49849 Med Genet 1996;33:498-503 Syndrome of the month J Med Genet: first published as 10.1136/jmg.33.6.498 on 1 June 1996. Downloaded from Defects in the determination of left-right asymmetry

Miranda Penman Splitt, John Burn, Judith Goodship

Left and right in the embryo is automatically Laterality defects with normal cilia defined by the formation of the anteroposterior The majority of patients with situs inversus or and dorsoventral axes. In an asymmetrical heterotaxy have no symptoms suggestive of organism, specification of the left-right axis ciliary dyskinesia. An important group of these must incorporate two distinct processes, the patients have complete absence of visceral generation of asymmetry and its orientation or asymmetry with evidence for either bilateral handedness. The orientation of the heart and left or bilateral right sidedness. This condition abdominal organs in vertebrates is non-random is known as isomerism sequence. Other de- and highly conserved both across and within scriptive terms include Ivemark syndrome, as- species.' Reversal of orientation may occur plenia/polysplenia syndrome, and the broader without concomitant defects in the generation term, laterality sequence. of asymmetry. However, failure to generate asymmetry is almost always combined with abnormal orientation. The first overt breaking CLINICAL FEATURES OF ISOMERISM SEQUENCE of symmetry across the midline of the embryo "Isomerism" refers to the paired structures occurs when the primitive heart tube loops to which usually have morphologically distinct the right but subtle asymmetries are evident as right and left forms, but in this condition are early as the primitive streak stage.2 mirror images of each other. Specifically, these A spectrum of malformations, ranging from are the cardiac atrial appendages, bronchi, and complete reversed situs to complete failure to lungs. Thus, in left isomerism sequence the establish asymmetry, is seen in man and it is heart has two long narrow atrial appendages likely that their aetiology and genetic basis and typically both lungs are bilobed with long will turn out to be extremely heterogeneous. hyparterial bronchi. In right isomerism se- Nevertheless, genetic animal models indicate quence both atrial appendages are pyramidal

that a spectrum of lateralisation defects can be in shape and the lungs are usually trilobed http://jmg.bmj.com/ produced by a single defective gene. In man with short eparterial bronchi bilaterally. Many most cases of disturbed laterality are sporadic earlier studies do not recognise atrial or bron- but there are several well recognised syndromes chial isomerisms as pathological criteria.89 which occur in families. Nevertheless, Ivemark8 in 1955 realised the The usual orientation of the heart and ab- importance of the absence of left-right asym- dominal organs is known as situs solitus. Situs metry in the pathogenesis of the condition inversus refers to a perfect reversal of situs - and suggested that it be called "asplenia a on October 2, 2021 by guest. Protected copyright. solitus with a left heart loop. Any arrangement teratologic syndrome of visceral symmetry". In other than situs solitus or situs inversus, that recent years it has been shown that isomerism of is, random orientation of different organs, is the atrial appendages is a much more constant known as heterotaxy or situs ambiguus. The feature than the state of the spleen or the estimated prevalence ofcomplete situs inversus presence of heterotaxy.'0l is around 1 in 10 OOO.3 An increased incidence There are no population based studies of of parental consanguinity has been found, sug- isomerism sequence. A population based study gesting that a proportion of cases are autosomal ofasplenia in Canada found the incidence to be recessive.`5 The incidence ofheterotaxy is gen- 1 per 22 000 live births.'2 Although it includes a erally much lower,34 but interestingly was found few cases ofisolated asplenia, it largely excludes to be equal to that of situs interversus in an cases of left isomerism sequence which is likely inbred Bedouin population (1 in 4000).6 to be at least as common. In a retrospective Cardiac anomalies are found in between 3 study of children who had undergone cardiac and 9% of cases of complete situs inversus. catheterisation, the incidence of complex heart Heterotaxy, on the other hand, is almost in- defect with heterotaxy and poly/asplenia was Department of Human variably associated with complex cardio- estimated to be 1/24 000 in a white English Genetics, University of vascular malformation as well as splenic and a population, accounting for about 1 % of con- Newcastle upon Tyne, variety of gastrointestinal anomalies. 19/20 Claremont Place, genital heart disease.'3 Right isomerism with Newcastle upon Tyne In the present state of knowledge, the most asplenia appears to be more common in NE2 4AA, UK logical way to categorise defects in laterality is males,'4 '5 whereas left isomerism/polysplenia M Penman Splitt on the basis of ciliary function. J Bum shows an equal sex ratio. J Goodship (JtMed Genet 1996;33:498-503) Both left and right isomerism sequence are associated with a wide spectrum of severe heart Correspondence to: Key words: asymmetry; laterality defects; isomerism Dr Penman Splitt. sequence; heterotaxy. malformations. '0 '" These include anomalies Defects in the determination of left-right asymmetry 499

The frequency of common heart lesions found in patients with isomerism sequence Left Right isomerism isomerism

(/0) (%/) J Med Genet: first published as 10.1136/jmg.33.6.498 on 1 June 1996. Downloaded from Interruption of IVC with azygos 75 7 continuation Total anomalous pulmonary venous 0 35 connection Common atrium 47 67 Single ventricle 30 70 Atrioventricular septal defect 68 93 Double outlet right ventricle 7 47 Pulmonary 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 18 for left isomerism.

