WAARDiNBURG SYNDROME — INHERITED DEAFNESS WITH PIGMENTARY INVOLVEMENT

Die kenmerke van die Waardenburgsindroom is die eerste keer in 1905 deur Hammerschlag bespreek. Waardenburg1 sou egter eers in 1951 die data byeen moes bring en dit as ’n nuwe sindroom aanbied. Daar is 6 basiese kenmerke van die sindroom wat die meeste werkers aanvaar, maar die werklike verhoudings wat elkeen verteenwoordig, verskil van studie tot studie. Afgesien hiervan is daar verslae van ander bevindings wat met die siekteaandoening skakel of parallel daarmee loop.

T H E W aardenburg syndrom e was first clearly de fined in 1951.The m ajor clinical im portance lies in the fact th at ab out 20% o f affected individuals are deaf.F urtherm ore, because the condition is inherited autosom al dom inantly, there is a risk o f the disorder be ing handed dow n from generation to generation.
The syndrom e consists o f six m ajor features which m ay appear in any com bination and to any degree in the affected individual.The six characteristics are: 1) Shortening o f the palpebral fissures due to malpositioning o f the canthic folds.2) H eterochrom ic irides, which is variegated eye colour.

H IST O R IC A L BACKGROUND
The first recorded report o f the syndrom e, which was later to bear W aardenburg's nam e, was in 1905 when H am m erschlag described a patient with 3 o f the 6 features constituting the syndrom e.Further reports followed from Van der Hoeve (1916) who described twins, M ende (1926) who dem onstrated the dom inant inheritance o f the defect, Gates (1938) who descrbed a Singalese family with blue eyes and W alsh (1947) who wrote an article concerning an affected brother and sister.Finally W aardenburg in U trecht in the N etherlands (1948) discussed his first case, a 72-year-old m an who m anifested some o f the sym ptom s.A fter reviewing the literature, W aardenburg examined 1 050 residents o f the schools for the deaf in H olland.He found 13 new cases with the same cluster o f characteristics and subsequently w rote his paper discussing the new syndrom e (W aardenburg 1).

T H E PR ESEN T STUDY
The D epartm ent o f H um an Genetics o f the U niversity o f Cape Town and G roote Schuur H ospital has u n d er taken a num ber o f studies in the schools for the deaf, in which the genetic nursing sisters working in this d e p a rt m ent have participated (Groenew ald and D uggan2).N early 4 000 children have been investigated and over 60 cases o f W a a rd e n b u rg 's sy n d ro m e h av e been diagnosed.The writer was personally involved in the last study in which 14 children with the syndrom e were identified.
As there are over 200 types o f deafness it m ay be d if ficult to distinguish one from another.This difficulty is increased as the degree o f deafness can vary greatly between cases o f the syndrom e.
The m ain feature we used to identify the children showing the syndrom e was eye colour.This is an easily observed phenom enon and therefore is fairly reliable for accurate diagnosis.Some o f the other pointers are p ro n e to su b jectiv e estim a tio n s (e.g . in te r-o c u la r distan ce as there are few tables giving 'n o rm a l' m easurem ents) or m ay be difficult to pick up (e.g. the presence o f a few white hairs representing a white forelock).W here the eye colour suggested the diagnosis, we examined the children fully for other signs o f the disorder.
In the present study our figures are based on the 14 children the writer saw in the most recent survey.Percentages given therefore m ay not be as significant as those in larger studies, but are still o f interest.
Table I shows the presence or absence o f each trait.A part from the first 3 children, who are siblings, the children are unrelated.
Table I.The features seen in the subjects o f the present study.

Key. • feature is present in the individual
In this paper there will be a brief discussion o f each sym ptom , a précis o f the available inform ation as well as the com parative incidence found in the literature.

