medgenet syndrome

49 Med Genet 1996;33:498-503

Syndrome of the month

Defects in the determination of left-right asymmetry

Miranda Penman Splitt, John Burn, Judith Goodship

Left and right in the embryo is automaticallydefined by the formation of the anteroposteriorand dorsoventral axes. In an asymmetricalorganism, specification of the left-right axismust incorporate two distinct processes, thegeneration of asymmetry and its orientation orhandedness. The orientation of the heart andabdominal organs in vertebrates is non-randomand highly conserved both across and withinspecies.' Reversal of orientation may occurwithout concomitant defects in the generationof asymmetry. However, failure to generateasymmetry is almost always combined withabnormal orientation. The first overt breakingof symmetry across the midline of the embryooccurs when the primitive heart tube loops tothe right but subtle asymmetries are evident asearly as the primitive streak stage.2A spectrum of malformations, ranging from

complete reversed situs to complete failure toestablish asymmetry, is seen in man and it islikely that their aetiology and genetic basiswill turn out to be extremely heterogeneous.Nevertheless, genetic animal models indicatethat a spectrum of lateralisation defects can beproduced by a single defective gene. In manmost cases of disturbed laterality are sporadicbut there are several well recognised syndromeswhich occur in families.The usual orientation of the heart and ab-

dominal organs is known as situs solitus. Situsinversus refers to a perfect reversal of situssolitus with a left heart loop. Any arrangementother than situs solitus or situs inversus, thatis, random orientation of different organs, isknown as heterotaxy or situs ambiguus. Theestimated prevalence of complete situs inversusis around 1 in 10 OOO.3 An increased incidenceof parental consanguinity has been found, sug-gesting that a proportion of cases are autosomalrecessive.`5 The incidence ofheterotaxy is gen-erally much lower,34 but interestingly was foundto be equal to that of situs interversus in aninbred Bedouin population (1 in 4000).6

Cardiac anomalies are found in between 3and 9% of cases of complete situs inversus.Heterotaxy, on the other hand, is almost in-variably associated with complex cardio-vascular malformation as well as splenic and avariety of gastrointestinal anomalies.

In the present state of knowledge, the mostlogical way to categorise defects in laterality ison the basis of ciliary function.(JtMed Genet 1996;33:498-503)

Key words: asymmetry; laterality defects; isomerismsequence; heterotaxy.

Laterality defects with normal ciliaThe majority of patients with situs inversus orheterotaxy have no symptoms suggestive ofciliary dyskinesia. An important group of thesepatients have complete absence of visceralasymmetry with evidence for either bilateralleft or bilateral right sidedness. This conditionis known as isomerism sequence. Other de-scriptive terms include Ivemark syndrome, as-plenia/polysplenia syndrome, and the broaderterm, laterality sequence.

CLINICAL FEATURES OF ISOMERISM SEQUENCE"Isomerism" refers to the paired structureswhich usually have morphologically distinctright and left forms, but in this condition aremirror images of each other. Specifically, theseare the cardiac atrial appendages, bronchi, andlungs. Thus, in left isomerism sequence theheart has two long narrow atrial appendagesand typically both lungs are bilobed with longhyparterial bronchi. In right isomerism se-quence both atrial appendages are pyramidalin shape and the lungs are usually trilobedwith short eparterial bronchi bilaterally. Manyearlier studies do not recognise atrial or bron-chial isomerisms as pathological criteria.89Nevertheless, Ivemark8 in 1955 realised theimportance of the absence of left-right asym-metry in the pathogenesis of the conditionand suggested that it be called "asplenia - ateratologic syndrome of visceral symmetry". Inrecent years it has been shown that isomerism ofthe atrial appendages is a much more constantfeature than the state of the spleen or thepresence of heterotaxy.'0lThere are no population based studies of

isomerism sequence. A population based studyof asplenia in Canada found the incidence to be1 per 22 000 live births.'2 Although it includes afew cases ofisolated asplenia, it largely excludescases of left isomerism sequence which is likelyto be at least as common. In a retrospectivestudy of children who had undergone cardiaccatheterisation, the incidence of complex heartdefect with heterotaxy and poly/asplenia wasestimated to be 1/24 000 in a white Englishpopulation, accounting for about 1% of con-genital heart disease.'3 Right isomerism withasplenia appears to be more common inmales,'4 '5 whereas left isomerism/polyspleniashows an equal sex ratio.Both left and right isomerism sequence are

associated with a wide spectrum of severe heartmalformations. '0 '" These include anomalies

Department ofHumanGenetics, University ofNewcastle upon Tyne,19/20 Claremont Place,Newcastle upon TyneNE2 4AA, UKM Penman SplittJ BumJ Goodship

Correspondence to:Dr Penman Splitt.