of both systemic and pulmonary venous drain- age, which occur as a consequence of atrial isomerism, and malformations which are thought to be secondary to distortion ofcardiac looping, septal defects and conotruncal an- omalies. The are summarised principal defects Figure 1 A high kilovoltage filtered chest radiograph in the table. The high incidence of total an- showing the bilateral, long hyparterial bronchi of left omalous pulmonary venous drainage, single bronchial isomerism. ventricle, and pulmonary outflow tract ob- struction leads to higher morbidity and mor- tality in right isomerism sequence.'9 musculoskeletal defects, most commonly ac- Patients with right isomerism sequence al- cessory digits and scoliosis, 6% facial defects, most always have asplenia. The converse, that and 7% CNS defects. In a review of midline asplenia is usually accompanied by right iso- anomalies in 166 patients with isomerism se- merism, is also true. Anderson et al" found no quence, males accounted for all those cases instances of complete absence of the spleen with imperforate anus and CNS involvement without evidence of isomerism of the atrial and over 80% of those with genitourinary and appendages in a survey of 1042 necropsies. vertebral anomalies29 (see section on X linked Rarely, patients with right isomerism sequence laterality disturbance). have between one and four non-uniform Bronchial isomerism can be shown on a spleens.20 Antibiotic prophylaxis and pneu- high voltage beam chest x ray30 (fig 1). Atrial mococcal vaccination should be standard morphology can be discerned on ultrasound by management in patients with asplenia. Left an experienced cardiologist. Cross sectional http://jmg.bmj.com/ isomerism sequence is usually accompanied views of the abdominal great vessels are said by the presence of multiple (more than six) to be very helpful." MRI may be useful to uniformly sized spleens or spleniculi but obtain complete anatomical information.'2 patients with smaller numbers of non-uniform Abdominal ultrasound should be routine as spleens are also found.20 Unlike asplenia, Howell Jolly bodies cannot always be relied on polysplenia is found just as frequently without as a sign of asplenia.16

isomerism, either with a normal heart or an on October 2, 2021 by guest. Protected copyright. isolated heart lesion.22 The association of poly- splenia with biliary atresia, absent gall bladder, AETIOLOGY AND GENETICS and intestinal malrotation is well recog- Mouse models nised.2324 Martinez-Frias et a122 also found The best evidence that complete situs inversus, positive associations between polysplenia and heterotaxy, and isomerism sequence may have diaphragmatic hernia, cleft lip, hemivertebrae, the same genetic basis comes from two mouse and agenesis of the corpus callosum. models: a spontaneous mutant inversus viscerum Intestinal rotation and fixation abnormalities (iV)33 and an insertional transgenic mutant in- (IRFA) are common: four patients (14%) in a version of embryo turning (inv). series of 28 required emergency surgery for Broadly speaking, situs is random in homo- intestinal obstruction.25 The authors put the zygote iv/iv animals, 50% having situs solitus case for routine GI imaging and elective Ladd and 50% situs inversus. Heterozygotes are en- procedure in cases of isomerism sequence. tirely normal. However, more detailed analysis Hiatus hernia is also a common complication.26 shows that around 30% of adults have ab- Other GI anomalies rarely associated with iso- normal spleens and venous abnormalities ana- merism sequence include anal stenosis, tra- logous to those commonly found associated cheo-oesophageal fistula,2' and annular or short with heterotaxy in humans.'5 Complex cardiac pancreas.2027 lesions associated with atrial isomerism have Anomalies in all other systems are found been reported in up to 40% of fetuses.'536 iv not uncommonly but are individually rare." 28 has been mapped to the subtelomeric region of Phoon and Neill2" found genitourinary defects mouse chromosome 12 which shows conserved in 11% of patients with asplenia sequence, synteny to 14q in the human.'7 the most common being horseshoe kidney and invlinv homozygotes all have complete or renal hypoplasia.28 In the same study 8% had partial situs inversus, severe jaundice, and kid- 500 Penman Splitt, Burn, Goodship