Shortening o f the Palpebral Fissures
D ystopia canthorum is the m alpositioning o f the canthic folds which causes the palpebral fissures (the line form ed by the eyelids) to b e.shortened horizontally.There is a know n norm al range for adult Caucasians with which patients can be com pared, but there is little inform ation related to other races or to children.However, m easurem ents can be taken to elim inate the diagnosis o f hypertelorism or o f convergent strabism us, both o f which can produce a m isleading appearance.
The apparent increased inter-ocular distance seen in W aardenburg syndrom e is show n in Diagram 1.In fact Stedm an's m edical dictionary defines dystopia canthrum as " W aardenburg's syndrom e" .A lthough dystopia canthorum is the m ost com m on feature seen in these patients, there are no clear-cut tables o f norm ality.V ariations which may occur could lead to conflicting reports o f the incidence o f this characteristic.
The percentages o f the affected patients showing this sign range froiji 99% (W aardenburg1) to ab o u t 50% (T safrir3).In the current study the writer found 79% with apparent hypertelorism .However, there m ay have been some ethnic bias as m ost o f the subjects were o f mixed racial origin.

Heterochromia Irides
In m ost people the irides are the same colour bilaterally.A notable feature in those with the syn drom e under discussion is the difference in the eye col o u r between the left and right iris or between segments o f the same iris.The heterochrom ia m ay range from both eyes being an abnorm al but distinctive bright blue to only one segment o f one iris showing th at colour.T here is little difficulty in recognising the colour o f the blue once it has been seen.
It is reported th at em bryologically the eyes are this deep blue colour initially, and that the norm al process o f change to the eye colour carried by the parental gametes is interrupted (Fisch4).The actual structure o f the iris is also undeveloped and hypoplastic.
There seems to be agreem ent that there is not much difference between the figures for C aucasians and Negroes showing this feature.W aardenburg1 reported 25% o f his cases showing true heterochrom ia, whereas 81% had some hypopigm entation.O ther reports vary from 50% (P antke et al5) to 87% (T safrir3).In the study in w hich th e w riter p artic ip a te d every child had heterochrom ic irides.H owever, as we had seen them in the schools for the d eaf and had used eye colour as a distinguishing feature, this may be a biased figure.
The hypoplastic irides seem to have no effect on the visual acuity.There is no photophobia nor nystagm us nor any other signs associated with albinism .Never theless, although the structure o f the fundus appears norm al, there have been reports o f albinoid areas in the fundus corresponding to the hypoplastic areas in the iris (Konigsm ark et al6).
C are m ust be taken th at the colour is not caused by o th er factors.These m ay include infectio n, nerve dam age, cutaneous albinism and an X-linked deafness (P antke5).In the w riter's observations o f the children in the schools for the hard o f hearing, there were two sisters who each had one blue eye.As they were also d eaf an erroneous " on the sp o t" diagnosis o f W aarden burg syndrom e could have been m ade.Both children, however, had a history o f eye infections after which the colour o f the eye changed.

Broad Prominent Nasal Root
It m ay be difficult to assess this trait, especially if inter-racial studies are done.There are few norm ality tables and those tabulated are only for C aucasians.One au th o r said th at this feature was only apparent due to the dystopia canthorum and the hypertrichosis o f the eyebrows (Fisch4).In fact he reported that a num ber o f his patients suffered from depressed nasal bridges and had had sinusitis while children as a consequence.W aardenburg1 thought this trait was due to hyperplasia o f the frontal bones as well as hypertrichosis.This could tie up with defective developm ent causing the white forelock and the occasions o f cleft lip and palate.
The presence o f this characteristic varies from a reported 78% (W aardenburg1) with a totally C aucasian study group, to 15% (T safrir3) with a totally N egroid group.In the w riter's group there were no easily recognised cases with this sign.
From the above it can be seen th at this peculiarity m ay not, in fact, be a distinctive com ponent o f the syn drom e.It m ay be apparent only in the presence o f other features.