498

on April 12, 2022 by guest. P

rotected by copyright.http://jm

g.bmj.com

/J M

ed Genet: first published as 10.1136/jm

g.33.6.498 on 1 June 1996. Dow

nloaded from

http://jmg.bmj.com/


The frequency of common heart lesions found in patientswith isomerism sequence

Left Rightisomerism isomerism(/0) (%/)

Interruption of IVC with azygos 75 7continuation

Total anomalous pulmonary venous 0 35connection

Common atrium 47 67Single ventricle 30 70Atrioventricular septal defect 68 93Double outlet right ventricle 7 47Pulmonary stenosis/atresia 48 78

The table refers to the mean of the percentages given in ref-erences 10, 16, and 17 for right isomerism and 10, 17, and 18for left isomerism.

of both systemic and pulmonary venous drain-age, which occur as a consequence of atrialisomerism, and malformations which arethought to be secondary to distortion of cardiaclooping, septal defects and conotruncal an-omalies. The principal defects are summarisedin the table. The high incidence of total an-omalous pulmonary venous drainage, singleventricle, and pulmonary outflow tract ob-struction leads to higher morbidity and mor-tality in right isomerism sequence.'9

Patients with right isomerism sequence al-most always have asplenia. The converse, thatasplenia is usually accompanied by right iso-merism, is also true. Anderson et al" found noinstances of complete absence of the spleenwithout evidence of isomerism of the atrialappendages in a survey of 1042 necropsies.Rarely, patients with right isomerism sequencehave between one and four non-uniformspleens.20 Antibiotic prophylaxis and pneu-mococcal vaccination should be standardmanagement in patients with asplenia. Leftisomerism sequence is usually accompaniedby the presence of multiple (more than six)uniformly sized spleens or spleniculi butpatients with smaller numbers of non-uniformspleens are also found.20 Unlike asplenia,polysplenia is found just as frequently withoutisomerism, either with a normal heart or anisolated heart lesion.22 The association of poly-splenia with biliary atresia, absent gall bladder,and intestinal malrotation is well recog-nised.2324 Martinez-Frias et a122 also foundpositive associations between polysplenia anddiaphragmatic hernia, cleft lip, hemivertebrae,and agenesis of the corpus callosum.

Intestinal rotation and fixation abnormalities(IRFA) are common: four patients (14%) in aseries of 28 required emergency surgery forintestinal obstruction.25 The authors put thecase for routine GI imaging and elective Laddprocedure in cases of isomerism sequence.Hiatus hernia is also a common complication.26Other GI anomalies rarely associated with iso-merism sequence include anal stenosis, tra-cheo-oesophageal fistula,2' and annular or shortpancreas.2027Anomalies in all other systems are found

not uncommonly but are individually rare." 28

Phoon and Neill2" found genitourinary defectsin 11% of patients with asplenia sequence,the most common being horseshoe kidney andrenal hypoplasia.28 In the same study 8% had

Figure 1 A high kilovoltage filtered chest radiographshowing the bilateral, long hyparterial bronchi of leftbronchial isomerism.

musculoskeletal defects, most commonly ac-cessory digits and scoliosis, 6% facial defects,and 7% CNS defects. In a review of midlineanomalies in 166 patients with isomerism se-quence, males accounted for all those caseswith imperforate anus and CNS involvementand over 80% of those with genitourinary andvertebral anomalies29 (see section on X linkedlaterality disturbance).

Bronchial isomerism can be shown on ahigh voltage beam chest x ray30 (fig 1). Atrialmorphology can be discerned on ultrasound byan experienced cardiologist. Cross sectionalviews of the abdominal great vessels are saidto be very helpful." MRI may be useful toobtain complete anatomical information.'2Abdominal ultrasound should be routine asHowell Jolly bodies cannot always be relied onas a sign of asplenia.16

AETIOLOGY AND GENETICSMouse modelsThe best evidence that complete situs inversus,heterotaxy, and isomerism sequence may havethe same genetic basis comes from two mousemodels: a spontaneous mutant inversus viscerum(iV)33 and an insertional transgenic mutant in-version of embryo turning (inv).

Broadly speaking, situs is random in homo-zygote iv/iv animals, 50% having situs solitusand 50% situs inversus. Heterozygotes are en-tirely normal. However, more detailed analysisshows that around 30% of adults have ab-normal spleens and venous abnormalities ana-logous to those commonly found associatedwith heterotaxy in humans.'5 Complex cardiaclesions associated with atrial isomerism havebeen reported in up to 40% of fetuses.'536 ivhas been mapped to the subtelomeric region ofmouse chromosome 12 which shows conservedsynteny to 14q in the human.'7

invlinv homozygotes all have complete orpartial situs inversus, severe jaundice, and kid-

499



g.bmj.com

/J M


g.33.6.498 on 1 June 1996. Dow

nloaded from

http://jmg.bmj.com/

Penman Splitt, Burn, Goodship

ney pathology.38 inv is the only known exampleof a mutation causing consistent reversal of theleft-right axis.