ney pathology.38 inv is the only known example the effect of twinning on the development of of a mutation causing consistent reversal of the left-right asymmetry may be an important fac- left-right axis. tor contributing to the increased incidence of congenital heart defects in monozygous twins.48 J Med Genet: first published as 10.1136/jmg.33.6.498 on 1 June 1996. Downloaded from Cytogenetic abnormalities There are two reports of patients with iso- X linked laterality sequence merism sequence and split hand/split foot syn- The only locus for heterotaxy to be mapped so drome associated with apparently balanced far (HTX) is on the X chromosome at Xq24- chromosomal rearrangements with breakpoints q27. 1.49 This gene was mapped in a large family at 7q22.139 Wilson et a140 reported a mother where affected males had various cardiac mal- and child with an identical apparently balanced formations and alterations of visceral situs. In translocation with breakpoints at 1 2q13.1 and addition, four of the 11 affected males had 13p13. The fetus had right isomerism sequence midline malformations including sacral agen- while the mother was entirely normal. 13pl3 esis, posteriorly placed anus, rectal stenosis, contains ribosomal DNA but the breakpoint meningomyelocele, cerebellar hypoplasia, and on 12q13.1 may disrupt a dominant gene or arhinencephaly. The presence ofa midline mal- unmask a recessive mutation. Two further cases formation in a male with heterotaxy is highly had de novo unbalanced chromosomal re- suggestive of X linked laterality sequence.50 arrangements: an interstitial deletion of 1 Oq Uterine septa and hypertelorism have been and a terminal deletion of 13q.4' There is one reported as manifestations in carrier females report of a case of monosomy 22 who had left in one family,5' and in a second family with isomerism sequence with polysplenia among apparently X linked laterality sequence52 fe- other abnormalities.42 A 22q11.2 deletion has males had asymtomatic situs inversus and im- been found in one patient with dextrocardia perforate anus. (I Cross, personal communication) and one patient with left isomerism sequence (S Hodgson, personal communication). Recessive genes The best evidence for an important recessive gene is the high incidence of consanguinity in Maternallenvironmental factors the parents of affected subjects3' 5 53-` and the The non-obese diabetic (NOD) mouse is an 10 fold increased incidence ofthe disorder in an animal model for insulin dependent diabetes inbred population."' However, the segregation mellitus. Fifty percent offetuses born to females ratio in this population is lower than would be who were hyperglycaemic and polyuric by early expected for a recessive disorder (0-09) and is pregnancy were found to have right isomerism very similar to that found by Rose et al'4 in sequence.43 In man, the association of laterality their series of Canadian patients. Of course, defects with maternal insulin dependent dia- low penetrance, as in the iv/iv mouse, could

betes is not well recognised. However, in a account for this but another possibility is that http://jmg.bmj.com/ study from Guy's Hospital, seven out of 102 the disease is controlled by two epistatic genes mothers who had had one child with isomerism one of which is a rare recessive. Family studies sequence were insulin dependent diabetics (R in humans are hampered by lack of large sib- Yates, personal communication). This is an ships; however there are three reports of large interesting association given the well known families where laterality sequence appears to be association of caudal regression syndrome with recessive and shows an intrafamilial variability maternal diabetes. Caudal regression is the similar to the iv/iv mouse.535657 Isolated sib result of defective development ofthe posterior pairs one of whom has isomerism sequence on October 2, 2021 by guest. Protected copyright. notochord.44 In Xenopus curtailment of de- and the other an isolated heart lesion are not velopment of dorsal anterior tissue including uncommon.5860 Several sib pairs where both notochord causes randomisation of heart loop- have isomerism sequence have been reported,30 ing.45 Thus the primary problem leading to seven concordant for right isomerism sequence, both laterality defects and caudal regression in three concordant for left, and four discord- the fetuses of diabetic mothers seems to be ant,1361-63 showing that bilateral left sidedness aberrant development of dorsoanterior midline and bilateral right sidedness may be caused structures, in particular the notochord. by the same genetic defect. Nevertheless, the The earliest investigations