2JMed Genet 1994;31:726-730

Syndrome of the month

Cleft hand/foot: clinical anddevelopmental aspects

Paul W Buss

AbstractIsolated limb reduction defects occur inapproximately 1 in 2000 live births withinwhich central ray anomalies are an im-portant subgroup. Most affected personshave mild or moderate functional im-pairment. Considerable psychologicalmorbidity may also occur. While therehave been major strides forwards in ourunderstanding of vertebrate limb de-velopment, the mechanisms responsiblefor central ray deformities remain poorlyunderstood. Several case reports ofcentralclefting anomalies associated with chro-mosomal rearrangements or interstitialdeletions of 7q21.2-q21.3 suggest that thischromosomal region is important for limbdevelopment.

(J Med Genet 1994;31:726-730)

While the term ectrodactyly literally means"missing digits", it is now used as a descriptiveterm for a central ray anomaly that presentsclinically as a central cleft of the hands or feet.'Historically, terms such as "lobster claw"2 andsplit hand3 have been used to describe thisdefect which results from absence, or re-duction, of one or more of the three centraldigits (fig 1). The earliest known descriptionof cleft hand was that by Pare4 although Barsky5suggested that this report represented twofingered hemimelia rather than true cleft hand.Central ray defects, according to Swanson'smodified classification, represent terminallongitudinal limb anomalies.6 Cleft limb has anumber of associations and as a result it can be

Department ofNeonatal Medicine,University of Bristol,Bristol BS2 8EG, UKP W Buss

Correspondence toDr Buss, Department ofPaediatrics, Royal GwentHospital, Newport, GwentNP9 2UB, UK.

a useful major feature for syndrome diagnosis.Large families with isolated cleft limbs have

been described which usually show autosomaldominant inheritance and marked variabilityin expression and penetrance, although severalautosomal recessive pedigrees have also beenreported.8'0 Birch-Jensen" estimated the in-cidence of cleft hand deformity at 1 in 90 000births. More recent epidemiological studiessuggest the incidence of central ray anomaliesto be closer to 1 in 10 000 (approximately 0.7per 10 000 live births).'2 '3 The data of Czeizelet all4 indicate that three-quarters (77%) ofcases present with unimelic involvement.

In 1960 Stevenson and Jennings'5 suggestedan abnormal segregation pattern in familieswith isolated ectrodactyly (pedigree analysisshowed an excess of affected sons of affectedfathers). David,'6 when describing three ped-igrees with isolated cleft limbs, suggested thepossibility of germinal mosaicism. X linkedinheritance has also been described in a sevengeneration Pakistani kindred.'7

Ford'8 hypothesised that "ectrodactyly" rep-resented an anomaly that could be explainedby a structural chromosomal defect althoughat that time it was acknowledged that tech-niques for chromosome analysis were poor.Since then a number of case reports have in-dicated that the 7q21.2-q21.3 region is a can-didate site for cleft limbs. 19-26 These haveresulted in considerable molecular interest inthis region.

Clinical featuresClinical problems associated with isolated clefthand and foot are usually cosmetic and psy-

~..Ag;4

Figure 1 Typical central clefts of hands and feet; wide central clefts with normal marginal (radial and ulnar) rays. Inthis case the child had EEC syndrome.

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Cleft handlfoot: clinical and developmental aspects

Table 1 List of conditions in which cleft limb may be afeature (McKusick No)

EEC syndrome (129900)Cornelia de Lange syndrome (122430)Acrorenal syndrome (102520)Focal dermal hypoplasia (305600)Ectrodactyly and cleft palate syndrome (129830)Ectrodactyly/mandibulofacial dysostosis (183700)Ectrodactyly and macular dystrophy (185800)

Non-specific associations with several anomalies are noted byCzeizel et al'4 and also with neural tube defects.