Cytogenetic abnormalitiesThere are two reports of patients with iso-merism sequence and split hand/split foot syn-drome associated with apparently balancedchromosomal rearrangements with breakpointsat 7q22.139 Wilson et a140 reported a motherand child with an identical apparently balancedtranslocation with breakpoints at 1 2q13.1 and13p 13. The fetus had right isomerism sequencewhile the mother was entirely normal. 13pl3contains ribosomal DNA but the breakpointon 12q13.1 may disrupt a dominant gene orunmask a recessive mutation. Two further caseshad de novo unbalanced chromosomal re-arrangements: an interstitial deletion of 1 Oqand a terminal deletion of 13q.4' There is onereport of a case of monosomy 22 who had leftisomerism sequence with polysplenia amongother abnormalities.42 A 22q11.2 deletion hasbeen found in one patient with dextrocardia(I Cross, personal communication) and onepatient with left isomerism sequence (S Hodgson,personal communication).

Maternallenvironmental factorsThe non-obese diabetic (NOD) mouse is ananimal model for insulin dependent diabetesmellitus. Fifty percent offetuses born to femaleswho were hyperglycaemic and polyuric by earlypregnancy were found to have right isomerismsequence.43 In man, the association of lateralitydefects with maternal insulin dependent dia-betes is not well recognised. However, in astudy from Guy's Hospital, seven out of 102mothers who had had one child with isomerismsequence were insulin dependent diabetics (RYates, personal communication). This is aninteresting association given the well knownassociation of caudal regression syndrome withmaternal diabetes. Caudal regression is theresult of defective development of the posteriornotochord.44 In Xenopus curtailment of de-velopment of dorsal anterior tissue includingnotochord causes randomisation of heart loop-ing.45 Thus the primary problem leading toboth laterality defects and caudal regression inthe fetuses of diabetic mothers seems to beaberrant development of dorsoanterior midlinestructures, in particular the notochord.The earliest investigations of left-right asym-

metry relate to twinning. In 1919, Spemannand Falkenberg produced conjoined twins innewts by mechanical constriction of the em-bryo.' They found that while the left twindeveloped normally the right twin had situsinversus in 50% of cases. This experiment isduplicated very nicely by the observation thatin human conjoined twins where the con-junction is lateral or oblique the right twinoften has abnormal asymmetry, situs inversus,heterotaxy, or isomerism.46 It is likely that thesame epigenetic mechanism accounts for theoccurrence of isomerism sequence as a dis-cordant trait in monozygous twins.47 Indeed,

the effect of twinning on the development ofleft-right asymmetry may be an important fac-tor contributing to the increased incidence ofcongenital heart defects in monozygous twins.48

X linked laterality sequenceThe only locus for heterotaxy to be mapped sofar (HTX) is on the X chromosome at Xq24-q27. 1.49 This gene was mapped in a large familywhere affected males had various cardiac mal-formations and alterations of visceral situs. Inaddition, four of the 11 affected males hadmidline malformations including sacral agen-esis, posteriorly placed anus, rectal stenosis,meningomyelocele, cerebellar hypoplasia, andarhinencephaly. The presence of a midline mal-formation in a male with heterotaxy is highlysuggestive of X linked laterality sequence.50Uterine septa and hypertelorism have beenreported as manifestations in carrier femalesin one family,5' and in a second family withapparently X linked laterality sequence52 fe-males had asymtomatic situs inversus and im-perforate anus.

Recessive genesThe best evidence for an important recessivegene is the high incidence of consanguinity inthe parents of affected subjects3' 5 53-` and the10 fold increased incidence ofthe disorder in aninbred population."' However, the segregationratio in this population is lower than would beexpected for a recessive disorder (0-09) and isvery similar to that found by Rose et al'4 intheir series of Canadian patients. Of course,low penetrance, as in the iv/iv mouse, couldaccount for this but another possibility is thatthe disease is controlled by two epistatic genesone of which is a rare recessive. Family studiesin humans are hampered by lack of large sib-ships; however there are three reports of largefamilies where laterality sequence appears to berecessive and shows an intrafamilial variabilitysimilar to the iv/iv mouse.535657 Isolated sibpairs one of whom has isomerism sequenceand the other an isolated heart lesion are notuncommon.5860 Several sib pairs where bothhave isomerism sequence have been reported,30seven concordant for right isomerism sequence,three concordant for left, and four discord-ant,1361-63 showing that bilateral left sidednessand bilateral right sidedness may be causedby the same genetic defect. Nevertheless, theuniformity of phenotype in several families inwhich all affected sibs have right isomerismsequence predicts the existence of a gene caus-ing bilateral right sidedness only.

