Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from British Heart journal, I975, 37, 84o-852. Syndromes of asplenia and polysplenia A review of cardiac and non-cardiac malformations in 6o cases with special reference to diagnosis and prognosis'

Vera Rose, T. Izukawa, and C. A. F. Moes From the Departments of Cardiology and Radiology and Research Institute of the Hospital for Sick Children, Toronto, Ontario, Canada

This reviw presents the cardiac and non-cardiac malformations in 6o cases with asplenia and polysplenia with special reference to distinguishing factors which may be helpful in the clinical recognition of these syn- dromes. The asplenia cases were predominantly male andpresented with cyanosis. Theyfrequently had transposttion of the great arteries (72%) with pulmonary stenosis or atresia (88%) and total anomalous pulmonary venous drainage (72%). Deaths were caused by cardiacfailure and anoxia in 57per cent of cases. Most of thepatients died in thefirstyear oflife (79%), but longer survival ispossible in the asplenia syndrome. The polysplenia cases were predominantly female and survived longer. The characteristic clinicalfindings were the relatively more benign presenting signs and the leftward or superiorly orientated P wave axis on the

electrocardiogram. Conotrumcal abnormalities were less comnon and total anomalous pulmonary venous http://heart.bmj.com/ drainage did not occur. On angiography the inferior vena caval drainage via the azygos system was clearly identified and this was present in all cases at surgery. Our study indicated that the cardiac anomalies in polysplenia were less severe than they were in asplenia and therefore the prognosis in the former syndrome is likely to be more favourable. Three families had two affected sibs but no single geneticfactor could be identified. The aetiology of these syndromes remains undeter- mined. on September 30, 2021 by guest. Protected copyright. The association of splenic anomalies with malposi- difficulties which may be encountered during cardiac tions and malformations of other organ systems, in catheterization procedures and to be able to predict particular, the cardiovascular system, have been the cardiac lesions which could be surgically re- well documented in the past 20 years (Polhemus and paired or palliated. Schafer, 1952, 1955; Ivemark, I955; Putschar and A review of the cases with splenic abnormalities Manion, I956; Ruttenberg et al., I964; Campbell from the necropsy series of the Cardiology Division, and Deuchar, I967; Moller et al., I967; Landing Hospital for Sick Children, Toronto, revealed 39 et al., 197I; Van Mierop, Gessner, and Schiebler, cases of asplenia and 13 cases of polysplenia. The I972; Freedom, I972). The complexityofthe cardiac heart was available for review in 32 cases of the malformation determines the clinical course and former and all of the latter. In addition, there are 6 prognosis and frequently precludes correction by surviving patients with asplenia syndrome and 2 surgical techniques. It is important, therefore, to with polysplenia in whom the splenic abnormalities recognize the patient who has the asplenia or poly- were suspected because of the presence of Howell- splenia syndrome, in order to anticipate potential Jolly bodies in the peripheral blood smear in the Received 20 December 1974. former and multiple spleens documented by radio- 2This work was supported by a grant from the Ontario Heart isotope spleen scan in the latter. It is suspected that Foundation, Toronto, Canada. more surviving cases with polysplenia may be Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

Syndromes of asplenia and polysplenia 84I presently unidentified since spleen scan has only TABLE 3 Associated non-cardiovascular malfor- recently been used for the identification of this con- mations in 52 necropsy cases dition. The necropsied group included cases in which the spleen was either entirely absent (cases of Abnormality Asplenia Polysplenia fimctional hyposplenia were excluded) or in which 39 cases I3 cases 4 to Io splenunculi were present (cases with one accessory spleen were not included). At necropsy, clinical and radiological findings Pulmonary Bilateral trilobed lungs 27 0 were reviewed, with particular reference to points Bilateral bilobed lungs 0 4 of difference between the two syndromes and their Bilobed (R) trilobed (L) I 2 clinical recognition. Lobation unknown I I 7 Gastrointestinal Heterotaxy I'5 Results Situs inversus 6 69% 6 54% Partial sitUs inversus 6 I Asplenia Normal visceral sitUs 12 6 Age at death and cause of death (Tables i and 2) Imperforate anus 2 The was in In this Annular pancreas I mortality high asplenia. necropsy Ectopic liver (in adrenal) I series 36 per cent of cases did not survive the first Hiatus hernia I week of life and 79 per cent were dead by the end of Absent gallbladder I the first year. Cardiac failure and anoxia were the predominant causes of death, followed by surgery. Genitourinary Infection was a relatively infrequent cause of death. Horseshoe kidney I Double collecting system I o5 Hydroureter 3 Cystic kidney I I \ o Pathological features: non-cardiac malfor- Absent right kidney and ureter - I mations (Table 3) The recognized tendency for bilateral symmetry of organs in asplenia syndrome Endocrine (Van Mierop et al., I972) was noted to be present. Fused or horseshoe adrenal 4 Absent L adrenal I Bicornuate uterus I Ovarian cysts I http://heart.bmj.com/ TABLE I Age at death CNS Age Asplenia Polyspknia Arteriovenous malformation of x No. % No. % midbrain Birth-i week I4 36 2 15 Musculoskeletal I-4 weeks 8 20 2 15 Scoliosis 2 1-3 months 6 I5 3 23 2 3-5 months 5 I 8 on September 30, 2021 by guest. Protected copyright. 6-i2 months I 3 0 0 There tended to be duplication of right-sided struc- Total under I year 3I 79 8 6i Total over I year 8 21 5 39 tures, with absence of those normally on the left. Other features, such as the symmetrical liver and abdominal heterotaxy, indicated a retention of the undifferentiated early embryonic state. Among the TABLE 2 Cause of death cases in which lung lobation was recorded 27 out of 28 had symmetrically trilobed lungs: I2 of these cases has visceral heterotaxy, 5 had abdominal situs Asplenia Polysplenia solitus, 4 had situs inversus, and 6 had partial situs Cardiac failure II I inversus. One case had thoracic situs inversus with Anoxia IO I partial abdominal situs inversus with the venae Complications of surgery 8 8 cavae as well as the pulmonary veins entering a Infection 4 I Haemorrhage 3 0 common atrium on the right side. The bronchial Sudden unexpected death 3 2 (late postoperative) anatomy could not be ascertained radiologically from the air bronchograms and was not recorded in the 39 I3 necropsy reports in this retrospective study. Abnormal visceral situs was present in 69 per Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

