DEXTROCARDIA WITH OTHER CARDIAC MALFORMATIONS
CHTD1, INCLUDED
LATERALITY, X-LINKED
SITUS INVERSUS, COMPLEX CARDIAC DEFECTS, AND SPLENIC DEFECTS, X-LINKED CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 1, X-LINKED, INCLUDED
HTX1
Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs ... - Heterotaxy Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder. - Multiple Types of Congenital Heart Defects Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions (summary by van de Meerakker et al., 2011). - Genetic Heterogeneity of Visceral Heterotaxy See also HTX2 (605376), caused by mutation in the CFC1 gene (605194) on chromosome 2q21.1; HTX3 (606325), which maps to chromosome 6q21; HTX4 (613751), caused by mutation in the ACVR2B gene (602730) on chromosome 3p22.1-p21.3; HTX5 (270100), caused by mutation in the NODAL gene (601265) on chromosome 10q22.1; and HTX6 (614779), caused by mutation in the CCDC11 gene (614759) on chromosome 18q. - Genetic Heterogeneity of Multiple Types of Congenital Heart Defects An X-linked form of CHTD, CHTD1, is caused by mutation in the ZIC3 gene on chromosome Xq26.2. CHTD2 is caused by mutation in the TAB2 gene (605101) on chromosome 6q25. A form of nonsyndromic congenital heart defects associated with cardiac rhythm and conduction disturbances (CHTD3; 614954) has been mapped to chromosome 9q.
Mathias et al. (1987) described a black family in which 9 males in 2 generations had variable expression of altered laterality of visceral organs inherited in an X-linked recessive pattern. Eight males had complex congenital heart defects, including ... Mathias et al. (1987) described a black family in which 9 males in 2 generations had variable expression of altered laterality of visceral organs inherited in an X-linked recessive pattern. Eight males had complex congenital heart defects, including various manifestations of dextrocardia, ventricular septal defect (VSD), atrial septal defect (ASD), patent ductus arteriosus (PDA), transposition of the great arteries (TGA), valvular stenosis, and pulmonary artery hypoplasia. Four patients were reported as having complete situs inversus affecting the heart and visceral organs. Two patients had polysplenia and 2 had asplenia. Other less common features included sacral agenesis, extrahepatic biliary atresia, duodenal atresia, and posteriorly placed anus. In the preceding generation, 4 males were said to have been similarly affected. Eleven of the affected individuals died before age 2 years. Mathias et al. (1987) concluded that the anomalies resulted from an inability of the embryo to establish normal left-right axis asymmetry during development. In a follow-up of the family reported by Mathias et al. (1987), Casey et al. (1993) reported that 3 of the affected males were living, whereas the remainder died by 3 years of age, usually due to complications of cardiac malformations. Ciliary structure and function were normal, as were chromosome studies. All but one of the affected males had congenital heart disease, and all but one of the affected males manifested alterations of visceral situs, including asplenia or polysplenia, symmetric liver, intestinal malrotation, and abnormal lung lobation. Other midline malformations identified were sacral agenesis, posteriorly placed anus, rectal stenosis, meningomyelocele, cerebellar hypoplasia, and arhinencephaly. None of the 8 living obligate carrier females and none of their 7 presumably unaffected sons exhibited signs or symptoms of heterotaxy. Soltan and Li (1974) reported a large kindred in which 4 males in 3 sibships had dextrocardia. One had corrected transposition of great arteries, ventricular septal defect and patent ductus arteriosus. A second had corrected transposition of the great arteries and VSD that closed spontaneously; a third had situs inversus viscerum, VSD, and pulmonic stenosis. The pedigree suggested X-linked recessive inheritance. Mikkila et al. (1994) described X-linked laterality defects in 2 male cousins. One infant had a large atrial septal defect, anomalous inferior vena cava, and atresia of the extrahepatic bile ducts. He died at age 7.5 months due to cardiac and hepatic insufficiency. Postmortem examination showed nonrotation of the intestines, polysplenia, and absence of the coccyx. The cousin showed oligohydramnios at 21 weeks' gestation and the pregnancy was terminated. Postmortem examination showed bilobed right lung, atrial septal defect, agenesis of both kidneys and ureters, malrotation of the intestines, and imperforate anus. Both mothers, who were sisters, and the grandmother had a uterine septum and mild hypertelorism, which the authors suggested may have represented gene carrier manifestations. Chhin et al. (2007) reported a brother and sister with X-linked visceral heterotaxy. The brother had dextro-looped transposition of the great arteries (D-TGA), single ventricle, pulmonary atresia, and polysplenia, whereas his affected sister had D-TGA, pulmonary and mitral atresia, and asplenia. Molecular analysis identified a mutation in the ZIC3 gene (300265.0009). The unaffected mother was a carrier. X-inactivation studies showed that the affected sister had skewed X-inactivation favoring expression of the mutant allele.
Megarbane et al. (2000) reported a Lebanese family in which 2 maternal cousins died very early in life from transposition of the great arteries associated with 1 or several other cardiac defects. Various minor midline defects were also ... Megarbane et al. (2000) reported a Lebanese family in which 2 maternal cousins died very early in life from transposition of the great arteries associated with 1 or several other cardiac defects. Various minor midline defects were also observed, including hypertelorism and broad nasal base, but there were no situs abnormalities other than a persistent left superior vena cava in 1 cousin. Specifically, there were no spleen, lung, or cerebromeningeal defects. A maternal uncle of these 2 babies was born cyanotic and died on the third postnatal day. Both infants were found to have a mutation in the ZIC3 gene (300265.0003) which was predicted to have some residual activity. Another unaffected maternal uncle was found to have the mutation, suggesting incomplete penetrance. The authors noted that this was the first case of incomplete penetrance in a male carrier of a chromosome X mutation ever reported. Megarbane et al. (2000) suggested that the TGA observed in these infants was a left-right body axis defect confined to the heart and noted that previous reports indicated intrafamilial variability of the situs defect.
In affected members of the family with X-linked heterotaxy originally reported by Mathias et al. (1987), Gebbia et al. (1997) identified a heterozygous mutation in the ZIC3 gene (300265.0001). They identified 4 different mutations in the ZIC3 (see, ... In affected members of the family with X-linked heterotaxy originally reported by Mathias et al. (1987), Gebbia et al. (1997) identified a heterozygous mutation in the ZIC3 gene (300265.0001). They identified 4 different mutations in the ZIC3 (see, e.g., 300265.0002 and 300265.0008) in 4 other families with X-linked heterotaxy. Ware et al. (2004) screened the coding region of the ZIC3 gene in 194 unrelated patients, including 61 patients with classic heterotaxy, 93 patients with heart defects characteristic of heterotaxy, and 11 patients with situs inversus totalis. They identified 5 novel ZIC3 mutations in 3 classic heterotaxy kindreds (see, e.g., 300365.0004-300365.0005). They also identified a ZIC3 mutation in a female patient with sporadic heterotaxy limited to the heart (300265.0006) as well as in a patient with atrial septal defect and pulmonic stenosis, but no other heterotaxic malformations (300265.0007). Ware et al. (2004) concluded that the phenotypic spectrum of ZIC3 mutations should be expanded to include affected females and congenital heart defects not typical for heterotaxy. Screening of a cohort of patients with sporadic heterotaxy indicated that ZIC3 mutations account for approximately 1% of affected individuals. - Associations Pending Confirmation For discussion of a possible relationship between variation in the SMAD2 gene and heterotaxy, see 601366.0001-601366.0002.