Recessive mutations in the regulatory do-main of the cardiac gap junction protein Con-nexin 43 have recently been reported in patientswith isomerism sequence.64 However, we andothers have been unable to replicate this findingin over 40 clinically similar patients.65

Dominant genesA recent report documents a number offamilieswith laterality disturbance where the most likely

500



g.bmj.com

/J M


g.33.6.498 on 1 June 1996. Dow

nloaded from

http://jmg.bmj.com/


Figure 2 Summary flow diagram for counselling laterality defects. CBF= ciliary beat defect. EM= electron microscopy.SI= situs inversus. CCHD= complex congenital heart defect. PCD=primary ciliary dyskinesia.

form of inheritance is autosomal dominant.66There are several instances of non-penetrancein obligate gene carriers and expression inaffected subjects is variable. This highlightsthe importance of careful pedigree taking infamilies with an affected child and also suggeststhat parents should be investigated routinelyfor evidence of situs inversus. It is possible thatsome isolated sib pairs will turn out to be theresult of germinal mosaicism of new dominantmutations.

Recurrence risks (fig 2)In his mass screening of the Norwegian popu-lation, Torgersen3 found recurrence of situsinversus in sibs in less than 1% of cases. In-terestingly, affected subjects in four of the fivefamilies he discovered also had bronchiectasisand nasal polyps suggesting that ciliary dyskinesiaaccounts for the majority of familial cases ofcomplete situs inversus (see later). An empiricalrecurrence risk for isomerism sequence of justunder 10% was estimated from a prospectiveseries of over 1000 mothers who were referredfor echocardiography because of a previously'affected child with congenital heart disease.67One case of isomerism sequence was detectedwhere the index case had a secundum ASD. Thisis higher than the risk of around 5% estimated inretrospective studies.'415 With improved treat-ment more children with complex heart lesionsare surviving to reproductive age. At presentthere are no reliable data available from whichto estimate recurrence risks in offspring.

Laterality defects with abnormal cilia:primary ciliary dyskinesiaAbout a quarter of patients with complete situsinversus have primary ciliary dyskinesia (PCD)(1 in 30000-40000). These patients were ori-

ginally described by Kartagener in 1933 ashaving the triad of situs inversus, sinusitis,and bronchiectasis.68 This eponym is no longerappropriate for two reasons. Firstly, while situsinversus is present from birth the other featuresare secondary to the dyskinetic cilia and maynot manifest until much later in life69 and,secondly, in familial cases only 50% of sibswith dyskinetic cilia have situs inversus.70 Thecilia in the respiratory epithelium of subjectswith PCD are either immotile or dyskin-etic leading to chronic respiratory tractinfection.7 72 Demonstration ofboth functionaland ultrastructural changes in the respiratoryepithelium is necessary to make the diagnosis.Cilia are most easily obtained by nasal brush-ings and ciliary beat frequency can be measuredvideophotometrically.73 The most consistentabnormality on electron microscopy is loss ofdynein arms, but many other abnormalitieshave been observed including complete ab-sence of cilia.6971 74

CLINICAL FEATURESSymptoms and signs are ofvariable age of onsetand severity. Over 90% of affected subjects aresymptomatic in childhood.75 Chronic rhinitisleads to sinusitus, opacity ofthe frontal sinuses,and nasal polyps. Recurrent infection of thelower respiratory tract and middle ear mayeventually progress to bronchiectasis, mast-oiditis, and conductive deafness. Patients oftencomplain of troublesome headaches.75 De-pressed motility of polymorphic leucocytes hasbeen shown, although bactericidal capacity isnormal.76 Affected men are usually infertileowing to immotile sperm flagellae but tworeports show that this is not invariable.7778 Thespermatozoa are otherwise normal and havebeen shown to be capable of fusing with and

501



g.bmj.com

/J M


g.33.6.498 on 1 June 1996. Dow

nloaded from

http://jmg.bmj.com/

Penman Splitt, Burn, Goodship

fertilising oocytes. Thus in vitro fertilisation inthese patients is a possibility.79 Women alsohave reduced fertility, probably because of re-duced ciliary movement in the Fallopiantubes.80 In a recent series one third of patientswith PCD were found to have other congenitalmalformations.8" Heart defects occurred in over10%. There are reports of patients with poly-splenia and biliary atresia and midline defectssuch as tracheo-oesophageal fistula.8"-84 One ofthe sibs reported by de la Monte and Hutchins8'had left isomerism sequence and polyspleniaas well as recurrent purulent rhinorrhoea andchronic tracheobronchitis. This example high-lights the possible overlap between lateralitydefects with and without ciliary dyskinesia.Patients with complex congenital heart diseasedo not routinely have ciliary biopsies. Ciliarydyskinesia has been shown in asymptomaticpatients with situs inversus86 and might easilybe overlooked in a patient with a heterotaxy.There is certainly a need for further elucidationof a possible common pathogenesis.