842 Rose, Izukawa, and Moes cent of cases. Abdominal heterotaxy occurred in I5 ASPLENIA (32 PM.CASES) patients, situs inversus in 6, and partial situs in- POSITIONS OF APEX AND AORTIC ARCH versus in 6. Among the I2 cases with normal vis- ceral situs, 5 had bilateral trilobed lungs and in 7 others the lung lobation was not recorded in the necropsy report. There were 2 cases with imperfor- ate anus. Three others with asplenia had annular pancreas, ectopic liver, and hiatus hernia. Fifteen per cent of cases with asplenia had renal abnormalities which included horseshoe kidney, double collecting system, hydroureter, and cystic kidney. There were 4 instances of fused or horseshoe adrenal glands. Three patients had an unusual physical appearance, with webbing of the neck, and were thought to be a Tumer phenotype. Chromo- APEX Left-18(569b) Right-13(410/o) some studies were not done on these cases. Midline-I (3%) ARCH OF AORTA Left-18 (560o) Riqht-12(380/6) Cardiovascular abnormalities (Tables 4 and 5, U ncertain- 2 (6%) Fig. I) Positional abnormalities of the heart were frequent, I3 of 32 hearts (4I%) having the apex FIG. I. on the right. cava drained was the right atrium. There was no Venous system (Fig. 2) Bilateral superior venae instance in our series in which we were able to cavae were present in I7 of 32 hearts (53 per cent). A document that the inferior vena cava returned to a single superior vena cava was located on the right in morphological left atrium. Among those cases with II (34 per cent) and on the left in 3 (io per cent) the inferior vena cava on the right, 8 had abdominal cases. The inferior vena cava in its supradiaphrag- situs solitus, 8 had visceral heterotaxy, and 3 had matic course was on the right in I9 (60%) and on partial situs inversus. In i case with partial situs the left in 9 (28%) cases, which suggests that the inversus, a right-sided inferior vena cava crossed to

systemic venous atrium was located in the corres- enter the systemic venous atrium which was situ- http://heart.bmj.com/ ponding position in cases in which the atrial mor- ated on the left. Of the 9 cases with a left-sided phology was not clearly defined (Van Praagh, inferior vena cava, 6 also had abdominal and atrial 1972; de la Cruz, Polansky, and Navarro-Lopez, situs inversus. I962). We accept the suggestion that the chamber Total anomalous pulmonary venous drainage into which the supradiaphragmatic inferior vena occurred in 23 or 72 per cent and partial anomalous

ASPLENIA (32 PM.CASES) on September 30, 2021 by guest. Protected copyright. VENOUS SYSTEM 1) SUPERIOR VENA CAVA 3) PULMONARY VEINS Bi IateraI - 17 ( 53%) Anomalous drain. (84°/) Riqht-II (34%) i) Totol-23(7296) Left - 3 (I 0%) ii) Partial -2 (b0/o) Uncertain-I (30/o) iii)Mixed-2 (60cV)

2) INFERIOR VENA CAVA 4) HEPATIC VEINS Left-9 (280%b) l.V.C - 23 (72%) Riqht- 19 (60/o) Direct to atrium - 5 (16%) Bilateral-I (30/o) Uncertain-4 (12%) Midline-I (30/o) Uncertain-2 (6b9)