chological rather than functional. Only in theless common variant monodactylous ec-trodactyly, where radial rays are also hy-poplastic, is function severely compromised.Considerable anatomical variability occurs.Cleft hand has been described with pre- andpostaxial duplication and reduction anomalies.'Absence ofthe central digits is the major featurewith varying association with both bony andsoft tissue syndactyly. Many cases will merelyhave one limb affected and others can havetetramelic involvement. Birch-Jensen" foundthat 58% of cases of cleft hands were bilateralwith an equal sex distribution. These clinicalfindings were confirmed by Barsky.' The ma-jority of cases of cleft hand are sporadic. InBirch-Jensen's study, " 50% had a family historyof limb defects while only 20% of Barsky'sgroup5 were familial. The study of Czeizel etall4 showed a high percentage of presentationas atypical forms, though this is based on a"wide" interpretation as to what actually con-stitutes atypical split hand/foot. The definitionof this varies between published reports butactually serves relatively little clinical purpose.It is also subject to wide differences in clinicalinterpretation. A consensus might be that atyp-ical cleft limb occurs when there is not totalabsence of the long finger or when there are,in addition, reduction anomalies affecting themarginal rays. This tends to be (though notalways) sporadic and unilateral, affectingmainly the upper limbs.

Clinically, few functional problems occur inthe upper limbs provided opposition is possible.However when a preaxial anomaly coexists orwhen monodactyly (a single digit) occurs,marked limitation of function can result. Func-tional limitation can result when central cleftsare particularly wide or deep and operativemanagement to close these can often result insignificant improvement in function. Lim-itation of function owing to syndactyly of thefingers may also occur and this also can beovercome surgically.27 In the lower limbs themajor practical difficulty encountered is one ofobtaining adequately wide fitting shoes.Many persons with "ectrodactyly" ex-

perience psychological problems. These oftenemerge in mid-childhood as a reluctance to usehands, even a need to hide them. Non-verbalcommunication may be affected by this andcommon important gestures, such as handshaking, are often avoided. These problemshave frequently not been overcome even inadult life (Buss, unpublished data). Providingadequate reassurance to parents of affectedchildren may allow them to help their childrendevelop a positive body image. Anecdotal re-ports of cases with tetrameiic involvement who

are professional artists, speed typists, and evenmarathon runners may also be of considerablereassurance.

Radiology usually reflects the clinical find-ings but sometimes transverse metacarpals orproximal phalanges affect the appearance. Oc-casionally atypical cleft hand and monodactylycoexist (fig 2). In the EEC syndrome (theectodermal dysplasia, ectrodactyly, and cleftingsyndrome), preaxial anomalies also may coexistwith a central cleft. While careful examinationof the parents' hands may be helpful, there islittle extra information to be gained from rou-tine radiography of the hands and feet of par-ents who are clinically normal.

Differential diagnosis: clinical approachRecognition of a central ray deformity may bea useful clue for the diagnosis of a number ofunderlying disorders (EEC syndrome, Corneliade Lange syndrome, acrorenal syndrome, etc)(table 1). When presented with a neonate witha central ray defect diagnostic difficulties mayarise. In such cases magnification of nails anddental x rays may help in identifying in-volvement of ectodermal structures (difficult inthe neonate/infant with oligosymptomatic EECsyndrome). It is also worthwhile reviewingthese children during the first year to confirmnormal development of ectodermal structuresand, if uncertain of this, electron microscopicexamination of the hair shaft may be helpfulin diagnosing ectodermal dysplasia (Buss, un-published data). In the newborn it is importantto document hair distribution and birth weight.A renal ultrasound scan may help make thediagnosis of the EEC or acrorenal syndrome.In older children and adults with "isolated"ectrodactyly, one often notes minor associatedectodermal anomalies (of the teeth in par-ticular). ' Language milestones should bechecked. Ectrodactyly associated with con-ductive deafness and mandibular hypoplasiahas been described in a father and son byPatterson and Stevenson28 and more recentlywith sensorineural deafness by Raas-Rothschildet alP although the latter report looks distinctlysimilar to oligosymptomatic EEC syndrome.The otic capsule is interestingly also of ec-todermal origin.30 Opitz and Frias3' describedan association with cleft palate as a separateentity, the ECP syndrome. Karsch32 recognised

Figure 2 Combined monodactyly with atypical cleftdeformity showing some preservation of marginal rays inright hand.