AETIOLOGY AND GENETICS

PCD commonly shows an autosomal recessiveinheritance pattern. Fifty percent of affectedsibs have situs inversus, suggesting that ori-entation of lateral asymmetry is random inthese people.7" As yet, no genes for PCD inman have been mapped. The ciliary axonemeis made up of over 100 polypeptides and dyneinitself is a complex protein with several differentsubunits, so there is likely to be great hetero-geneity."There is one report of a family sug-gesting either X linked or autosomal dominantinheritance.88 Some sporadic cases may be newdominant mutations.What is the basis of random situs de-

termination in PCD? Afzelius7' postulated thatnormal visceral asymmetry is determined bythe coordinated movement of embryonic ciliaand that in the absence of ciliary movementsitus will be random. However, the presenceof ciliary dyskinesia is not a sine qua non forrandomisation of situs. The hpy mouse, forexample, has immotile cilia, hydrocephalus,and polydactyly but consistently normal situs.89The alternative more plausible hypothesis re-lates to the fact that dyneins are also presentin the cell cytoplasm and control cell polarity.Dyneins are microtubule associated ATPasesthat induce movement towards the minus endof microtubules.90 In lower organisms, for ex-ample nematodes, centrosome position, theorientation of spindle formation, and thereforecell cleavage determines cell fate in the firstfew cell divisions.9192 The plane of cleavageis crucial in determining the position of thedaughter cells relative to adjacent cells andtherefore subsequent cell-cell interactions. Inhigher organisms, however, "left" and "right"cell fates appear to be unfixed until a muchlater development stage.93

Several candidate loci are suggested byanimal models. These include human chro-mosome 14q (iv mouse locus) and also in-cidentally where cytoplasmic dynein heavychain maps,94 chromosome 12p (syntenic tothe hpy mutation on mouse chromosome 689),

and the X chromosome (the WIC-Hyd rat isan excellent model for human PCD showingX linked inheritance95 ).

ConclusionThere are still many more questions than an-swers in our understanding of the molecularbasis of laterality disturbance in man. Progressin the elucidation of the genetic basis of left-right asymmetry is likely to come from thestudy of animal models. The recent excitingdiscovery that, in frogs and birds, ectopic ex-pression of important signalling molecules suchas Wnt, activin, and Sonic hedgehog result inrandom heart looping represents the start ofthis process.961 Brown NA, Wolpert L. The development of handedness in

left/right asymmetry. Development 1990;109:1-9.2 Cooke J. Vertebrate embryo handedness. NTature 1995;374:

681.3 Torgersen J. Genic factors in visceral asymmetry in the

development and pathological changes of the lungs, heartand abdominal organs. Arch Pathol 1949;47:556-93.

4 Campbell M. The mode of inheritance in isolated laevo-cardia and dextrocardia and situs inversus. Br Heart .71963;25:803-13.

5 CockayneEA. The genetics of transposition of the viscera.Q _J Med 1983;31:479-93.

6 Uma R, Usha R, Tahseen SK, Al-Ghanin M, Farag TI.Dextrocardia + / - situs inversus among Bedouins. BritishMedical Genetics Conference, York, 1995:A55(abstract).

7 Merklin RJ, Varano NR. Situs inversus and cardiac defects.A study of111 cases of reversed asymmetry.. ThoracCardiovasc Surg 1995;45:334-42.

8 Ivemark BI. Implications of agenesis of the spleen on thepathogenesis of conco-truncus anomalies in childhood.Acta Paediatr Scand 1955 ;44: 1 -110.

9 Ruttenberg HD, Neufeld HN, Lucas RV, et al. Syndromeof congenital cardiac disease with asplenia. Aml.7 Cardiol1964;12:387-406.

10 Ho SY, Cook A, Anderson EH, Allan LD, Fagg N. Iso-merism of the atrial appendages in the fetus. Pediatr Pathol1991;11:589-608.

11 Anderson C, Devine WA, Anderson RH, Debich DE,Zuberbuhler JR. Abnormalities of the spleen in relationto congenital malformations of the heart: a survey ofnecropsy findings in children. Br Heart3 1990;63:122-8.

12 Webber SA, Sandor GGS, Patterson MWH, et al. Prognosisin asplenia syndrome - a population based review. CardiolYoung 1992;2:129-35.

13 Gatrad AR, Read AP, Watson GH. Consanguinity andcomplex cardiac anomalies with situs ambiguus. Arch DisChild 1984;59:242-5.

14 Rose V, Izukawa T, Moes CAF. Syndromes of asplenia andpolysplenia: a review of cardiac and noncardiac mal-formations in 60 cases with special reference to diagnosisand prognosis. BrHeart37 1975;37:840-52.

15 Burn J, Coffey R, Allan LD, Robinson P, Pembrey ME,Macartney FJ. Isomerism: a genetic analysis. In: DoyleEF, Engle MA, Gersony WM, Rashkind WJ, Talner NS,eds. Paediatric cardiology. New York: Springer Verlag, 1986:1126-8.