FIG. 2. Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

Syndromes of asplenia and polysplenia 843

ASPLEN IA (32 PM. CASES) GREAT VESSELS DUCTUS ARTERIOSUS Normal rel-6(19%) 1) Patent T.. (D - 6 (1996) Bilateral-i (30%) (l- 17 (53%) Riqht-7 (22%) D.O.R.V.- 3 (9%o) Left- 10 (31%) 2) Closed- 13 (41%) 3) Uncertai n -I (3%)

PULMONARY VALVE CORONARY ARTERIES Normal-7 (22%) 1) Two-24(759o) Pul. stenosis- 11 (34%) 2) Single-6(190I0) Pul. atresia -14 (44%) 3) Uncertain - 2 ()

FIG. 3. pulmonary venous drainage in 2 or 6 per cent of TABLE 4 Positions of cardiac apex cases. Mixed anomalous pulmonary venous drainage and aortic arch refers to pulmonary venous drainage into more than one site. Asplerna Polysplekra The morphological distinction of the atria was (No.) (No.) difficult in most cases. The diagnosis of single atrium was made in cases of absent septum or in Apex those with very large secundum and primum de- Left I8 7 fects with a vestigial septum often represented by Right I3 5 Midline I a bar of tissue running between the anterior and http://heart.bmj.com/ posterior wall of the atrium. Aortic arch Left I8 4 Great vessel abnormalities (Fig. 3) Transposi- Right I2 8 tion of the great arteries was common (72%). Unverified 2 Transposition of the great arteries in the d-position

ASPLENIA (32 PM. CASES) INTRACARDIAC on September 30, 2021 by guest. Protected copyright. A) CORONARY SINUS D) VENTRICLES Absent- 27 (85%) Two - 18 (56%) Present-3 ( 9%) Single- 14(44°h) Uncertain 2 (6%h)

B) ATRIAL SEPTUM E) VENTRICULAR SEPTUM 1) Prim.+ Sec. (18 cases) -21 (66%) A-V canal - 16 (84%) 2) Prim. only No V.S.D. - 2 (10%) -Il (34%) Muscular-I (6%) C) A-V VALVES Single -28 (870%) Two-4 (13%)

FIG. 4. Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

844 Rose, Izukawa, and Moes

TABLE 5 Associated cardiovascular abnormalities TABLE 6 Asplenia survivors

Abnormality Asplenia Polysplenia 6 cases - all male % of total % of total Age at last visit No. Surgery (shunts) Cardiac malpositions 44 41 < i year 2 0 <3 years 2 I Venous system I2-I8 years 2 2 Systemic veins Bilateral superior vena cava 53 33 Inferior vena cava drainage via azygos o 84 Pulmonary veins Despite the severity of the congenital malforma- Total anomalous pulmonary tions in these children, these infants were born at venous drainage 72 0 term and their mean birthweight was not signifi- Partial anomalous pulmonary venous drainage 6 42 cantly different from that of controls (Registrar- General of Ontario, i966). All cases presented with Great vessels cyanosis. The electrocardiogram showed a normal Transposition 72 8 or rightwardly directed P axis. The plain chest film Pulmonary stenosis or atresia 78 33 was helpful in documenting the abnormal cardiac Coronary arteries and visceral situs and the symmetrical liver (Fig. 5). Single coronary artery I9 0 The persistence of the left superior vena cava could also be detected on the chest film and was Intracardiac (Fig. 6), Single ventricle 44 8 confirmed by angiography (Fig. 7). The side-by- Single AV valve 87 I7 side relation between the aorta and the inferior vena Absent coronary sinus 85 33 cavae in their abdominal course (Elliot, Cramer, and Amplatz, I966) is exemplified in one of our cases (Fig. 8). Howell-Jolly bodies were seen in I5 occurred in 17 or 53 per cent and in the 1-position in of I7 cases who had blood smears taken. A splenic 6 or i9 per cent of cases. Three patients or 9 per scan to confirm the diagnosis of asplenia was done cent had a double outlet right ventricle. Pulmonary in 6 instances (Fig. 9). http://heart.bmj.com/ stenosis or atresia was present in 25 or 78 per cent of cases. A single coronary artery occurred in 6 or I9 per cent. TABLE 7 Clinicalfeatures Intracardiac malformations (Fig. 4) A single atrioventricular valve was present in 28 or 87 per Asplenia Polysplenia cent. A single ventricle was present in I4 or 44 per cent of cases. A single atrioventricular valve was Sex ratio on September 30, 2021 by guest. Protected copyright. present in all cases with single ventricle and in 14 (M/F) 1.7/I o.5/I of the I8 cases with two ventricles. In the remaing 60% males 28% males 4 cases the atrioventricular valve was divisible into Gestation Normal Normal mitral and tricuspid components. There was a high incidence of absent coronary sinus (85%). Septum Birthweight and secundum defects of septum (mean) 326I g 33I3 g primum the atrial Control 3322 g were present in 2I or 66 per cent and the remainder had prnmum defects only. Presenting signs Cyanosis 45 (Ioo%) 6(4%) Survivors (Table 6) There are 6 surviving Murmurs 4(30%) Dyspnoea 3 (24%) patients identified by means of the Howell-Jolly bodies and the spleen scan. All the survivors are Howell-Jolly bodies male and 3 of them have had systemic-to-pul- Present IoO monary shunts performed and are doing well. Two Absent 2 II Unknown 28 4 of the survivors are over the age of IO years. Spleen scan Absent spleen Multiple spleens Clinical features (Table 7) There was a pre- (8 cases) (6 cases) (2 cases) ponderance ofmale patients with asplenia syndrome. Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