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Table 2 Review of reported cases of ectromelia associated with anomalies of chromosome 7q21

Author Clinical description 7q deletionlkaryotype

Del Porto et al" Male infant, low set ears, hypotonia, beaked nose, bilateral del(7) (ql I-q2 1 or q22)cleft foot

Pfiefer et al2" Female aged 2 years, microcephaly, low set ears, mental del(7) (q I .2-q22. 1)retardation, cleft palate, R cleft hand and foot

Tajara et at2' Male aged 3 years, microcephaly, anteverted nares, del(7) (qI 11.2-q22)micrognathia, retardation, clefting of three limbs

Morey et at22 Premature male, R cleft hand, amelia of lower limbs, facial del(7) (q2 1 .3-q3 1.3)dysmorphism, ASD. Died at 7 months

Sharland et at2' Male infant, tetramelic ectrodactyly, low set ears, Complex rearrangement t(5;7;9)hypertelorism with breaks at 7q21.2 and 7q31.3

Roberts et at24 Male, tetramelic ectrodactyly, mild facial dysmorphism and Complex rearrangementmild developmental delay (intrachromosomal) del(7)

(q2 1.3-22. 1)Naritomi et at2' Male, trimelic ectrodactyly, bifid uvula, high arched palate ins(3;7) (q21;q34q22). Break at

7q22q34Genuardi et al2' 5 generation family, 7 affected, 5 male. Unimelic (3 cases), Balanced translocation t(2;7)

tetramelic (4 cases). Two with sensorineural deafness. One (q2 1.1 ;q22. 1)case with tibial hypoplasia

an association with impaired vision owing tocataract and macular dystrophy.For parents of isolated cases empirical re-

currence risks are low but there is a potentialrisk to offspring of affected persons of 50%.With possible heterogeneity and altered pene-trance risks may be lower.33 Certainly isolatedcleft limbs can produce sohie very difficultdiagnostic as well as counselling situations.Constriction amputation of digits may bedifficult to distinguish from unimelic atypicalcleft limb. Clues as to a constrictive aetiologymight include the observation of amnioticstrands at birth or lymphoedema distal to apossible constriction ring. Soft tissue syn-dactyly also occurs in constriction anomaliesbut is usually distal.34 In such cases no otherbony anomalies are usually radiologically pres-ent and occasionally the astute neonatal res-ident will have asked for the placenta to beexamined showing an amniotic tear. Unilaterallimb reduction deficits may also have a vascularorigin and the clinician should be aware ofrelevant points in the history, for example,chorionic villus sampling, presence of twins(reversed arterial perfusion), and any oc-currences that may have compromised fetalcirculation. It can be difficult to separate someof these potential causes and in the atypicalisolated unimelic case explanation of a numberof potential aetiologies may occasionally benecessary.

Cleft hand and foot malformation and 7qabnormalitiesEight recent case reports of ectrodactyly and7q21 .2-q21.3 anomalies are summarised intable 2. It is of interest that six of seven isolatedcases reported are male (note the pre-ponderance of males observed by Stephensonand Jennings'5 and in the familial cases ofCzeizel et all4). The significance of this is un-clear. Genuardi et al6 recently reported a familysegregating a balanced translocation with abreakpoint at 7q22. 1, in which two out ofnine translocation carriers had limb deficiencies(similar abnormalities were present in a furtherfive persons in whom chromosome analysis wasnot possible). Overall there is a wide range ofclinical involvement from apparently isolatedcleft limbs to ectromelia associated with fatalanomalies. None of the isolated cases had uni-

lateral cleft limbs, although three members ofa family26 showed unimelic involvement. Themajority of the reported cases have typical cleftlimbs.Few other reports exist that link central ray

anomalies with chromosome 7. Klep-de Pateret al5 described a female infant with cleft palateand digital reduction deformities of the secondand fifth digits of the right hand (not typicalcentral cleft) and no evidence of ectodermaldysplasia.35 This case had a karyotype 46,XX,del(7) (qi 1 -÷q22). A number ofadditional casereports of deletions involving the 7q22 bandhave not been associated with ectrodactyly.36