16 ChiuI, HowS, WangJ, et al. Clinical implications of atrialisomerism. Br Heart _7 1988;60:72-7.

17 Sapire DW, Ho SY, Anderson RH, Rigby ML. Diagnosisand significance of atrial isomerism. An7i Cardiol 1986;58:342-6.

18 SharmaS, Devine W, Anderson RH, Zuberbuhler JR. Iden-tification and analysis of left atrial isomerism. Am J Cardiol1987;60:1157-60.

19 Phoon CK, Neill CA. Asplenia syndrome - risk factors forearly unfavorable outcome. Arn _7 Cardiol 1994;73: 1235-7.

20 Landing BH. Five syndromes (malformation complexes)of pulmonary symmetry, congenital heart disease, andmultiple spleens. Pediatr Pathol 1984;2:125-51.

21 Peoples WM, Moller JH, Edwards JE. Polysplenia: a reviewof 146 cases. Pediatr Cardiol 1983;4:129-37.

22 Martinez-Frias ML, Urioste M, Bermejo E, et al. Primarymidline developmental field. II. Clinical/epidemiologicalanalysis of alteration of laterality (normal body symmetryand asymmetry). An, _7 Med Genet 1995;56:382-8.

23 Carmi R, Magee CA, Neill CA, Karrer FM. Extrahepaticbiliary atresia and associated anomalies: etiologic hetero-geneity suggested by distinctive patterns of associations.AmJMed Genet 1993;45:683-93.

24 Chandra RS. Biliary atresia and other structural anomaliesin the congenital polysplenia syndrome. 7 Pediatr 1974;8S:649-55.

25 Chang J, Brueckner M, Touloukian RJ. Intestinal rotationand fixation abnormalities in heterotaxia: early detectionand management. _7 Pediatr Surg 1993;28:1281-5.

26 WangJ, Chang M. Association of hiatus hernia with aspleniasyndrome. Am j Cardiol 1995;75:317.

27 Wainwright H, Nelson M. Polysplenia syndrome and con-genital short pancreas. Amn 7 Med Genet 1993;47:318-20.

502



g.bmj.com

/J M


g.33.6.498 on 1 June 1996. Dow

nloaded from

http://jmg.bmj.com/


28 Phoon CK, Neill CA. Asplenia syndrome: insight into em-

bryology through an analysis of cardiac and extracardiacanomalies. Am ]f Cardiol 1994;73:581-7.

29 Evans JA, Greenberg CR, Chudley AE. Midline anomaliesin individuals with asplenia. Proceedings of the David SmithWorkshop on Malformations 1993(abstract).

30 Burn J. Disturbance of morphological laterality in humans.In: Bock GR, Marsh J, eds. Biological asymmetry andhandedness. Chichester: Wiley, 1991:282-99.

31 Huhta JC, Smallhorn JF, Macartney FJ. Two dimensionalechocardiogaphic diagnosis of situs. Br Heart ]f 1982;48:97-108.

32 Wang JK, Li YW, Chiu IS, et al. Usefulness of magneticresonance imaging in the assessment of venoatrial con-nections, atrial morphology, bronchial situs, and otheranomalies in right atrial isomerism. Am].7 Cardiol 1994;74:701-4.

33 Hummel KP, Chapman DB. Visceral inversion and as-sociated anomalies in the Mouse. ]f Hered 1959;50:9-13.

34 Yokoyama T, Copeland NG, Jenkins NA, et al. Reversal ofleft-right asymmetry: a situs inversus mutation. Science1993;260:679-82.

35 SeoJ, Brown NA, Ho SY, Anderson RH. Abnormal lateralityand congenital cardiac anomalies, relations of visceral andcardiac morphologies in the iv/iv mouse. Circulation 1993;86:642-50.

36 Icardo JM, Sanchez de Vega MS. Spectrum of heart mal-formations in mice with situs solitus, situs inversus andassociated visceral heterotaxy. Circulation 1991;84:2547-58.

37 Brueckner M, D'Eustachio P, Horwich AL. Linkage map-ping of mouse gene, iv, that controls left-right asymmetryof the heart and viscera. Proc Natl Acad Sci USA 1989;86:5035-8.

38 Morishima M, Miyagawa-Tomita S, Takao A, Ishibashi M,Yokoyama T, Overbeek PA. Morphological study of theinv situs inversus mutant mouse. In: Clark EB, MarkwaldRR, Takao A, eds. Developmental mechanisms of heart dis-ease. New York: Futura Publishing Co, 1995;621-4.

39 Genuardi M, Gurrieri F, Neri G. Genes for split hand/splitfoot and laterality defects on 7q22.1 and Xq24-q27. 1. AmMed Genet 1994;50:101.

40 Wilson GN, Stout JP, Schneider NR, Zneimer SM, GilstrapLC. Balanced translocation 12/13 and situs abnormalities:homology of early pattern formation in man and lowerorganisms? Am Med Genet 199 1;38:601-7.

