ASPLENIA WITH CARDIOVASCULAR ANOMALIES
IVEMARK SYNDROME POLYSPLENIA SYNDROME, INCLUDED
HETEROTAXY, VISCEROATRIAL, AUTOSOMAL RECESSIVE, INCLUDED
POLYASPLENIA, INCLUDED
VAH, AUTOSOMAL RECESSIVE, INCLUDED
RAI
Right atrial isomerism is a severe complex congenital heart defect resulting from embryonic disruption of proper left-right axis determination. RAI is usually characterized by complete atrioventricular septal defect with a common atrium and univentricular AV connection, total anomalous ... Right atrial isomerism is a severe complex congenital heart defect resulting from embryonic disruption of proper left-right axis determination. RAI is usually characterized by complete atrioventricular septal defect with a common atrium and univentricular AV connection, total anomalous pulmonary drainage, and transposition or malposition of the great arteries. Affected individuals present at birth with severe cardiac failure. Other associated abnormalities include bilateral trilobed lungs, midline liver, and asplenia, as well as situs inversus affecting other organs. Left atrial isomerism (LAI) is a related disorder with a somewhat better prognosis. LAI is characterized by bilateral superior vena cava, interruption of the intrahepatic portion of the inferior vena cava, partial anomalous pulmonary venous drainage, and ventricular septal defect. Patients with LAI may have polysplenia and bilateral bilobed lungs, as well as situs inversus affecting other organs. Both RAI and LAI malformation complexes have classically been referred to as Ivemark syndrome (summary by Eronen et al., 2004 and Kaasinen et al., 2010).
Ivemark (1955) published a 4-part report of his investigation of the relationship between anomalies of the atrioventricular region and of the conotruncus. He noted that during embryogenesis the spleen is being formed while the heart is still in ... Ivemark (1955) published a 4-part report of his investigation of the relationship between anomalies of the atrioventricular region and of the conotruncus. He noted that during embryogenesis the spleen is being formed while the heart is still in a stage of critical modeling. By selecting cases of cardiac malformation associated with absence of a spleen, Ivemark (1955) postulated that the uniformity of the material is based upon selecting the period when organogenesis of the heart went astray, rather than on similarities in morphology of the malformed hearts. Ivemark (1955) described the pathology of the splenic agenesis syndrome and reported 14 new cases with autopsy, as well as 55 cases collected from the literature. He also reported 4 new cases of multiple or rudimentary spleens occurring with cardiovascular anomalies, and 6 examples from the literature. Simpson and Zellweger (1973) summarized various features of Ivemark syndrome. Hypoplasia of the spleen is sometimes the finding rather than aplasia. Congenital absence of the spleen is usually accompanied by complex cardiac malformations, malposition and maldevelopment of the abdominal organs, and abnormal lobation of the lungs. Heinz and Howell-Jolly bodies in the peripheral blood are hematologic signs of absent spleen. A patient with the typical asplenia syndrome had a sib who at autopsy showed multiple accessory spleens, persistent atrioventricularis communis and partial transposition of the abdominal viscera (Polhemus and Schafer, 1952). In another family, 3 sibs had asplenia with cyanotic heart disease (Ruttenberg et al., 1964). Chen and Monteleone (1977) reported 2 affected boys in one family and 2 first cousins in another. Overall empiric recurrence risk after birth of a single case is probably on the order of 5% or less. Hurwitz and Caskey (1982) reported affected brothers, bringing to 8 the number of families with multiple affected sibs. Congenital heart malformation and septicemia were features. They also reported an instance of parental consanguinity, bringing to 4 the number of such instances. They identified 32 cases among 4,059 autopsies done in a period of 21 years in the Texas Children's Hospital. All were seemingly sporadic. A male excess was noted in both familial and autopsy cases. The authors favored autosomal recessive inheritance with male preponderance. The designation polysplenia syndrome is used for a complex association of abnormalities of the spleen and of visceral lateralization with congenital heart malformations (Moller et al., 1967; Rose et al., 1975). Visceral and cardiac situs may be disparate--so-called situs ambiguus. Polysplenia suggests bilateral 'left-sidedness' (Moller et al., 1967) and mirror imaging of the lungs is frequent such that both lungs have the appearance of the left lung, with 2 lobes and hyparterial bronchi. Anomalous pulmonary venous return is frequent. The hepatic segment of the inferior vena cava is often missing. Return of blood from the lower part of the body is by the azygous or hemiazygous system, a venous defect that occurs almost only in this