Right Atrial Isomerism

A number sign (#) is used with this entry because of evidence that right atrial isomerism (RAI) is caused by homozygous mutation in the GDF1 gene (602880) on chromosome 19p12.

Description

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).

Clinical Features

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.

Cytogenetics

Freeman et al. (1996) described a 6-year-old girl with a balanced 11;20 translocation (46,XX,t(11;20)(q13.1;q13.13)pat), asplenia, pulmonic stenosis, Hirschsprung disease, minor anomalies, and mental retardation. Fukushima et al. (1993) also reported an individual with situs abnormalities and a balanced chromosome rearrangement involving a breakpoint at 11q13. Freeman et al. (1996) stated that PCR analysis of microsatellite markers excluded uniparental disomy for chromosomes 11 and 20. Segregation analysis of markers in the 11q13 region in the proposita and her phenotypically normal carrier sibs did not show a unique combination of maternal and paternal alleles in the patient. Freeman et al. (1996) discussed several possible explanations for the simultaneous occurrence of situs abnormalities and a balanced 11;20 translocation: chance, further chromosome rearrangement in the patient, gene disruption and random situs determination, and gene disruption plus transmission of a recessive or imprinted allele from the mother.

Inheritance

Parental consanguinity in 3 families and 4 instances of multiple affected sibs (Simpson and Zellweger, 1973) supported autosomal recessive inheritance. The authors noted that most cases are sporadic.

Molecular Genetics

Using linkage analysis and a candidate gene approach, Kaasinen et al. (2010) identified compound heterozygosity for a nonsense mutation (C227X; 602880.0001) and a 1-bp insertion (602880.0004) in the GDF1 gene in 5 affected sibs from a Finnish family with RAI who were originally described by Eronen et al. (2004). The sibs' unaffected parents and 3 unaffected maternal aunts were each heterozygous for 1 of the mutations. The nonsense and frameshift mutations were found in heterozygosity in Finnish blood donors at a frequency of 1 and 2 in 346, respectively, and the nonsense mutation was also present in 1 of 271 UK Caucasian blood donors.

In a cohort of 2,871 probands with congenital heart disease, comprising 2,645 parent-offspring trios and 226 singletons, Jin et al. (2017) performed whole-exome sequencing and identified 1 proband (1-05386) with right isomerism who was compound heterozygous for mutations in the GDF1 gene: the C227X mutation and a 4-bp deletion (602880.0005). The patient exhibited abdominal heterotaxy and asplenia as well as multiple cardiac anomalies, including dextrocardia, double-outlet right ventricle, obstructed total anomalous pulmonary venous return, valvular and subvalvular pulmonary stenosis, persistent left superior vena cava, right-dominant atrioventricular canal, common atrium, and single ventricle.

History

In 6 children in whom orthotopic cardiac transplantation had been performed for severe visceroatrial heterotaxia, Britz-Cunningham et al. (1995) found mutations in the gene encoding connexin-43 (CX43; 121014). Four of 6 patients were compound heterozygotes for CX43 mutations, indicating autosomal recessive inheritance. However, several groups were unable to find CX43 mutations in patients with heterotaxy. Gebbia et al. (1996) studied a total of 38 cases of sporadic and familial heterotaxy and found no mutations in CX43. Splitt et al. (1997) found no mutations in 48 patients with visceroatrial heterotaxy attending U.K. Regional Paediatric Cardiology Centres. Debrus et al. (1997) screened the entire coding sequence and direct flanking sequences of the CX43 gene in a selected group of 25 patients (19 familial cases) with a wide variety of lateralization defects and cardiovascular malformations. They detected only a single-bp insertion in the 3-prime untranslated region of 1 patient. To test the possibility of mutations in other parts of the CX43 gene, the gene was located on the physical map of chromosome 6, and flanking polymorphic markers were genotyped. Haplotype analysis excluded the CX43 gene locus in nearly all of the familial cases of lateralization defects. Thus, the results of did not support the suggestion that this gene is implicated in human autosomal recessive lateralization defects. On the basis of analysis in the 3 previous reports and in 11 patients of their own, Toth et al. (1998) concluded that 'it is more and more likely that the results reported by Britz-Cunningham et al. (1995) were a laboratory artifact.' There had been a total of 78 cases of heterotaxy in which no CX43 mutation could be found in the 200 basepairs containing all of the nucleotide changes reported by Britz-Cunningham et al. (1995).