of left-right asym- uniformity of phenotype in several families in metry relate to twinning. In 1919, Spemann which all affected sibs have right isomerism and Falkenberg produced conjoined twins in sequence predicts the existence of a gene caus- newts by mechanical constriction of the em- ing bilateral right sidedness only. bryo.' They found that while the left twin Recessive mutations in the regulatory do- developed normally the right twin had situs main of the cardiac gap junction protein Con- inversus in 50% of cases. This experiment is nexin 43 have recently been reported in patients duplicated very nicely by the observation that with isomerism sequence.64 However, we and in human conjoined twins where the con- others have been unable to replicate this finding junction is lateral or oblique the right twin in over 40 clinically similar patients.65 often has abnormal asymmetry, situs inversus, heterotaxy, or isomerism.46 It is likely that the same epigenetic mechanism accounts for the Dominant genes occurrence of isomerism sequence as a dis- A recent report documents a number offamilies cordant trait in monozygous twins.47 Indeed, with laterality disturbance where the most likely Defects in the determination of left-right asymmetry 501 J Med Genet: first published as 10.1136/jmg.33.6.498 on 1 June 1996. Downloaded from

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.66 ginally described by Kartagener in 1933 as There are several instances of non-penetrance having the triad of situs inversus, sinusitis, in obligate gene carriers and expression in and bronchiectasis.68 This eponym is no longer affected subjects is variable. This highlights appropriate for two reasons. Firstly, while situs the importance of careful pedigree taking in inversus is present from birth the other features families with an affected child and also suggests are secondary to the dyskinetic cilia and may that parents should be investigated routinely not manifest until much later in life69 and, for evidence of situs inversus. It is possible that secondly, in familial cases only 50% of sibs some isolated sib pairs will turn out to be the with dyskinetic cilia have situs inversus.70 The result of germinal mosaicism of new dominant cilia in the respiratory epithelium of subjects http://jmg.bmj.com/ mutations. with PCD are either immotile or dyskin- etic leading to chronic respiratory tract Recurrence risks (fig 2) infection.7 72 Demonstration ofboth functional In his mass screening of the Norwegian popu- and ultrastructural changes in the respiratory lation, Torgersen3 found recurrence of situs epithelium is necessary to make the diagnosis. inversus in sibs in less than 1 % of cases. In- Cilia are most easily obtained by nasal brush- terestingly, affected subjects in four of the five ings and ciliary beat frequency can be measured on October 2, 2021 by guest. Protected copyright. families he discovered also had bronchiectasis videophotometrically.73 The most consistent and nasal polyps suggesting that ciliary dyskinesia abnormality on electron microscopy is loss of accounts for the majority of familial cases of dynein arms, but many other abnormalities complete situs inversus (see later). An empirical have been observed including complete ab- recurrence risk for isomerism sequence of just sence of cilia.6971 74 under 10% was estimated from a prospective series of over 1000 mothers who were referred CLINICAL FEATURES for echocardiography because of a previously Symptoms and signs are ofvariable age ofonset 'affected child with congenital heart disease.67 and severity. Over 90% of affected subjects are One case of isomerism sequence was detected symptomatic in childhood.75 Chronic rhinitis where the index case had a secundum ASD. This leads to sinusitus, opacity ofthe frontal sinuses, is higher than the risk of around 5% estimated in and nasal polyps. Recurrent infection of the retrospective studies.'415 With improved treat- lower respiratory tract and middle ear may ment more children with complex heart lesions eventually progress to bronchiectasis, mast- are surviving to reproductive age. At present oiditis, and conductive deafness. Patients often there are no reliable data available from which complain of troublesome headaches.75 De- to estimate recurrence risks in offspring. pressed motility of polymorphic leucocytes has been shown, although bactericidal capacity is Laterality defects with abnormal cilia: normal.76 Affected men are usually infertile primary