Synonyms:  Levoisomerism, car­dio­splenic syndrome, heterotaxy.

Definition: Disorder characterized by complex congenital cardiac malformations, splenic dysgenesis, and a tendency toward symmetric development of normally asymmetric organs (isomerism). In polysplenia there is a tendency for bilateral left-sidedness.

Classification: The cardiosplenic syndromes are subdivided by splenic morphology and include polysplenia syndrome “bilateral left-sidedness” and asplenia syndrome bilateral right-sidedness” (Ivemark syndrome).

Prevalence:  Rare, but no data regarding the incidence of poly­splenia syndrome are available. The prevalence of polysple­nia in a series of cases of cardiac malposition undergoing autopsy was 26%¹.

Associated anomalies: The cardiac anomalies are mainly shunting anomalies such as atrial septal defect, endocardial cushion defect, bilateral left atrium, partial anomalous venous return (to the ipsilateral atrium), ventricular septal defects, double outlet right ventricle and pulmonary stenosis. Carpenter syndrome (acrocephalo­polydactyly) has been associated with accessory spleens^2,3. There are fewer and more benign anomalies than in asplenia, and 5-10% of infants may have no associated anomalies.

Etiology: Multifactorial, except for reports of familial clustering of polysplenia syndrome which support an autosomal recessive form of inheritance^4,5. Two other reports suggest an autosomal dominant inheritance^6,7.

Pathogenesis: A variety of explanations for the splenic and/or situs abnormalities have been proposed: 1) unspecified teratogenic insult^8-11, 2) aberrant expression of left isomerism¹², 3) mechanical vascular disturbance leading to splenic dysgenesis¹³, 4) the concept of the midline as a “developmental field”¹⁴.

Clinical features: Acyanosis is the rule in polysplenia .

Prognosis: Depends on the severity of the cardiac anomalies, but even with surgical correction or palliation the one-year survival rate is approximately 50%¹⁵. The association of congenital heart block with polysplenia has a particularly poor prognosis^16,17.

Diagnosis:  The prenatal diagnosis is suggested by the presence of complex congenital heart disease associated with situs ambiguous^16,18,19.

Differential diagnosis:  Other abnormalities of situs must be differentiated from polysplenia. The isolated presence of an accessory spleen has also been reported.

Obstetric management: Prior to fetal viability, pregnancy termination may be offered. Delivery in a tertiary care setting is recommended.

MESH Spleen BDE 0092 (asplenia) MIM 208530 ICD9 759.0 CDC 759.000

Address correspondence to Rudolph P. Fedrizzi, MD, Vanderbilt University Medical Center, Dept. of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, 21^st and Garland, Nashville, TN 37232-2519. Ph: 615-343-3447 Fax: 615-383-9386. ¶Dept. of Radiology

Introduction

Congenital heart defects occur with an estimated frequency of 40-80:10,000 live births²⁰. The majority of cases have a multifactorial origin, with less than 5% of cardiac defects estimated to result from a single gene defect²¹. Prenatal ultrasonography, fetal echocardiography and color flow Doppler techniques allow antenatal recognition and characterization of most cardiac anomalies²². This report contributes two additional cases of antenatally diagnosed polysplenia syndrome and reviews the literature.

Case #1

A 26-year-old healthy G₄P₂₀₁₂ was referred at 31 weeks gestation for suspected hydrops and persistent fetal bradycardia of 60 beats per minute (bpm). The ultrasound evaluation (fig. 1-4) revealed severe fetal hydrops, mild hydramnios, no identifiable spleen, hypoplastic thorax, complete heart block with a ventricular rate of 45 bpm, a large ventricular septal defect with an endocardial cushion defect, possible single atrium, interrupted inferior vena cava and a single umbilical artery. The liver was midline and a horseshoe kidney was visible. The patient subsequently underwent induction of labor with vaginal delivery of a stillborn female.

Fig. 1: Dextrocardia with malposition of the stomach on the right side. The apex of the heart (arrow) is on the same side as the stomach. A complete form of endocardial cushion defect is noted, with a single atrium.

Fig. 2: The pulmonary artery is enlarged.

Fig. 3: A large midline liver is visible.

Fig. 4: A horseshoe kidney is seen with the isthmus in front of the great vessels.