Syndromes of asplenia and polysplenia 84S

FIG. 5. Plain x-ray of a case of asplenia syndrome liver. showing symmetrical FIG. 7 Cineangiogram of a case of asplenia syn- drome showing bilateral superior venae cavae. http://heart.bmj.com/ on September 30, 2021 by guest. Protected copyright.

FIG. 8 Cineangiogram of a case of asplenia syn- FIG. 6 Plain x-ray of a case of asplenia syndrome drome showing aorta and inferior vena cava located showing bilateral superior venae cavae. side by side to the left of the spine. Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

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FIG. 9 Splenic scan of a case of asplenia syndrome showing transverse liver and no spleen. A = anterior view; P=posterior view. Familial cases (Fig. io) In this series of 6o cases normal population (Registrar-General of Ontario, with asplenia and polysplenia there were 2 families I966). Asplenia syndrome occurred more fre- in which 2 sibs were affected with asplenia and one quently in late born children of mothers whose family in which 2 sibs were affected with poly- mean age was not significantly different from that of splenia. None of the 3 families had a history of the general population (mean maternal age was consanguinity. A retrospective study of I7 pat- 27.07 years). The birth order effect was tested ients' families with asplenia syndrome showed that (Haldane and Smith, I948) and showed an actual the maternal and paternal ages were not signifi- mean of 360, a theoretical mean of 287.I, with a cantly different from the ages of the parents in the difference which was more than the standard error of 36.6 and, therefore, significant. The pregnancy http://heart.bmj.com/ ASPLENIA AND POLYSPLENIA history did not bring to light any particular event FAMILY HISTORY during early gestation which might have been the B. FAMILY cause of development of the asplenia syndrome. Miscarriages were not frequent in this group, the rate was 8.65 per cent, comparable to that found in the general population (Warburton and Fraser, x964). The recurrence rate in all the sibs of patients

19b2 1966 on September 30, 2021 by guest. Protected copyright. Asplenia Asplenia with asplenia syndrome was 4.65 per cent. The segregation ratio as a test for autosomal recessive H. FAMIILY inheritance was 8.9 per cent, well below the 25 per D-T

Syndromes of asplerna and polysplenia 847 POLYSPLENIA (12 PM. CASES) a right-sided structure, was absent in i patient. Two POSITIONS OF APEX AND AORTIC ARCH of the cases (i5%) had renal abnormalities. A cystic kidney was present in one and the right kidney and ureter were absent in the other. Cardiovascular abnormalities (Tables 4 and 5, Fig. ii) Positional anomalies of the cardiac apex were frequent, 42 per cent of cases had dextrocardia; 67 per cent had a right aortic arch. Compared with the cases of asplenia the positional anomalies and aortic arch were not significantly different. Venous system: systemic veins (Fig. 12) Of the 12 cases, 33 per cent had bilateral superior vena cavae. A single superior vena cava was on the right in 33 per cent, and on the left in 33 per cent ofcases. APEX Left-7(58%) Riqht-5(4201o) Azygos return of the inferior vena cava was present AORTIC ARCH Left-4 (33%) Right-8 (670%6- in most of the cases with the azygos vein coursing FIG. II. on either the right or the left side. Pulmonary veins Partial anomalous pulmonary absence of those normally on the right. Four cases venous drainage was observed in 5 or 42 per cent of had bilateral bilobed lungs, and 2 had bilobed right cases, and in the remaining cases, the pulmonary and trilobed left lungs. In the 2 latter cases with veins drained normally. thoracic situs inversus, i had abdominal situs in- versus with the vena cava as well as the pulmonary Great vessel abnormalities (Fig. 13) The great veins entering a single atrium on its right lateral arteries were normally related in io or 84 per cent aspect. The other had partial abdominal situs in- of cases and pulmonary stenosis or atresia were versus with the azygos continuation of the inferior present in 42 per cent of cases. vena cava on the left side of the spine entering the Intracardiac malformations (Fig. I4) Defects left side of this atrium which was large and also of the atrial and ventricular septa and atrioventric- received the common left pulmonary vein. The ular valve abnormalities occurred less frequently in coronary sinus drained into this left-sided atrium as polysplenia than in asplenia. http://heart.bmj.com/ well. A smaller right-sided atrium drained the common right pulmonary vein. In 7 cases the loba- Survivors Of 8 surviving patients where the tion of the lungs was not known. The bronchial diagnosis was suspected from clinical and catheter- anatomy was not ascertainable. Abnormal visceral ization data, 2 have so far been identified by spleen situs occurred in 7 of the I3 cases. The gall bladder, scan.