ciliary dyskinesia owing to immotile sperm flagellae but two About a quarter of patients with complete situs reports show that this is not invariable.7778 The inversus have primary ciliary dyskinesia (PCD) spermatozoa are otherwise normal and have (1 in 30000-40000). These patients were ori- been shown to be capable of fusing with and 502 Penman Splitt, Burn, Goodship fertilising oocytes. Thus in vitro fertilisation in and the X chromosome (the WIC-Hyd rat is these patients is a possibility.79 Women also an excellent model for human PCD showing have reduced fertility, probably because of re- X linked inheritance95 ). duced ciliary movement in the Fallopian tubes.80 In a recent series one third of patients Conclusion J Med Genet: first published as 10.1136/jmg.33.6.498 on 1 June 1996. Downloaded from with PCD were found to have other congenital There are still many more questions than an- malformations.8" Heart defects occurred in over swers in our understanding of the molecular 10%. There are reports of patients with poly- basis of laterality disturbance in man. Progress splenia and biliary atresia and midline defects in the elucidation of the genetic basis of left- such as tracheo-oesophageal fistula.8"-84 One of right asymmetry is likely to come from the the sibs reported by de la Monte and Hutchins8' study of animal models. The recent exciting had left isomerism sequence and polysplenia discovery that, in frogs and birds, ectopic ex- as well as recurrent purulent rhinorrhoea and pression ofimportant signalling molecules such chronic tracheobronchitis. This example high- as Wnt, activin, and Sonic hedgehog result in lights the possible overlap between laterality random heart looping represents the start of defects with and without ciliary dyskinesia. this Patients with complex congenital heart disease process.96 do not have ciliary biopsies. Ciliary 1 Brown NA, Wolpert L. The development of handedness in routinely left/right asymmetry. Development 1990;109:1-9. dyskinesia has been shown in asymptomatic 2 Cooke J. Vertebrate embryo handedness.NTature 1995;374: patients with situs inversus86 and might easily 681. 3 Torgersen J. Genic factors in visceral asymmetry in the be overlooked in a patient with a heterotaxy. development and pathological changes of the lungs, heart There is certainly a need for further elucidation and abdominal organs. Arch Pathol 1949;47:556-93. 4 Campbell M. The mode of inheritance in isolated laevo- of a possible common pathogenesis. cardia and dextrocardia and situs inversus. Br Heart .7 1963;25:803-13. 5 CockayneEA. The genetics of transposition of the viscera. AETIOLOGY AND GENETICS Q _J Med 1983;31:479-93. PCD shows an autosomal recessive 6 Uma R, Usha R, Tahseen SK, Al-Ghanin M, Farag TI. commonly Dextrocardia + / - situs inversus among Bedouins. British inheritance pattern. Fifty percent of affected Medical Genetics Conference, York, 1995:A55(abstract). sibs have situs inversus, suggesting that ori- 7 Merklin RJ, Varano NR. Situs inversus and cardiac defects. A study of111 cases of reversed asymmetry.. Thorac entation of lateral asymmetry is random in Cardiovasc Surg 1995;45:334-42. these As yet, no genes for PCD in 8 Ivemark BI. Implications of agenesis of the spleen on the people.7" pathogenesis of conco-truncus anomalies in childhood. man have been mapped. The ciliary axoneme Acta Paediatr Scand 1955 ;44:1110.- is made ofover 100 polypeptides and dynein 9 Ruttenberg HD, Neufeld HN, Lucas RV, et al. Syndrome up of congenital cardiac disease with asplenia. Aml.7 Cardiol itself is a complex protein with several different 1964;12:387-406. so there is likely to be great hetero- 10 Ho SY, Cook A, Anderson EH, Allan LD, Fagg N. Iso- subunits, merism of the atrial appendages in the fetus. Pediatr Pathol geneity."There is one report of a family sug- 1991;11:589-608. gesting either X linked or autosomal dominant 11 Anderson C, Devine WA, Anderson RH, Debich DE, Zuberbuhler JR. Abnormalities of the spleen in relation inheritance.88 Some sporadic cases may be new to congenital malformations of the heart: a survey of dominant mutations. necropsy findings in children. Br Heart3 1990;63:122-8. 12 Webber SA, Sandor GGS, Patterson MWH, et al. Prognosis What is the basis of random situs de- in asplenia syndrome - a population based review. Cardiol http://jmg.bmj.com/ termination in PCD? Afzelius7' postulated that Young 1992;2:129-35. 