, there are six transcription factor genes that are responsible for the development of the types of Waardenburg syndrome. These are PAX3, MITF, SLUG, EDN3, EDNRB and SOX10 (Table 1). Of these six transcription factor genes, four have been shown to have relationships in their activation and gene products. PAX3 gene product by PAX3 gene which is known to be involved in the development of WS I was shown to transactivate MITF, a WS2 gene.
SOX10 which is a product of the WS IV gene transactivates the WS 2 – related MITF gene. On the other hand, MITF can also transactivate another WS II gene, the SLUG gene. This implies an epistatic cascade among the mentioned WS genes while there is an obvious interaction of WS IV EDN3 and EDNRB genes. EDN1 influences the elevation of the adenosine monophosphate or cAMP and consequently, the melanogenesis in melanocytes of humans. cAMP affects the regulation of MITF which implicates the involvement of EDN3 an EDNRB (Tachibana, 2006).
Following this, since there is a cascade of transactivation of the four WS genes, this means that there is involvement of the six transcription factor genes in the cascade of melanocytic cells, inhibition of melanogenesis and production of melanocyte stimulating hormone. Melanocytes are integral parts of hair, skin, eye and ear pigment. Regulation and abnormalities in the pathways mentioned above complete the picture regarding the development of Waardenburg syndrome (Figure 1). Figure 1.
Hierarchical relationships of the six Waardenburg gene products (Tachibana, 2003). In summary, Waardenburg syndrome is a medical condition the origin of which can be traced back to the neural crest induction and migration up to the production of melanocytes important to the function of essential organ and systems affected by the disease. During embryogenesis, neural crest derived cells migrate and colonize regions of the embryo for the formation of cranial, cardiac, vagal, sacral and enteric systems.
Cranial neural crest-derived cells are the progenitors of the pigment cells or melanocytes needed by the ears, eyes, skin, hair and gastrointestinal tract for the performance of function and failure to reach these regions lead to formation of these organs. Levels and variations of such failures constitute the Waardenburg syndrome types. Six genes were observed to be involved in these conditions and appropriate mechanisms were identified in the production of their phenotypes which invariably lead to inhibition of melanocytes.
References
Faivre, L. and M. Vekemans. (2005a). Waardenburg syndrome type I.Orphanet Encyclopedia. Retrieved 6 July 2007 from http://www. orpha. net/data/patho/GB/uk-WS1(05). pdf Faivre, L. and M. Vekemans. (2005b). Waardenburg syndrome type II. Orphanet Encyclopedia. Retrieved 6 July 2007 from http://www. orpha. net/data/patho/GB/uk-WS2(05). pdf Faivre, L. and M. Vekemans. (2005c). Waardenburg syndrome type III. Orphanet Encyclopedia. Retrieved 6 July 2007 from http://www. orpha. net/data/patho/GB/uk-WS3(05). pdf Knecht, A. K. and M. Bronner-Fraser. (2002). Induction of the neural crest: A multigenic process. Genetics 3, 452. Le Douarin, N. M. & Kalcheim, C. (1999). The Neural Crest 2nd Edition.
Cambridge, UK: Cambridge Univ. Press. Liem, K. F. , Tremml, G. , Roelink, H. & Jessell, T. M. (1995). Dorsal differentiation of neural plate cells induced by BMP mediated signals from epidermal ectoderm. Cell 82, 969–979 Osumi-Yamashita, N. & K. Eto. (1990). Mammalian cranial neural crest cells and facial development. Develop. Growth & Differ. , 32 (5), 451-459. Pardono, E. , Mazzeu, J. , Lezirovitz, K. , Auricchio, M. , Iughetti, P. , Nascimento, R. , Mingroni-Netto, R. , and P. Otto. (2006). Waardenburg Syndrome: Description of two novel mutations in the PAX3 gene, one of which incompletely penetrant