POLYSPLENIA (12 PM. CASES) VENOUS SYSTEM on September 30, 2021 by guest. Protected copyright. 1) SUPERIOR VENA CAVA 3) PULMONARY VEINS Bilateral - 4 (33c%,) Normal - 6 (50%) Left - 4 ( 330/o) / N Cardiac (partial to Right-4 (33%) R A.)- 5 (42%) Uncertain -I (80°)

2) INFERIOR VENA CAVA 4) HEPATIC.VEINS Direct to atrium (L) -2 (b16%) Direct to atria - 10(84%) AZYGOS SYSTEM U ncertain - 2 (Ic6%) Right-5](84/6

FIG. 12. Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

848 Rose, Izukawa, and Moes

POLYSPLENIA (12PM.CASES)

GREAT VESSELS A) DUCTUS ARTERIOSUS Normal- 10 (84%) Patent i) Left-3 1(500) T.G.A.-I (80/o) ii) Riqht-3J D.O.R.V.-i (80/o) Closed - 3 (25%) Uncertain-3 (254'o)

PULMONARY VALVE B) CORONARY ARTERIES Normal -7 (58%) Two- 10 (84%) -Stenosis-valvc-1(I] Uncertain-2 (Ib%) subvalve-3J Atresia -1 (90%6)

FIG. 13. Clinical features (Table 7) There was a pre- despite the fact that resolution of the splenic masses dominance of female patients in this group. The is not ideal. mean birthweight was normal as compared to con- trols. Seven cases presented with cyanosis, 5 with murmurs, and 3 with dyspnoea. The electrocardio- Discussion gram characteristically showed a leftward and sup- Although case reports of asplenia associated with eriorly directed P wave axis in all but one of the cardiovascular defects and situs inversus had been

cases. Among the radiological signs, the inferior published during the nineteenth century, the first http://heart.bmj.com/ vena caval drainage via the azygos system was a suggestion that asplenia might constitute a clinical useful sign (Fig. 15) as was the separation of the syndrome was made by Polhemus and Schafer aorta and inferior vena cava coursing on either side (1952, I955), and a detailed analysis of the aggre- of the spine (Fig. i6). Howell-Jolly bodies were not gation of defects as well as a review of the published seen in any of the 9 cases in which they were reports by Ivemark (I955) appeared three years searched for. The splenic scan was helpful in later in a notable paper. Morphogenetically the making the diagnosis of polysplenia (Fig. I7), splenic abnormalities and associated defects are on September 30, 2021 by guest. Protected copyright. POLYSPLENIA (12PM. CASES) INTRACARDIAC A) CORONARY SINUS D) VENTRICLES Absent-5 (42%) Normal - 7 (58%) Present-4 (33%) Single-I (80/%) Uncertain -3 (250/o) Small LV 3% SmaIIR.V-lJI ) BY ATRIAL. SEPTUM Primum + sec.-3 (26%) E) VENTRICULAR SEPTUM Single-2 (16%b) Prirmum-2 (Ib%) F 1) Fallot-3 Sec.-3 V.S.D. i ii)Canal-4 (67%) EO.-2 (16%)(2b6o) .iii )Muscular-IJ Intact-3 (25%) C) A-V VALVES No septum -I (8%) Normal - 6 (50%) Si nqle - 2 (16%) Abn. mitral valve - (340/0) i) Atresia-I ii) Small-I iii) Displaced-I iv) Thick-i FIG. 14. Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

Syndromes of asplenia and polysplenia 849

FIG. 15 Cineangiogram of a case of polysplenia syn- drome showing inferior vena caval drainage via a right-sided azygos vein. FIG. I6 Cineangtogram of a case of polysplenia syndrome showing the aorta and inferior vena cava running on either side of the spine. likely to be caused by an unknown teratogenic in- regard these conditions, from a clinical standpoint, sult between the 3ISt and 40th days of gestation as separate congenital syndromes. (Putschar and Manion, I956; Landing et al., I97I). Although the fatality rate is high in asplenia, sur- During the past IO years a number of case reports vival is possible (and it was notable that survivors http://heart.bmj.com/ and reviews has indicated that a predictable pattern in our series did not have anomalies of the pul- of malformations exists in cases with either absent monary venous return). In comparing the number spleen or polysplenia, which would permit one to of cases of asplenia and polysplenia who died at on September 30, 2021 by guest. Protected copyright.

p LPO

FIG. I7 Splenic scan of a case of polysplenia syndrome showing a right sided liver and multiple spleens. LPO = left posterior oblique; P=posterior. Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