41 Carmi R, Rosenbaum KR. Human situs determination isprobably controlled by several different genes. Am ]f MedGenet 1992;44:246-7.

42 DeCicco F, Steele MW, Pan S, Park SC. Monosomy ofchromosome no 22: a case report. ]f Pediatr 1973;83:836-8.

43 Morishima M, Miura S, Ando M, Takao A. Visceroatrialheterotaxy syndrome in the nonobese diabetic mouse.

In: Clark EB, Takao A, eds. Developmental cardiolog:morphogenesis and function. Mount Kisco, New York:Futura, 1990:431-41.

44 Lynch S, Bond P, Copp A, et al. A gene for autosomaldominant sacral agenesis maps to the holoprosencephalyregion at 7q36. Nature Genet 1995;11:93-5.

45 Danos MC, Yost HJ. Linkage of cardiac left-right asymmetryand dorsal anterior development in Xenopus. Developmzent1995;121:1467-74.

46 Rossi MB, Burn J, Ho SY, et al. Conjoined twins, rightatrial isomerism, and the sequential analysis. Br Heart ]f1987;58:518-24.

47 Wilkinson JL, Holt PA, Dickinson DF, Jivani SK. Aspleniasyndrome in one of monozygotic twins. Eur ]f Cardiol1979;10:3-1-304.

48 Burn J, Corney G. Congenital heart defects and twinning.

Acta Genet Med Gemellol 1984;33:61-9.49 Casey B, Devoto M, Jones KL, Ballabio A. Mapping a gene

for familial situs abnormalities to human chromosomeXq24-q27.1. Nature Genet 1993;5:403-7.

50 Fullana A, Garcia-Frias E, Martinez-Frias ML, Razquin S,Quero J. Caudal deficiency and asplenia anomalies in sibs.Am .7 Med Genet 1986;suppl 2:23-9.

51 Mikkila SP, Janas M, Karikoski R, Tarkkila T, SimolaKOJ. X-linked laterality sequence in a family with carriermanifestations. Am Med Genet 1994;49:435-8.

52 Casey B, Gebbia M, Devoto M, Nelson DL, Aylsworth AS.Females with midline malformations and complex reversalof left-right asymmetry in a family with X-linked het-erotaxy. Am ]f Hum Genet Suippl 1995;57:A85.

53 Arnold GL, Bixler D, Girod D. Probable autosomal re-

cessive inheritance of polysplenia, situs inversus and car-

diac defects in an Amish family. Am _7 Med Genet 1983;16:35-42.

54 Distefano G, Romeo MG, Grasso S, et al. Dextrocardiawith and without situs viscerum inversus in two sibs. Am]Med Genet 1987;27:929-34.

55 Schonfeld EA, Frischman B. Syndrome of spleen agenesis,defects of the heart and vessels and situs inversus. HelvPaediatrActa 1958;6:636-40.

56 Zlotogora J, Schimmel MS, Glaser Y. Familial situs inversusandcongenital heart defects. Am .7 Med Genet 1987;26:181-4.

57 Czeizel A. Familial situs inversus and congenital heart de-fects. Am .7 Med Genet 1987;28:227-8.

58 Silver W, Steier M, Chandra N. Asplenia syndrome withcongenital heart disease and tetralogy of Fallot in siblings.Am _Cardiol 1972;30:91-4.

59 Katcher AL. Familial asplenia, other malformations, andsudden death. Pediatrics 1980;65:633-5.

60 Fuhrmann W. Congenital heart disease in sibships ascer-tained by two affected siblings. Humangenetik 1968;6:1-12.

61 Polhemus DW, Schafer WG. Congenital absence of thespleen: syndrome with atrioventricularis and situs inversus.Pediatrics 1952;9:696-708.

62 Zlotogora J, Elian E. Asplenia and polysplenia syndromeswith abnormalities of lateralisation in a sibship. MedGenet 1981;18:301-2.

63 Niikawa N, Kohsaka S, Mizumoto M, Hamada I, Kajii T.Familial clustering of situs inversus totalis, and aspleniaand polysplenia syndromes. Amn _7 Med Genet 1983;16:43-7.

64 Britz-Cunningham SH, Shah MM, Zuppan CW, FletcherWH. Mutations of the Connexin43 gap-junction in patientswith heart malformations and defects of laterality. N EnglMed 1995;332:1323-9.

65 Penman Splitt M, Burn J, Goodship J. Connexin43 mutationsin sporadic and familial defects of laterality. N Engl _] Med1995;333:941.

66 Alonso S, Pierpont ME, Radtke W, et al. Heterotaxia syn-drome and autosomal dominant inheritance. Am _7 MedGenet 1995;56:12-15.

67 Allan LD, Crawford DC, Chita SK, Anderson RH, TynanMJ. Familial recurrence of congenital heart disease in aprospective series of mothers referred for fetal echo-cardiography. Am ]f Cardiol 1986;58:334-7.