Hypertrichosis and Synophrys o f the Eyebrows
A fourth sign observed in the syndrom e is an overgrow th o f the eyebrows, especially o f the m edial third.This tends to cause an approxim ation o f the eyebrows or even results in them grow ing together (synophrys).The original paper reported an incidence o f 45% o f patients showing this trait which seems to be supported by other evidence.An exception is T safrir3 who desribes only 17% o f her subjects showing this sign.This may be due to the lack o f facial hair in the N egro.In the present study 57% o f the children had overgrow n eyebrows.
This feature does occur in other syndrom es such as the C ornelia de Lange and other rare disorders as well as in norm al people.However in W aardenburg syndrom e there is no increase in body hair, which facilitates d if ferential diagnosis.

White Forelock
This trait may be present as a few white hairs in the centre o f the anterior hairline to a full blaze o f unpigm ented hair.There m ay also be white hairs in the eyebrow s a n d eyelashes.A n o th e r re la te d sign is p re m a tu re grey in g w hich p re su m a b ly c a n n o t be recognised in young children.However prem atu re grey ing can run in families who do not have the W aard en burg syndrom e.
A n interesting observation is reported by Feingold et al who had some subjects with the forelock present at b irth , but who said th at it disappeared as they grew older (M cKusick7).
In his original article W aardenburg1 stated th at 17% o f his subjects show ed som e degree o f greyness.
Petersen et aP reported that 48% o f his cases had poliosis (general greying o f the hair) and 33% showed prem ature greying.He did not say w hether these signs appeared in the sam e people.In the w riter's sam ple there were two children with small white forelocks.

Deafness
The degree o f deafness in the W aardenburg syndrom e ranges from com plete deaf-m utism to bilateral or unilateral partial loss o f hearing.There seem to be c o n flicting reports as to the actual type o f deafness involv ed.H owever, accum ulated evidence points to the h ea r ing loss being in the m iddle and lower ranges rath er than in the upper ranges.The deafness is present at birth and is not progressive.
T safrir3 recorded 62,5% o f her cases with some h ear ing loss as com pared to W aard en b u rg 's1 report o f 20% .This was in spite o f the fact th at W aardenburg traced his cases th rough the schools for the deaf.The d if ference m ay be due to the fact th at he was able to trace m ore relatives o f his subjects (in H olland) th an T safrir was able to do in South A frica.
In this study there was not sufficient time to study all the fam ily m em bers who were not in the special schools.The writer therefore found th at all the subjects were hard o f hearing.For this reason these results for this characteristic cannot be taken as truly representative o f the incidence o f deafness.It does, how ever, point out the m ost serious problem th at these children have to face.gives the figure o f 3% ) and vitiligo (T safrir3 quotes 16,7% and G orlin7 gives the figure as 15%).Fisch4 reported seeing some o f his subjects with a dappled skin.We found one child with obvious vitiligo and it is interesting th at his b ro th e r h ad a w hite forelock.Vitiligo appears to be one aspect o f W aard en b u rg 's syn drom e which he did not docum ent.As the defect is passed from generation to generation, different aspects o f the syndrom e m ay be observed in related individuals.T hus, due to the variable expres sivity o f the gene, the correct diagnosis m ay not be recognised.

Histological and Auditory Investigations
T here has on ly been one re co rd e d case o f a histological investigation.Fisch4 reported the p o st m ortem result o f a young child who died following surgery for oesophageal atresia.He studied the inner ear and the brain.It was found th at the organ o f C orti was absent in all the coils o f the cochlea.H e also found th at parts o f the auditory nerves were poorly developed.The other findings were norm al.
In 1968 M arcus found th at auditory exam ination o f 16 cases o f W aardenburg syndrom e showed only one o f them to have a norm al vestibular system (Konigsm ark and G orlin6).

POSSIBLE EM B R Y O LO G IC A L BASES FOR W A A RD EN B U R G SYNDROM E
There are several hypotheses as to the basic defect causing this syndrom e.No single hypothesis is fully sup ported and, until fu rth er investigation is done, workers will have to weigh the pros and cons o f each study.