8So Rose, Izukawa, and Moes

different times in the first year of life and thereafter, was, therefore, a useful distinguishing anatomical there was no statistically significant difference be- finding. Of interest from the embryological stand- tween them. Since survival is possible with asplenia, point and the concept of bilateral right-sidedness palliative surgery should be considered. In 1956 (Van Mierop et al., I972) was the absence of the Putschar and Manion in an extensive survey of the coronary sinus in 84 per cent of necropsies in published reports described 29 cases of asplenia asplenia. Single ventricle, single atrium, and com- without heart disease, but only occasional reports mon atrioventricular valve occurred with greater have appeared since (Kessler and Smulewicz, frequency in asplenia. In this group the atrial I973). There were no cases of asplenia without septum was often no more than a vestigial bar of associated heart disease in our own records. The tissue and the large secundum and primum defects exact incidence of polysplenia without heart disease described in our study (Fig. 4) could be regarded as is not known. Surgery in both conditions carries a single atrium in most cases. A single atrioventricular high risk. valve was present in all cases with single ventricle. Among the necropsy findings, the non-cardiac In only 4 cases was the atrioventricular valve divi- abnormalities fitted the pattern of isomerism de- sible into mitral and tricuspid components and these scribed by Van Mierop and co-workers (1972), were patients who had 2 ventricles. A single coronary Moller et al. (I967), and Landing et al. (I97i). The artery was found in I9 per cent of our asplenia cases. frequency of visceral heterotaxy with asplenia has This was found in one case of the series of Rutten- been described by Van Praagh and co-workers berg et al. (I964) and has not been reported in (I964, I965) and the resulting difficulties in ascer- others. taining visceroatrial situs are well known. Visceral Among the clinical features, male preponderance and atrial situs appeared to be discordant in 3 cases. was striking in asplenia while there was a female In one case of asplenia who had thoracic situs in- predominance in the polysplenia group. Parental versus and partial situs inversus of the viscera, a age, gestational age, and birthweight were normal right-sided inferior vena cava crossed and drained as compared to the general population (Registrar- into a left-sided systemic venous atrium. In one case General of Ontario, I966). The significance of the of polysplenia with abdominal situs inversus the increased birth order might have been more reveal- venae cavae as well as the pulmonary veins entered ing had we been able to analyse separately cases a single atrium on its right lateral aspect. In another where mothers were older (e.g. over 35 years) and case of polysplenia with partial abdominal situs likely to have completed their families. However, http://heart.bmj.com/ inversus and thoracic situs inversus azygos continua- since the number of families we were able to investi- tion of the inferior vena caval drainage as well as the gate was not large enough for such a separate common left pulmonary veins and coronary sinus analysis, a likely explanation of the high birth drained into the left-sided part of a large common rank could have been the deliberate limitation of atrium. The renal anomalies occurred in I5 per cent family size after the birth of an affected child. A of asplenia and I5 per cent of polysplenia cases similar birth order effect was found in family in our series. Freedom (I972) reported an incidence studies of patients with another type of severe con-

of renal abnormalities in 25 per cent of his series. genital heart disease (Chen, Thompson, and Rose, on September 30, 2021 by guest. Protected copyright. The salient features of the cardiovascular abnor- I97I). malities confirmed to a large extent those already Cyanosis was the presenting sign in all cases of published (Ivemark, I955; Ruttenberg et al., I964; asplenia whereas only half of the polysplenia cases Moller et al., I967; Van Mierop et al., 1972). presented in this way. Notable among the distinguishing anatomical feat- The consistent electrocardiographic abnormality ures was the high incidence of transposition of the was a leftward or superiorly directed P wave great arteries with pulmonary atresia or stenosis in vector or coronary sinus rhythm which was found asplenia. The associate frequency of total anomalous in 92 per cent of cases of polysplenia. Analysis of pulmonary venous drainage suggests that it might the P wave vector is useful in detecting atrial situs in contribute to the severity of symptoms and early dextrocardia. It has been suggested that infradia- death in patients with that condition. Conotruncal phragmatic interruption of the inferior vena cava is abnormalities were less common in polysplenia, and the cause of unusual atrial depolarization in poly- only partial anomalies of pulmonary venous return splenia (Momma and Linde, I970; Van der Horst occurred. Among the systemic venous abnormalities, and Gotsman, I972). the absence of the infrahepatic segment of the in- Radiologically the plain x-ray film ofthe chest and ferior vena cava with drainage via the azygos system upper abdomen is helpful in suggesting that the was not seen in any cases of asplenia and was splenic abnormality is present. The cardiac and present in 84 per cent of the polysplenia cases and visceral situs, the position of the liver and of the Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