Aetiology and developmental aspectsThe general association of cleft limb with an-omalies of ectodermal structures is not par-ticularly surprising as there are similarities inlimb development to that of several ectodermalstructures. Wolpert's experiments which con-firmed earlier observations of a crucial relianceof embryonic limb ectoderm on the underlyingmesoderm are not merely of historical import-ance.37 He postulated the presence of a sig-nalling mechanism (probably a diffusiblemorphogen) which could be interpreted as apositional signal for regional developmentwithin the progress zone of the developing limbbud mesoderm. Historically it has seemed likelythat the endogenous signalling morphogen inthe limb bud of mammals may be related toretinoic acid (possibly 3'4'didehydroretinoicacid).38 However an exciting recent report in-dicates that a newly identified gene encodingthe signalling molecule, Sonic hedgehog, maybe involved in establishing polarising activityin the developing limb bud and hence antero-posterior patterning.39

Developmental digit anomalies such as thoseseen in central ray anomalies, however, arenot easily explained by a diffusible morphogenmodel. Homeobox genes are consistently ex-pressed in the developing limb bud and digitsin a way that reflects their location within ahomeobox cluster (temporospatial colinearity).These genes are activated sequentially by vary-ing concentrations of retinoic acid within thelimb bud. The expression of genes of the ho-meobox 4 (HOX D) type is necessary for nor-mal limb development in mice4' and chick.42Transcript expression can be predictably

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Cleft hand/foot: clinical and developmental aspects

altered in experimental animal models by im-plantation of retinoic acid soaked beads instrategic positions within the developing limbbud with resultant anomalies43 including mirrorhands and polydactyly. Central ray digit re-

duction anomalies have not yet been observedin these experiments. It may be that the an-

omaly represents a localised disturbance ofHOX expression at the ectodermal/meso-dermal junction. Recent work has shown dis-tinct expression ofMSX1 (HOX 7) and MSX2(HOX 8) at this site in limbs4445 and teeth.46Additionally combined expression of bothHOX D and of HOX A (localised to 7pl 1)appears necessary for organised cellular differ-entiation in the developing limb bud. The mshrelated MSX1 and MSX2 genes, althoughwidely distributed in the early limb bud, are

later organised at the distal part of the bud andare responsible for limb growth, possibly bymaintaining a pool of undifferentiated cells atthe progress zone.47 Although great strides havebeen made in our knowledge of vertebratelimb patterning in the context of central ray

anomalies, it must also be conceded that cur-

rently there are no obvious developmentalgenes which map to the 7q candidate region.In addition there are no ectrodactylous mouse

mutants which map to the homologous regionon mouse chromosome 5. It is interesting tonote, however, that mutation of MSX2 (HOX8) has been associated with craniosynostosisand limb defects (including triphalangealthumb and metatarsal shortening).48Mice have been bred with dactylaplasia

which closely resembles the human cleft limb.In these it has been hypothesised that the an-

omaly occurs as a result of effects from twoloci.49 Whether this could be extrapolated tohuman cleft limb is debatable but a similarexplanation was put forward by David."6 Theassociation of cleft limb with absence of longbones50 suggests that the defect may oc-

casionally be a result of a common defect inregional limb specification. A child exposed inutero to a retinoic acid derivative during thecrucial time of limb development with absentdigits and syndactyly has been reported.5' Morerecently two case reports of limb anomalies ina fetus and child with prenatal exposure toisotretinoin have been reported.52 One couldpostulate that the mechanism underlying thismay be a failure of differentiation resulting frommisexpression of homeobox genes. However, itmay be worth noting that other teratogens suchas ethanol have also been postulated to cause

ectrodactyly,53 in this particular case with no

clear underlying mechanism.Evidence is clearly accumulating to make

the 7q21.2-q21.3 locus a prime candidate forisolated ectrodactyly. While it has also beenpostulated as a locus for investigation in syn-

dromes such as the EEC syndrome54 (con-tiguous genes), it is likely that cleft limbrepresents a genetically heterogeneous con-

dition and the 7q genes represent just one

potential defect affecting a common pathwayfor limb differentiation.

The author wishes to acknowledge that his work on cleft limbswas conducted as Action Research Training Fellow in MedicalGenetics at the Institute of Medical Genetics, University ofWales College of Medicine, Cardiff.

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