Migration o f Cerebro-spinal Fluid Blebs
T safrir3 feels th at this is the m ost likely cause o f the defect.She hypothesises th at during em bryological developm ent a fault occurs in which blebs or blisters o f C .S .F .are form ed.These interfere with the norm al developm ent o f the neural crest cells.
The theory th at the blisters o f C .S .F .cause the same developm ental fault in every case seems unlikely.

First Arch Syndrome
There are a num ber o f genetic disorders which could resemble the W aardenburg syndrom e.Some o f them are the Pierre-R obin syndrom e, the Treacher Collins syn drom e and the cleft lip and palate syndrom e.All o f these have som e form o f interference with the form attion o f the features in the m idline o f the face.However, people with the W aardenburg defect appear to have less involvem ent o f the m idline structures and have a high proportion o f deafness.This reduces the likelihood o f a connection between the tw o syndrom es.

Possible Connections With Status Dysraphicus
Status dysraphicus is the failure o f the development o f the m idline structures, not only o f the face but o f any other part o f the body such as syringom elia.This may tie up with the presence o f the forelock, dystopia canthorum and other facial lesions, but does not explain why there is vitiligo, deafness and no other midline deform ities.

Developmental Fault in the Neural Crest
Several w orkers have shown th at the neural crest is concerned with the form ation o f the auditory organs and the pigm entary cells (H orstadius, Du Shane and Rawles in Fisch4).If there is a m alform ation in the em bryological stage, one can hypothesise the developm ent of faulty hearing and pigm entation.This theory is sup ported by w ork done on mice by Deal, as reported in Konigsm ark and G orlin6.

Relationships With Other Pigmentary Hearing Defects
It is a know n fact th at white anim als are often deaf or h ard o f h earin g .T here have been a nu m b er o f histological studies carried out on the ears o f these anim als and it has been suggested that the defect occurs in the first few days o f intra-uterine life, at least in the case o f white cats (Bosher and Hallpike in M ckusick7).There m ay be other instances o f deafness and piebald colouring, but until researchers can find the cause and the tie-up between the two it will be difficult to trace the origin o f the defect.

Genetic Considerations
Although there has been no irrefutable p ro o f as to the em bryological basis o f the W aardenburg syndrom e, the actual mechanism o f the inheritance is easier to prove and accept.
W aardenburg him self produced large family trees showing th at the syndrom e had an autosom al dom inant inheritance, th at is, the expression o f a trait in an individual who carries both the " n orm al" and the " a b n o rm al" gene on his autosom es.The autosom es are chrom osom es o th er than his sex chrom osom es.
This fact has been generally accepted.A lthough there is a dom inant form o f inheritance there is very variable expressivity and penetration.This m eans th at any o f the signs in any com bination and degree may ap p ear in the affected individual.W hen the parent with the defect shows one aspect, such as the white forelock, the child m ay or m ay not show this feature and m ay easily show any o f the other phenom ena.
Studies on the chrom osom es have not revealed any abnorm alities.How ever, techniques are im proving rapidly and future research m ay indeed be able to p in point the defective area.
The nurse should recognise the risk run by each generation o f inheriting this disorder.Due to the h a rd ships which can result from deafness, especially if u n treated, medical staff at genetic clinics are available to give counselling when requested.This should m ake the fam ily aw are o f the chance o f the defect being inherited by the offspring and thus bring to their atten tio n the im portance o f having each child checked for hearing p ro blems (B eighton10).A nother trait which m ay cause problem s is noticeable vitiligo or an extensive white forelock.There is little which can be done to disguise the unpigm ented skin but hair dye can be used on the forelock.
T herefore, although this syndrom e does not have an effect on the life-span o f the individual concerned, there are difficulties for which he needs help.The am b u lato ry surgery facilities concept is sim ilar to the narco-clinic concept in the R .S .A .