68 Kartagener M, Stucki P. Bronchiectasis with situs inversus.Arch Pediatr 1962;79:193-207.

69 Sturgess JM, Thompson MW, Czegledy-Nagy E, TurnerJAP. Genetic aspects of immotile cilia syndrome. Ani _]Med Genet 1986;25:149-60.

70 Moreno A, Murphy EA. Inheritance of Kartagener's syn-drome. Am]f Med Genet 1981;8:305-15.

71 Afzelius BA. A human syndrome caused by immotile cilia.Science 1976;193:317-19.

72 Rossman CM, Forrest JB, Lee RMK, Newhouse MT. Thedyskinetic cilia syndrome: ciliary motility in the immotilecilia syndrome. Chest 1983;78:580-2.

73 Rutland J, Cole PJ. Non-invasive sampling of the nasalcilia for measurement of beat frequency and study ofultrastructure. Lancet 1980;ii:564-5.

74 Rott HD. Kartagener's syndrome and the syndrome ofimmotile cilia. Hum Genet 1979;46:249-61.

75 Afzelius BA. The immotile-cilia syndrome and other ciliarydiseases. Int Rev Exp Pathol 1979;19:1-43.

76 Valerius NH, Knudsen BB, Pedersen M. Defective neutro-phil motility in patients with primary ciliary dyskinesia.Eur] Clin Invest 1983;13:489-94.

77 Jonsson MS, McCormick JR, Gillies CG, Gondos B.Kartagener's syndrome with motile spermatozoa. NEngl Med 1982;307:1131-3.

78 Samuel I. Kartagener's syndrome with normal spermatozoa.3rAMA 1987;258: 1329-30.

79 Aitken RJ, Ross A, Lees MM. Analysis of sperm functionin Kartagener's syndrome. Fertil Steril 1983;40:696-8.

80 McComb P, Langley L, Villalon M, Verdugo P. The oviductcilia and Kartagener's syndrome. Fertil Steril 1986;46:412-16.

81 Engesaeth VG, Warner JO, Bush A. New associations ofprimary ciliary dyskinesia syndrome. Pediatr Pulmonol1993;16:9-12.

82 Teichberg S, Markowitz J, Silverberg M, et al. Abnormal ciliain a child with the polysplenia syndrome and extrahepaticbiliary atresia. ] Pediatr 1982;100:399-401.

83 Schidlow DV, Katz SM, Turtz MG, Donner RM, CapassoS. Polysplenia and Kartagener syndromes in a sibship:association with abnormal respiratory cilia. ]Pediatr 1982;100:401-3.

84 Gershoni-Baruch R, Gottfried E, Pery M, Sahin A, EtzioniA. Immotile cilia syndrome including polysplenia, situsinversus, and extrahepatic biliary atresia. Am] Med Genet1989;33:390-3.

85 de la Monte SM, Hutchins GM. Brief clinical report. Sisterswith polysplenia. Am .7 Med Genet 1985;21:171-3.

86 Kroon AA, Hiej JMH, Kuijper WA, Veerman AJP, van derBaan S. Function and morphology of respiratory cilia insitus inversus. Clin Otolaryngol 1991;16:294-7.

87 Afzelius BA. Genetical and ultrastructural aspects of theimmotile-cilia syndrome. Am Hum Genet 198 1;33:852-64.

88 Narayan D, Krishnan SN, Upender M, et al. Unusualinheritance of primary ciliary dyskinesia (Kartagener'ssyndrome). Med Genet 1994;31:493-6.

89 Bryan JHD. The immotile cilia syndrome. Mice versus man.Virchows Arch 1983;399:265-75.

90 McIntosh JR, Porter ME. Enzymes for microtubule-de-pendent motility. Biol Chem 1989;264:6001-4.

91 Priess JR. Establishment of initial asymmetry in earlyCaenorhabditis elegans embryos. Cur Opin Genet Dev1994;4:563-8.

92 Rhyu MS, Knoblich JA. Spindle orientation and asymmetriccell fate. Cell 1995;82:523-6.

93 Hoyle C, Brown NA, Wolpert L. Development of left/righthandedness in the chick heart. Development 1992;11S:107 1-8.

94 Narayan D, Desai T, Banks A, et al. Localization of thehuman cytoplasmic dynein heavy chain (DNECL) to1 4qter by fluorescence in situ hybridization. Genomics1 994;22:660-1.

95 Torikata C, Kijimoto C, Koto M. Ultrastructure of res-piratory Cilia of WIC-Hyd male rats. Am] Pathol 1991;138:341-7.

96 Yost HJ. Vertebrate left-right development. Cell 1995;82:689-92.

503



g.bmj.com

/J M


g.33.6.498 on 1 June 1996. Dow

nloaded from

http://jmg.bmj.com/

medgenet syndrome

Documents