syndrome. Cardiac defects include atrial and ventricular septal defects, pulmonic stenosis, endocardial cushion defects, and others. Gatrad et al. (1984) described consanguinity with complex cardiac anomalies with situs ambiguus. Rose et al. (1975) reported 2 sisters with the polysplenia syndrome, and Hallett et al. (1979) described 2 affected brothers. Arnold et al. (1983) reported an Amish family in which 5 persons in 2 generations showed congenital cardiac and visceral defects consistent with the polysplenia syndrome. The parents of 4 affected sibs were fourth cousins; a deceased sister of the father was affected. Families in which 1 person had the developmental complex with polysplenia and another person had it with asplenia (Polhemus and Schafer, 1952; Zlotogora and Elian, 1981; Niikawa et al., 1983) suggest that the asplenia and polysplenia syndromes are a single entity. Asplenia and polysplenia have similar cardiac anomalies, although asplenia tends to be associated with severe atrioventricular canal malformations and marked deficiency of the interventricular septum whereas with polysplenia the AV canal defects are usually less severe and there are greater abnormalities of the interatrial septum (Hutchins et al., 1983). De la Monte and Hutchins (1985) reported sisters with polysplenia syndrome. Affected sibs were also reported by Arnold et al. (1983), Hallett et al. (1979), Niikawa et al. (1983), and Kawagoe et al. (1980). Czeizel (1987) described 4 affected sibs among the offspring of a gypsy couple who were first cousins. One of the 4 had transposition of the great vessels. A second had a ventricular septal defect and an atrial septal defect, and a third had truncus communis and atrial septal defect (ASD). All showed intrauterine growth retardation. Distefano et al. (1987) described 2 sibs, born to consanguineous Sicilian parents, who died of severe congenital heart disease. Both the brother and the sister had dextrocardia; however, only the girl had situs viscerum inversus. At necropsy she had a right spleen and right pulmonary isomerism (3 lobes in each lung, as commonly found in the asplenia syndrome). Thus, isolated dextrocardia, situs viscerum inversus, and the asplenia-polysplenia complex may be part of a single dysmorphogenetic process. Rodriguez et al. (1991) reported a patient with polyasplenia and caudal deficiency including imperforate anus, ambiguous external genitalia, multiple contractures of the lower limbs with short femora, and agenesis of the corpus callosum. Although this patient apparently represents the first recognized case of agenesis of the corpus callosum in association with polyasplenia and caudal deficiency, the literature on 7 additional patients with polyasplenia and caudal deficiency was reviewed. The association of a laterality sequence with caudal deficiency may represent a distinct autosomal recessive entity. Cesko et al. (1997) described 2 sibs with Ivemark syndrome. In both cases, absent spleen, symmetric liver, and trilobed lungs were associated with complex cardiac malformations. In the first infant, minor facial abnormalities were noted, including hypertelorism, low-set ears, and choanal stenosis. In the second case, the syndrome was diagnosed prenatally by fetal echocardiography at 20 weeks. Cesko et al. (1997) noted that fetal echocardiography is an effective means of prenatal detection of Ivemark syndrome. Eronen et al. (2004) described a nonconsanguineous Finnish family in which 4 consecutive children, 1 female and 3 males, had right atrial isomerism. All 4 succumbed and underwent autopsy. Heart defects included single ventricle with dysplastic atrioventricular valve, total anomalous pulmonary venous drainage, and malposition of the great arteries with pulmonary stenosis. All had asplenia, large transverse liver located in the midline, and bilaterally trilobed lungs; 2 also had dextrocardia and abdominal situs inversus. Two sibs had no surgery and died as newborns; 2 had cardiac surgery and died before 2 years of age. No signs of cardiac or abdominal laterality defects were found in either parent.
Right atrial isomerism (RAI) is a heterotaxy syndrome with disturbances in left-right axis development, resulting in complex heart malformations and abnormal lateralization of other thoracic and abdominal organs. Using linkage analysis and a positional candidate gene approach, Kaasinen ... Right atrial isomerism (RAI) is a heterotaxy syndrome with disturbances in left-right axis development, resulting in complex heart malformations and abnormal lateralization of other thoracic and abdominal organs. Using linkage analysis and a positional candidate gene approach, Kaasinen et al. (2010) found compound heterozygosity for truncating mutations in the growth/differentiation factor-1 gene (GDF1; 602880.0001, 602880.0004) in 5 sibs with RAI. The family had been described by Eronen et al. (2004). Individuals heterozygous for the mutations were clinically healthy.