BOOK REVIEWS
The underlying philosophy is th at the required surgical services can be com pleted safely within one day from adm ission to discharge.This is a m ajor resource for m eeting the increased dem ands on health services.
Aspects discussed in planning such a unit include: fram ew ork for the planning and building processes; standards to be set; budgeting; personnel aspects; ancillary services; ethics; legal aspects and public rela tions; equipm ent evaluation and use.
The chapter (Ch.10) on em otional aspects o f surgery provides insight into the em otional trau m a necessarily associated with surgery -how ever m inor.
The final chapter (Ch.13) is a guide to setting up a policy and procedure m anual for am bulatory surgery facilities.Aspects covered in reasonable detail include employm ent practices; posture and body m echanics; the principles o f sterile technique, operative skin p re p ara tion; surgical trays; guidelines for assisting the patient from recovery to am bulation and nursing care plans.Die slapbanduitgaw e van hierdie outeurs wat handel oor die bejaarde pasiënt is verdeel in twee afdelings: A FD ELIN G I Hierdie afdeling handel oor die ouer persoon en sy versorgingsbehoeftes. Fasette wat hierin behandel word is onder andere: * die effekte van veroudering * die bejaarde en die gem eenskap * die bejaarde en sy gesin * die bejaarde in die geriatriese eenheid Spesifieke behoeftes m et betrekking to t toiletgew oontes, voeding, sintuiglike deteriorasie, rehabilitasie en term inate versorging word ook bespreek.

A FD ELIN G II
In hierdie afdeling word aandag gegee aan die siektetoestande waarm ee die bejaarde problem e ondervind, byvoorbeeld ten opsigte van sirkulatoriese toestande, siektes van die senuweestelsel, organiese g ee ste ssie k te to e sta n d e , infektiew e to e sta n d e ensovoorts.

S.P. HUM AN
e r t r i c h o s i s F o r e lo c k D e a f n e s s R H

D
ia g ra m 1 D y s to p ia C a n th o r u m A -in crease d B -n o rm a l B D iag ram 2 H y p e rte lo ris m A -in crease d B -in crease d D ia g ra m 3 In te rn a l S tra b is m u s A -n o rm a l B -d e c re a se d Diagrams showing the varying measurements in 3 anatomical conditions o f the eye A -inner canthic fold m easurem ents B -interpupillary distance In hypertelorism the whole eye-orbit is displaced laterally, while in internal strabism us and W aardenburg syndrom e it is norm ally positioned.It m ay therefore be o f value to m easure the inter-pupillary distance.The presence o f epicanthic folds can be excluded by check ing the positions o f the inferior lachrym al punctae.In the event o f epicanthic folds the points are norm ally positioned, whereas in dystopia canthorum they are displaced laterally.
D iff e re n tia l d ia g n o se s can be w ro n g ly m a d e .H ypertelorism m ay result in the child being diagnosed as havng Down syndrom e, especially where deafness causes an ap p aren t low I.Q .C utaneous albinism o r classical piebaldism is an au tosom al d o m in an t tra it w hich is n o t related to deafness, b u t which does have a triangular shaped forelock from the an terior hairline som etim es involving th e m e d ia l th ird o f th e e y e b ro w s (H a rris a n d H irschhorn9).
Dominant Inheritance and VariableExpressivity in Waardenburg's Syndrome (adapted from Waardenburg1).C O M M EN TThe features which constitute W aardenburg syn drom e were first discussed in 1905 by H am m erschlag.How ever, it rem ained for W aard en b u rg 1 in 1951 to assim ilate the d ata and to present it as a new syndrom e.There are six basic features o f the syndrom e which m ost workers accept, but the actual prop o rtio n s by which each is represented vary from study to study.A part from this there are reports o f other findings which are linked or ru n parallel with the disorder.There are tw o m ain problem s for which help needs to be given to those m anifesting the syndrom e.The m ost im p o rtan t one is deafness.A ssistance can be given by means o f hearing aids a n d /o r training in the schools for the d eaf or h ard o f hearing.It m ust be rem em bered that the deafness can be p ro fo u n d regardless o f the involve ment o f the p a re n t's hearing.