13 Gatrad AR, Read AP, Watson GH. Consanguinity and normal visceral asymmetry is determined by complex cardiac anomalies with situs ambiguus. Arch Dis the coordinated movement of embryonic cilia Child 1984;59:242-5. 14 Rose V, Izukawa T, Moes CAF. Syndromes of asplenia and and that in the absence of ciliary movement polysplenia: a review of cardiac and noncardiac mal- situs will be random. However, the presence formations in 60 cases with special reference to diagnosis and prognosis. BrHeart37 1975;37:840-52. of ciliary dyskinesia is not a sine qua non for 15 Burn J, Coffey R, Allan LD, Robinson P, Pembrey ME, randomisation of situs. The hpy mouse, for Macartney FJ. Isomerism: a genetic analysis. In: Doyle EF, Engle MA, Gersony WM, Rashkind WJ, Talner NS, on October 2, 2021 by guest. Protected copyright. example, has immotile cilia, hydrocephalus, eds. Paediatric cardiology. New York: Springer Verlag, 1986: and but consistently normal situs.89 1126-8. polydactyly 16 ChiuI, HowS, WangJ, et al. Clinical implications of atrial The alternative more plausible hypothesis re- isomerism. Br Heart _7 1988;60:72-7. lates to the fact that dyneins are also present 17 Sapire DW, Ho SY, Anderson RH, Rigby ML. Diagnosis and significance of atrial isomerism. An7i Cardiol 1986; in the cell cytoplasm and control cell polarity. 58:342-6. are microtubule associated ATPases 18 SharmaS, Devine W, Anderson RH, Zuberbuhler JR. Iden- Dyneins tification and analysis of left atrial isomerism. Am J Cardiol that induce movement towards the minus end 1987;60:1157-60. of microtubules.90 In lower organisms, for ex- 19 Phoon CK, Neill CA. Asplenia syndrome - risk factors for early unfavorable outcome. Arn _7 Cardiol 1994;73: 1235-7. ample nematodes, centrosome position, the 20 Landing BH. Five syndromes (malformation complexes) orientation of formation, and therefore of pulmonary symmetry, congenital heart disease, and spindle multiple spleens. Pediatr Pathol 1984;2:125-51. cell cleavage determines cell fate in the first 21 Peoples WM, Moller JH, Edwards JE. Polysplenia: a review few cell divisions.9192 The plane of cleavage of 146 cases. Pediatr Cardiol 1983;4:129-37. 22 Martinez-Frias ML, Urioste M, Bermejo E, et al. Primary is crucial in determining the position of the midline developmental field. II. Clinical/epidemiological cells relative to adjacent cells and analysis of alteration of laterality (normal body symmetry daughter and asymmetry). An, _7 Med Genet 1995;56:382-8. therefore subsequent cell-cell interactions. In 23 Carmi R, Magee CA, Neill CA, Karrer FM. Extrahepatic however, "left" and "right" biliary atresia and associated anomalies: etiologic hetero- higher organisms, geneity suggested by distinctive patterns of associations. cell fates appear to be unfixed until a much AmJMed Genet 1993;45:683-93. later development stage.93 24 Chandra RS. Biliary atresia and other structural anomalies in the congenital polysplenia syndrome. 7 Pediatr 1974; Several candidate loci are suggested by 8S:649-55. animal models. These include human chro- 25 Chang J, Brueckner M, Touloukian RJ. Intestinal rotation and fixation abnormalities in heterotaxia: early detection mosome 14q (iv mouse locus) and also in- and management. _7 Pediatr Surg 1993;28:1281-5. cidentally where cytoplasmic dynein heavy 26 WangJ, Chang M. Association ofhiatus hernia with asplenia syndrome. Amj Cardiol 1995;75:317. chain maps,94 chromosome 12p (syntenic to 27 Wainwright H, Nelson M. Polysplenia syndrome and con- the hpy mutation on mouse chromosome 689), genital short pancreas. Amn 7 Med Genet 1993;47:318-20. Defects in the determination of left-right asymmetry 503

28 Phoon CK, Neill CA. Asplenia syndrome: insight into em- 60 Fuhrmann W. Congenital heart disease in sibships ascer- bryology through an analysis of cardiac and extracardiac tained by two affected siblings. Humangenetik 1968;6: anomalies. Am ]f Cardiol 1994;73:581-7. 1-12. 29 Evans JA, Greenberg CR, Chudley AE. Midline anomalies 61 Polhemus DW, Schafer WG. Congenital absence of the in individuals with asplenia. Proceedings of the David Smith spleen: syndrome with atrioventricularis and situs inversus. Workshop on Malformations 1993(abstract). Pediatrics 1952;9:696-708.