Autopsy

The autopsy revealed poly­splenia with multiple splenules in the retroperitoneum of the right upper quadrant. Bilateral hypoplastic bilobate lungs with bilateral mor­phologically left bronchi, central liver with agenesis of the gallbladder, and complete malrotation of the gastrointestinal tract were also present. The cardiac malformations included mirror-image dextrocardia with a single atrium with bilateral superior venae cavae and anomalous pulmonary venous return. The tricuspid valve was dysplastic. Poststenotic dilatation of the pulmonary artery was also present. The hepatic portion of the inferior vena cava was absent with azygos  continuation of systemic venous return.

Case #2

A 31-year-old G₁P₀ was referred at 37 weeks gestation for fetal dextrocardia and suspected complex cardiac defect. Ultrasound evaluation revealed dextrocardia, a complete endocardial cushion defect, a probable truncus defect and a right-sided descending aorta. The stomach was right-sided, no fetal spleen was visualized and a pelvic kidney was present. Percutaneous umbilical blood sampling revealed a 46,XY karyotype. Delivery was performed by primary cesarean section at 40 weeks because of an unfavorable cervix and non-reassuring antepartum fetal surveillance. The 3536g newborn had Apgars of 9 at 1 and 10 minutes, respectively. On the second day of life, cardiac catheterization revealed a common atrium, interrupted inferior vena cava with azygos continuation to the left superior vena cava, a common atrioventricular valve, aortic stenosis, a large patent ductus arteriosus and a large main pulmonary artery. Abdominal ultrasound revealed retrogastric tissue consistent with multiple splen­ules, visceral situs inversus, and a horseshoe kidney. No promising corrective surgical options were felt to be available, and only supportive care was provided. The neonate died on the sixth day of life. The family declined autopsy.

Discussion

Definition

The cardiosplenic syndromes are characterized by complex congenital cardiac disease, splenic dysgenesis or aplasia, and a tendency toward symmetrical development of normally asymmetric organs. Isomerism is the term used to describe this abnormal arrangement of the visceral organs. This tendency toward isomerism explains why the cardiosplenic syndromes are considered conditions of “situs ambiguous”¹².

Classification

Polysplenia syndrome can be considered a condition of left isomerism (bilateral left-sidedness). Typically, multiple splenic masses are present along with bilateral bilobate lungs with bilateral hyparterial bronchi (bronchus passing below the pulmonary artery), and interruption of the inferior vena cava with venous drainage through the azygos  system. The most common cardiac anomalies include ventriculoseptal defects, bilateral superior venae cavae, endocardial cushion defects, partial anomalous pulmonary venous return and left ventricular outflow obstruction^4,23-25.

By contrast, asplenia syndrome is a syndrome of right-isomerism. It is characterized by splenic agenesis, bilateral trilobed lungs with eparterial bronchi (bronchus passing above the pulmonary artery), bilateral superior venae cavae with right atrial isomerism, and a relationship whereby the aorta and inferior vena cava occupy the same side of the spine. In addition, transposition of the great vessels, severe pulmonary stenosis or atresia, and anomalous pulmonary venous return are common^4,8,12,25-27.

 Both disorders share other abnormalities including abdominal heterotaxia and gastrointestinal malrotation. Genitourinary and central nervous system anomalies are uncommon.

Prevalence

The cardiosplenic syndromes are rare. Asplenia has been estimated to occur in 0.25:10,000 live births⁴ and 1:1750 autopsy examinations¹⁰. No similar incidence data are available for polysplenia. The prevalence of polysplenia in a series of cardiac malpositions undergoing autopsy was 26%¹. Polysplenia appears to occur with equal frequency in both sexes, while there is a nearly 2:1 male predominance for asplenia^4,12,23,24.

Associated anomalies

Carpenter syndrome (acrocephalopolydactyly) has been associated with accessory spleens^2,3.

Etiology

Most cases are sporadic and felt to be multifactorial in origin. Familial clustering of polysplenia syndrome has been reported and supports an autosomal recessive mode of inheritance^4,5. A single recessive gene in a mouse model has been demonstrated to result in cardiovascular anomalies and situs inversus²⁸. One report of asplenia and polysplenia complex in siblings with situs inversus totalis in a parent supports autosomal dominant inheritance⁷. Another report of two first cousins with polysplenia suggests that inheritance may follow a pattern of autosomal dominance with incomplete penetrance⁶. A recent report of 12 fetuses with cardio-splenic syndrome who had prenatal karyotyping revealed no cases of aneuploidy²⁹.

