Waardenburg syndrome

Waardenburg Syndrome

The Neural Crest

During human embryological development and differentiation , primordial or rudimentary stages of the organ and peripheral systems are first formed . The ectoderm of the embryo gives rise to the epidermis , the central nervous system , the peripheral nervous system and several non-neuronal cells of the head and heart . Formation of the neural ectoderm occurs during the third week of gestation (Le Douarin Kalcheim , 1999 Wilson Hemmati-Brivanlou , 1997

A segment of the dorsal ectoderm serves as the template of the neural ectoderm to form the region of the

embryo known as the neural plate This process of neural plate formation is usually called neural induction . After neural induction , three derivatives are then produced from the ectoderm from three independent processes (Liem et al . 1995 Le Douarin Kalcheim , 1999

One process called neurulation leads to the formation of the neural tube which serves as the primordial of the central nervous system made up of the brain , spinal cord and neurons to name a few . Another process leads to the formation of the outer ectoderm also referred to as ectodermis which later on differentiates to skin , hair , nails , mouth epithelium and related structures . The third process produces the neural crest which subsequently differentiates into the peripheral nervous system , adrenal medulla , melanocytes , facial cartilage and tooth dentine (Le Douarin Kalcheim , 1999

The neural crest is an intermediate structure produced by the interaction between the neural plate and the surface ectoderm . The neural crest is sometimes considered as the fourth germ layer . Neural crest cells delaminate from the dorsal neural tube when the dorsal tips of the neural folds join together . After delamination , these cells migrate from their origins in the neuraxis by traversing designating paths to settle on peripheral targets (Le Douarin Kalcheim , 1999 Wilson Hemmati-Brivanlou , 1997

Crest-derived cells have the potential of differentiating into many types of tissue cell types such as Schwann cells or glial cells , adrenal medullar cells , epidermal pigment cells and head connective tissue cells . Schwann cells or glial cells make up sensory , sympathetic and parasympathetic systems as well as enteric nervous systems . Neural crest cells express only the characteristics that are suitable for the organ to which they have colonized (Knecht Bronner-Fraser , 2002

The process of induction by the non-neural ectoderm on the neural plate lateral cells was shown to be facilitated by the Wnt gene family members , more specifically the Wnt-6 . Neural crest cells , upon induction , express slug , a transcription factor that controls delamination or dissociation of cells from the epithelial layer of the embryo . This transcription factor is hypothesized to activate factors that detach the taut connections between crest cells , permitting changes in the shape and other characteristics towards less of the neuroepithelial cells and more of mesenchymal cells (Le Douarin Kalcheim , 1999

Neural crest cells in the head delaminate prior to the neural folds fusion . Neural crest cells migrating during the epithelial-to-mesenchymal differentiation cease the synthesis of the cell surface adhesion molecule but synthesize it again during their aggregation for the spinal and sympathetic ganglia formation (Le Douarin Kalcheim , 1999 Wilson Hemmati-Brivanlou , 1997

Neural crest migration pathways are initiated from designated sites along the axis of the cranial-caudal region of the dorsal neutral tube referred to as the neuraxis . These migration routes guide the dividing cells derived from the neural crest starting from the origin into the targets . After reaching the targets , crest-derived cells discontinue their division and initiate the expression of the phenotypes appropriate for the target . This means that the origin of the crest cell in the neuraxis dictates the target it will colonize (Knecht Bronner-Fraser 2002

During migration , crest-derived cells come across signaling molecules such as growth and trophic factors as well as fibronectin , laminin and collagen IV . These molecules enhance the continuous migration and proliferation of crest-derived cells . Receptors that are needed for interaction with environmental conditions are developed during this migration . There is a significant increase in the number of crest-derived cells upon reaching their specific target (Liem et al 1995 Le Douarin Kalcheim , 1999

Cranial development traces its origin in the cranial neural crest Crest-derived cells present in the head region form craniofacial mesenchyme which later differentiates into cartilage and bone tissues neurons and glia of the cranial region and facial connective tissues Other crest-derived cells on the other hand follow routes along pharyngeal structures to form thymus connective tissue , tooth primordial odontoblasts , and middle ear and jaw bones . On the other hand , the crest-derived cells in the trunk region differentiate into the following derivatives : sympathic adrenal cells , trunk sensory neurons and glia and pigment cells by following three respective pathways (Le Douarin Kalcheim , 1999 Wilson Hemmati-Brivanlou , 1997

The vagal and sacral neural crests cell progenies form the enteric nervous system . The pathway of the vagal crest-derived cells is along the length of the bowel . On the other hand , the pathway of the sacral crest-derived cells is through the post umbilical gut . Blockage or failure of the neural crest-derived cells to arrive on the colon from these sector leads to the absence of enteric ganglia which consequently leads to the lack of peristaltic movements in the concerned segment of the colon , a condition referred to as Hirschsprung 's disease (Le Douarin Kalcheim , 1999

Cardiac neural crest cells follow pathways through the pharyngeal arches 4 and 6 where they form the septum that divides the pulmonary artery from the aorta . Failure or blockage of the migration and colonization of cardiac neural crest-derived cells through this route leads to thymus thyroid , parathyroid gland defects and a condition called common cardiac outflow tract (Osumi-Yamashita Eto 1990 Le Douarin Kalcheim , 1999

Waardenburg Syndrome Types

Waardenburg syndrome is a deafness dis 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 diss 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 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 HYPERLINK "http /www .orpha .net /data /patho /GB /uk-WS1 (05 .pdf 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 ,

br Nascimento , R , Mingroni-Netto , R , and

. Otto (2006 . Waardenburg Syndrome : of two novel mutations in the PAX3 gene , one of which incompletely penetrant . Genetics and Molecular Biology , 29 , 4 601-604

Read , A .P V .E . Newton (1997 . Waardenburg syndrome . J Med Gene 34 ,656-665

Tachibana , M , Bayashi , Y Y . Matsushima (2003 . Mouse models for four types of Waardenburg Syndrome . Pigment Cell Res , 16 , 448-454

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. A Hemmati-Brivanlou , A (1997 . Vertebrate neural induction : Inducers , inhibitors , and a new synthesis . Neuron 18 699-710

Zlotogora ,J , Lerer ,I , Bar-David , S , Ergaz ,Z . and D . Abeliovichl (1995 . Homozygosity for Waardenburg Syndrome .Am . J . Hum . Genet . 56 1173-1178

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