Syndromes of asplenia and polysplenia 85z stomach are easily ascertained. More difficult to one with tetralogy of Fallot. More recently, Simp- ascertain from the conventional radiograph is the son and Zellweger (I973) reported one child with presence of eparterial or hyparterial bronchi which splenic agenesis and one with splenic hypoplasia in are a clue to lobation of the lungs and would sug- a family. The role of genetic factors in asplenia and gest bronchopulmonary isomerism in these syn- polysplenia remains undefined. It is more likely dromes (Landing et al., I97I). Angiographically, that these conditions result from the interaction of the drainage via the azygos system of the inferior both genetic and environmental factors as suggested vena cava is helpful in identifying specifically by Nora (I97I). In a family with one affected child the polysplenia cases. The aorta-to-inferior vena and no other affected relatives, the recurrence risk cava relation demonstrated in some of these cases should be very low. The incidence of asplenia in is a useful sign (Elliot et al., I966) for confirming the the general population is difficult to assess. Nine diagnosis in suspected cases. patients with this syndrome in our series were born The persistence of Howell-Jolly bodies in the in Metropolitan Toronto between I955 and I964. peripheral blood smear is a very useful means of The minimal incidence is therefore i in about confirming splenic agenesis or hypofunction pro- 40,000 live births. The calculated sib frequency if vided it is remembered that Howell-Jolly bodies asplenia were a multifactorial condition (Edwards, can be transiently present in the normal newborn I960) would be 0.235 x io-O or 0.49 per cent which (Padmanabhan, Risemberg, and Rowe, I973). These is below the actual incidence of 4.65 per cent we inclusions are also seen in the late stages of the found. Our family data, therefore, did not suggest maturing erythroblast, in megaloblastic and haemo- any single genetic factor nor did they bring to light lytic anaemias, thalassaemia, leukaemia, and some any teratological insult which could have been types of steatorrhoea. A more specific diagnosis of responsible for the development of the splenic and asplenia and polysplenia can be made by radioiso- associated anomalies. tope scanning of the liver and spleen (Shah et al., Freedom when absence We wish to thank Dr. J. Huber, Professor of Pathology, I964; and Treves, I973) and Dr. R. D. Rowe, Professor and Head of the Division of the spleen can be shown or multiple spleens of Cardiology, at the Hospital for Sick Children, Tor- identified. onto, for helpful criticism and advice. Dr. Su-Chiung While most of the cases of splenic abnormalities Chen performed the family studies of cases with asplenia with congenital heart disease are sporadic, a number syndrome. of surveys in the past have shown a clear tendency http://heart.bmj.com/ for congenital heart disease in general to occur in References several family members (Nora, I97I). It was, there- Campbell, M., and Deuchar, D. C. (i967). Absent inferior fore, not surprising to find three families with more vena cava, symmetrical liver, splenic agenesis, and situs inversus, and their embryology. British HeartJournal, 29, than one sib affected in our series. In each of the 268. asplenia families there was concordance of the Chen, S., Thompson, M. W., and Rose, V. (I97I). Endo- cardiac defect. In the polysplenia family, one sib cardial fibroelastosis: family studies with special reference had tetralogy of Fallot and one had hypoplastic to counseling. Journal of Pediatrics, 79, 385. de la Cruz, M. V., Polansky, B. J., and Navarro-Lopez, F.

left heart syndrome. While this may suggest that on September 30, 2021 by guest. Protected copyright. (I962). The diagnosis of corrected transposition of the these syndromes could be heritable conditions with great vessels. British HeartJournal, 24,483. autosomal recessive transmission, our asplenia Edwards, J. H. (ig60). The simulation of Mendelism. Acta patients' family analysis did not confirm this. We Genetica et Statistica Medica, I0, 63. found a segregation ratio of 8.9 per cent which was Elliot, L. P., Cramer, G. G., and Amplatz, K. (I966). The anomalous relationship of the inferior vena cava and far below the 25 per cent expected if this were a true abdominal aorta as a specific angiographic sign in asplenia. autosomal recessive condition (Li and Mantel, Radiology, 87, 859. I968). There was no history of consanguinity in the Freedom, R. M. (I972). The asplenia syndrome: a review of families. The occurrence of splenic abnormalities significant extracardiac structural anomalies in 29 necrop- sied patients. Journal of Pediatrics, 8i, I130. in sibships has been reported in four instances: Freedom, R. M., and Treves, S. (I973). Splenic scintigraphy Polhemus and Schafer (1952) reported 2 sibs of and radionucide venography in the heterotaxy syndrome. whom one had asplenia and one polysplenia; in Radiology, 107, 38I. Ruttenberg et al.'s series (I964) 3 sibs with asplenia Haldane, J. B. S., and Smith, C. A. B. (I948). A simple exact test for birth-order effect. Annals of Eugenics, 14, I I7. were born in one family; Schonfeld and Frischman Ivemark, B. I. (I955). Implications of agenesis ofthe spleen on (I958) reported a case of asplenia in the offspring the pathogenesis of conotruncus anomalies in childhood: of a consanguineous marriage who had 3 out of 4 analysis of the heart malformations in splenic agenesis sibs with multiple congenital abnormalities; and syndrome, with fourteen new cases. Acta Paediatrica, 44, Suppl. 104, I. Silver, Steier, and Chandra (I972) reported a Kessler, H., and Smulewicz, J. J. (1973). Microgastria assoc- family in which there was one case of asplenia and iated with agenesis of the spleen. Radiology, 107, 393. Br Heart J: first published as 10.1136/hrt.37.8.840 on 1 August 1975. Downloaded from