30 Burn J. Disturbance of morphological laterality in humans. 62 Zlotogora J, Elian E. Asplenia and polysplenia syndromes J Med Genet: first published as 10.1136/jmg.33.6.498 on 1 June 1996. Downloaded from In: Bock GR, Marsh J, eds. Biological asymmetry and with abnormalities of lateralisation in a sibship. Med handedness. Chichester: Wiley, 1991:282-99. Genet 1981;18:301-2. 31 Huhta JC, Smallhorn JF, Macartney FJ. Two dimensional 63 Niikawa N, Kohsaka S, Mizumoto M, Hamada I, Kajii T. echocardiogaphic diagnosis of situs. Br Heart ]f 1982;48: Familial clustering of situs inversus totalis, and asplenia 97-108. and polysplenia syndromes. Amn _7 Med Genet 1983;16: 32 Wang JK, Li YW, Chiu IS, et al. Usefulness of magnetic 43-7. resonance imaging in the assessment of venoatrial con- 64 Britz-Cunningham SH, Shah MM, Zuppan CW, Fletcher nections, atrial morphology, bronchial situs, and other WH. Mutations of the Connexin43 gap-junction in patients anomalies in right atrial isomerism. Am].7 Cardiol 1994; with heart malformations and defects of laterality. N Engl 74:701-4. Med 1995;332:1323-9. 33 Hummel KP, Chapman DB. Visceral inversion and as- 65 Penman Splitt M, Burn J, Goodship J. Connexin43 mutations sociated anomalies in the Mouse. ]f Hered 1959;50:9-13. in sporadic and familial defects of laterality. N Engl _] Med 34 Yokoyama T, Copeland NG, Jenkins NA, et al. Reversal of 1995;333:941. left-right asymmetry: a situs inversus mutation. Science 66 Alonso S, Pierpont ME, Radtke W, et al. Heterotaxia syn- 1993;260:679-82. drome and autosomal dominant inheritance. Am _7 Med 35 SeoJ, Brown NA, Ho SY, Anderson RH. Abnormal laterality Genet 1995;56:12-15. and congenital cardiac anomalies, relations of visceral and 67 Allan LD, Crawford DC, Chita SK, Anderson RH, Tynan cardiac morphologies in the iv/iv mouse. Circulation 1993; MJ. Familial recurrence of congenital heart disease in a 86:642-50. prospective series of mothers referred for fetal echo- 36 Icardo JM, Sanchez de Vega MS. Spectrum of heart mal- cardiography. Am ]f Cardiol 1986;58:334-7. formations in mice with situs solitus, situs inversus and 68 Kartagener M, Stucki P. Bronchiectasis with situs inversus. associated visceral heterotaxy. Circulation 1991;84:2547- Arch Pediatr 1962;79:193-207. 58. 69 Sturgess JM, Thompson MW, Czegledy-Nagy E, Turner 37 Brueckner M, D'Eustachio P, Horwich AL. Linkage map- JAP. Genetic aspects of immotile cilia syndrome. Ani _] ping of mouse gene, iv, that controls left-right asymmetry Med Genet 1986;25:149-60. of the heart and viscera. Proc Natl Acad Sci USA 1989; 70 Moreno A, Murphy EA. Inheritance of Kartagener's syn- 86:5035-8. drome. Am]f Med Genet 1981;8:305-15. 38 Morishima M, Miyagawa-Tomita S, Takao A, Ishibashi M, 71 Afzelius BA. A human syndrome caused by immotile cilia. Yokoyama T, Overbeek PA. Morphological study of the Science 1976;193:317-19. inv situs inversus mutant mouse. In: Clark EB, Markwald 72 Rossman CM, Forrest JB, Lee RMK, Newhouse MT. The RR, Takao A, eds. Developmental mechanisms of heart dis- dyskinetic cilia syndrome: ciliary motility in the immotile ease. New York: Futura Publishing Co, 1995;621-4. cilia syndrome. Chest 1983;78:580-2. 39 Genuardi M, Gurrieri F, Neri G. Genes for split hand/split 73 Rutland J, Cole PJ. Non-invasive sampling of the nasal foot and laterality defects on 7q22.1 and Xq24-q27. 1. Am cilia for measurement of beat frequency and study of Med Genet 1994;50:101. ultrastructure. Lancet 1980;ii:564-5. 40 Wilson GN, Stout JP, Schneider NR, Zneimer SM, Gilstrap 74 Rott HD. Kartagener's syndrome and the syndrome of LC. Balanced translocation 12/13 and situs abnormalities: immotile cilia. Hum Genet 1979;46:249-61. homology of early pattern formation in man and lower 75 Afzelius BA. The immotile-cilia syndrome and other ciliary organisms? Am Med Genet 199 1;38:601-7. diseases. Int Rev Exp Pathol 1979;19:1-43. 41 Carmi R, Rosenbaum KR. Human situs determination is 76 Valerius NH, Knudsen BB, Pedersen M. Defective neutro- probably controlled by several different genes. Am ]f Med phil motility in patients with primary ciliary dyskinesia. Genet 1992;44:246-7. Eur ] Clin Invest 1983;13:489-94. 42 DeCicco F, Steele MW, Pan S, Park SC. Monosomy of 77 Jonsson MS, McCormick JR, Gillies CG, Gondos B. chromosome no 22: a case report. ]f Pediatr 1973;83: Kartagener's syndrome with motile spermatozoa. N 836-8. Engl Med 1982;307:1131-3. 43 Morishima M, Miura S, Ando M, Takao A. Visceroatrial 78 Samuel I. Kartagener's syndrome with normal spermatozoa. heterotaxy syndrome in the nonobese diabetic mouse. 3rAMA 1987;258: 1329-30. In: Clark EB, Takao A, eds. Developmental cardiolog: 79 Aitken RJ, Ross A, Lees MM. Analysis of sperm function morphogenesis and function. Mount Kisco, New York: in Kartagener's syndrome. Fertil Steril 1983;40:696-8. Futura, 1990:431-41. 