Pathogenesis

Although described separately, the cardiosplenic syndromes are probably best considered as different manifestations of the same embryopathy^{12,14,18,24,30}. The human spleen first appears embryologically at approximately 36 days gestation. Septation of the conotruncus, lobulation of the lung and rotation of the gut all occur at that time as well. It has been proposed that a teratogenic insult during the 31^st-36^th days could account for the constellation of defects observed^8-11.

Another proposal suggested that the abnormal expression of right- or left-isomerism leads to an abnormality or absence of contralateral structures, although no explanation of the actual mechanism for this was offered¹². The presence of the cardiosplenic syndrome in a case of hypoplastic ectopic spleen and attenuated splenic artery led Monie to conclude that dysgenesis of the spleen is a secondary result of a mechanical vascular disturbance resulting from isomerism¹³.

Finally, Opitz and Gilbert proposed the concept of the midline as a “developmental field” in which the development of visceral laterality is determined in a controlled, spatially and temporally coordinated manner ¹⁴.

Pathology—clinical features

Acyanosis at birth is typical of polysplenia, whereas cyanosis is the rule in asplenia due to pulmonary outflow obstruction from stenosis or atresia. The presence of Howell-Jolly or Heinz bodies in peripheral erythrocytes is strongly suggestive of splenic absence¹². There is no similar clinical marker for polysplenia. Angiocardiographic, echocardiogra­phic, and radiologic techniques allow for thorough, non-surgical neonatal assessment of the characteristic anomalies of polysplenia syndrome.

Prognosis

Polysplenia has a somewhat better prognosis than asplenia, given that its cardiac anomalies are typically less complex. In a review of 146 cases 50% died by four months and 25% survived beyond five years. Only 10% lived to adolescence²³. A combined series of cases of cardiosplenic syndrome undergoing surgical correction or palliation revealed the one-year survival rate to be approximately 50%¹⁵. As in our first case, the association of congenital complete heart block with polysplenia has a particularly poor prognosis with mortality exceeding 90%^16,17.

Diagnosis

The fetal spleen can usually be detected by 18-20 weeks gestation in the left gastrorenal angle. Nomograms of splenic dimensions have been published^31,32. However, the absence of the fetal spleen or the presence of multiple splenules on antenatal ultrasonographic examination is very difficult to perceive. Instead, the prenatal diagnosis of polysplenia is suggested by the association of complex congenital heart disease and situs ambiguous^9,16,34,35. The relationship among the inferior vena cava, aorta, and spine displayed by ultrasonography has been shown to be a reliable method to diagnose situs in the newborn²¹. This technique can be applied to the fetus in utero as well. Normally, the aorta lies to the left of the spine and the inferior vena cava lies to the right. The diagnosis of situs inversus is made when the mirror image of the normal pattern is seen. Right isomerism is suggested when the aorta and vena cava are found together on the same side of the spine. Particular to the diagnosis of polysplenia syndrome is the demonstration of inferior vena caval interruption with azygos continuation²¹. Fetal echocardiography and color flow Doppler techniques facilitate in utero imaging of vascular structures and can identify anomalies of systemic and pulmonary venous return common in polysplenia^16,19,21,33. It has been suggested that an effort should be made to demonstrate the spleen in every fetus with a complex cardiac malformation or dysrhythmia (especially complete heart block)¹⁸.

Differential diagnosis

Several entities share characteristics with the polysplenia syndrome. As noted earlier, asplenia syndrome is the most similar related condition of situs ambiguous. The isolated findings of thoracic isomerism and visceral heterotaxia without associated cardiac anomalies have also been described. Dextrocardia or mesocardia refer to the location of the cardiac apex and may not be associated with cardiac disease or abnormalities of corporal situs²⁵. The isolated presence of an accessory spleen has also been described.

Obstetric management

Prior to fetal viability, pregnancy termination can be offered. Delivery in a tertiary care center with immediate access to a pediatric cardiology specialist offers the best opportunity to maximize perinatal outcome.

References

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