852 Rose, Izukawa, and MoFs

Landing, B. H., Lawrence, T. K., Payne, V. C., Jr., and Wells, Shah, K. D., Neill, C. A., Wagner, H. N., and Taussig, H. B. T. R. (I97i). Bronchial anatomy in syndromes with ab- (I964). Radioisotope scanning of the liver and spleen in normal visceral sitUs, abnormal spleen and congenital dextrocardia and in situs inversus with levocardia. Circula- heart disease. AmericanJournal of Cardiology, 28, 456. tion, 29, 23I. Li, C. C., and Mantel, N. (I968). A simple method of esti- Silver, W., Steier, M., and Chandra, N. (I972). Asplenia mating the segregation ratio under complete ascertain- syndrome with congenital heart disease and tetralogy of ment. American Journal of Human Genetics, 20, 6i. Fallot in siblings. AmericanJournal ofCardiology, 30, 9I. Moller, J. H., Nakib, A., Anderson, R. C., and Edwards, J. E. Simpson, J., and Zellweger, H. (1973). Case report. (I967). Congenital cardiac disease associated with poly- Familial occurrence of Ivemark syndrome with splenic splenia: a developmental complex of bilateral 'leftsided- hypoplasia and asplenia in sibs. Journal of Clinical Gen- ness'. Circulation, 36, 789. etics, I0, 303. Momma, K., and Linde, L. M. (1970). Cardiac rhythms in van der Horst, R. L., and Gotsman, M. S. (I972). Abnormali- dextrocardia. AmericanJournal of Cardiology, 25, 420. ties of atrial depolarization in infradiaphragmatic inter- Nora, J. J. (I97i). Etiologic factors in congenital heart diseases. ruption of inferior vena cava. British Heart Journal, 34, In Symposium in Pediatric Cardiology. Pediatric Clinics of 295. North America, I8, 1059. Van Mierop, L. H. S., Gessner, I. H., and Schiebler, G. L. Padmanabhan, J., Risemberg, H. M., and Rowe, R. D. (I973). (I972). Asplenia and polysplenia syndrome. Birth De- Howell-Jolly bodies in the peripheral blood of full-term fects: Original Article Series VIII (I), 74. and premature neonates. Johns Hopkins Medical Journal, Van Praagh, R. (I972). The segmental approach to diagnosis 132, 146. in congenital heart disease. Birth Defects: Original Article Polhemus, D. W., and Schafer, W. B. (1952). Congenital Series VIII (I), 4. absence of the spleen: syndrome with atrioventricularis Van Praagh, R., Van Praagh. S., Vlad, P., and Keith, J. D. and situs inversus. Pediatrics, 9, 696. (I964). Anatomic types of congenital dextrocardia, diag- Polhemus, D. W., and Schafer, W. B. (I955). Congenital nostic and embryologic implications. American J7ournal of absence of the spleen. Pediatrics, I6, 495. Cardiology, 13, 5I0. Putschar, W. G., and Manion, W. C. (1956). Congenital Van Praagh, R., Van Praagh, S., Vlad, P., and Keith, J. D. absence of the spleen and associated anomalies. American (I965). Diagnosis of the anatomic types of congenital Journal of Clinical Pathology, 26, 429. dextrocardia. American Journal of Cardiology, 15, 234. Registrar-General of Ontario (I966). Vital Statistics for I966. Warburton, D., and Fraser, F. C. (I964). Spontaneous abor- Province of Ontario. Frank Fogg, Queen's Printer. tion risks in man: data from the reproductive histories Ruttenberg, H. D., Neufeld, H. N., Lucas, R. V., Jr., Carey, collected in a medical genetics unit. American Journal of L. S., Adams, P., Jr., Anderson, R. C., and Edwards, J. E. Human Genetics, I6, i. (I964). Syndrome of congenital cardiac disease with asplenia: distinction from other forms of congenital heart disease. American)Journal ofCardiology, 13, 387. Requests for reprints to Dr. Vera Rose, Division of Schonfeld, E. A., and Frischman, B. (I958). Syndrome of Cardiology, The Hospital for Sick Children, 555 spleen agenesis, defects of the heart and vessels and situs University Avenue, Toronto M5G iX8, Ontario, http://heart.bmj.com/ inversus. Helvetica Paediatrica Acta, 13, 636. Canada. on September 30, 2021 by guest. Protected copyright.