80 McComb P, Langley L, Villalon M, Verdugo P. The oviduct cilia and Kartagener's syndrome. Fertil Steril 44 Lynch S, Bond P, Copp A, et al. A gene for autosomal 1986;46: http://jmg.bmj.com/ dominant sacral agenesis maps to the holoprosencephaly 412-16. region at 7q36. Nature Genet 1995;11:93-5. 81 Engesaeth VG, Warner JO, Bush A. New associations of 45 Danos MC, Yost HJ. Linkage of cardiac left-right asymmetry primary ciliary dyskinesia syndrome. Pediatr Pulmonol anterior development in Xenopus. 1993;16:9-12. and dorsal Developmzent 82 Teichberg S, Markowitz J, Silverberg M, et al. Abnormal cilia 1995;121:1467-74. in a child with the polysplenia syndrome and 46 Rossi MB, Burn J, Ho SY, et al. Conjoined twins, right extrahepatic the sequential analysis. Br Heart ]f biliary atresia. ] Pediatr 1982;100:399-401. atrial isomerism, and 83 Schidlow DV, Katz SM, Turtz MG, Donner RM, Capasso 1987;58:518-24. S. Polysplenia and Kartagener syndromes in a sibship: 47 Wilkinson JL, Holt PA, Dickinson DF, Jivani SK. Asplenia association with abnormal respiratory cilia. ]Pediatr 1982; syndrome in one of monozygotic twins. Eur ]f Cardiol

100:401-3. on October 2, 2021 by guest. Protected copyright. 1979;10:3-1-304. 84 Gershoni-Baruch R, Gottfried E, Pery M, Sahin A, Etzioni 48 Burn J, Corney G. Congenital heart defects and twinning. A. Immotile cilia syndrome including polysplenia, situs Acta Genet Med Gemellol 1984;33:61-9. inversus, and extrahepatic biliary atresia. Am] Med Genet 49 Casey B, Devoto M, Jones KL, Ballabio A. Mapping a gene 1989;33:390-3. for familial situs abnormalities to human chromosome 85 de la Monte SM, Hutchins GM. Brief clinical report. Sisters Xq24-q27.1. Nature Genet 1993;5:403-7. with polysplenia. Am .7 Med Genet 1985;21:171-3. 50 Fullana A, Garcia-Frias E, Martinez-Frias ML, Razquin S, 86 Kroon AA, Hiej JMH, Kuijper WA, Veerman AJP, van der Quero J. Caudal deficiency and asplenia anomalies in sibs. Baan S. Function and morphology of respiratory cilia in Am .7 Med Genet 1986;suppl 2:23-9. situs inversus. Clin Otolaryngol 1991;16:294-7. 51 Mikkila SP, Janas M, Karikoski R, Tarkkila T, Simola 87 Afzelius BA. Genetical and ultrastructural aspects of the KOJ. X-linked laterality sequence in a family with carrier immotile-cilia syndrome. Am Hum Genet 198 1;33:852- manifestations. Am Med Genet 1994;49:435-8. 64. 52 Casey B, Gebbia M, Devoto M, Nelson DL, Aylsworth AS. 88 Narayan D, Krishnan SN, Upender M, et al. Unusual Females with midline malformations and complex reversal inheritance of primary ciliary dyskinesia (Kartagener's of left-right asymmetry in a family with X-linked het- syndrome). Med Genet 1994;31:493-6. erotaxy. Am ]f Hum Genet Suippl 1995;57:A85. 89 Bryan JHD. The immotile cilia syndrome. Mice versus man. 53 Arnold GL, Bixler D, Girod D. Probable autosomal re- Virchows Arch 1983;399:265-75. cessive inheritance of polysplenia, situs inversus and car- 90 McIntosh JR, Porter ME. Enzymes for microtubule-de- diac defects in an Amish family. Am _7 Med Genet 1983; pendent motility. Biol Chem 1989;264:6001-4. 16:35-42. 91 Priess JR. Establishment of initial asymmetry in early 54 Distefano G, Romeo MG, Grasso S, et al. Dextrocardia Caenorhabditis elegans embryos. Cur Opin Genet Dev with and without situs viscerum inversus in two sibs. Am 1994;4:563-8. ]Med Genet 1987;27:929-34. 92 Rhyu MS, Knoblich JA. Spindle orientation and asymmetric 55 Schonfeld EA, Frischman B. Syndrome of spleen agenesis, cell fate. Cell 1995;82:523-6. defects of the heart and vessels and situs inversus. Helv 93 Hoyle C, Brown NA, Wolpert L. Development of left/right PaediatrActa 1958;6:636-40. handedness in the chick heart. Development 1992;11S: 56 Zlotogora J, Schimmel MS, Glaser Y. Familial situs inversus 107 1-8. and congenital heart defects. Am .7 Med Genet 1987;26: 94 Narayan D, Desai T, Banks A, et al. Localization of the 181-4. human cytoplasmic dynein heavy chain (DNECL) to 57 Czeizel A. Familial situs inversus and congenital heart de- 1 4qter by fluorescence in situ hybridization. Genomics fects. Am .7 Med Genet 1987;28:227-8. 1 994;22:660-1. 58 Silver W, Steier M, Chandra N. Asplenia syndrome with 95 Torikata C, Kijimoto C, Koto M. Ultrastructure of res- congenital heart disease and tetralogy of Fallot in siblings. piratory Cilia of WIC-Hyd male rats. Am] Pathol 1991; Am _Cardiol 1972;30:91-4. 138:341-7. 59 Katcher AL. Familial asplenia, other malformations, and 96 Yost HJ. Vertebrate left-right development. Cell 1995;82: sudden death. Pediatrics 1980;65:633-5. 689-92.