Heterotaxy and Isomerism (Situs Ambiguus)

A spectrum of laterality defects in which the thoracoabdominal organs are abnormally arranged across the left–right axis, corresponding neither to situs solitus nor to situs inversus totalis, with complex congenital heart disease, splenic anomalies, intestinal malrotation and, in some cases, ciliary dysfunction; heterogeneous aetiology, with X-linked ZIC3, NODAL pathway genes and genes of the left–right organiser and motile cilia.

Literature and regulatory information updated: 17 October 2026.

0. Initial Reference Table

1. Introduction

1.1. The left–right axis and situs terminology

The human body is externally almost symmetrical, but the arrangement of the thoracic and abdominal organs is asymmetrical and constant: in situs solitus the heart, spleen and stomach lie on the left, while the liver and gallbladder are on the right [26]. The left–right axis of the embryo is defined after the rostrocaudal and dorsoventral axes have been established, and rightward looping of the heart tube is the first morphological sign of this asymmetry [26]. The heart is the first organ to express laterality, which explains the association between heterotaxy and congenital heart disease and the systemic nature of the defect [18]. When the arrangement of all organs is mirror-reversed, the term situs inversus totalis is used, which occurs in about 1 in 10,000 individuals, generally without physiological consequences, according to the Oxford Desk Reference: Clinical Genetics and Genomics (Oxford Desk Reference) and GeneReviews, although with an incidence of congenital heart disease of 3–9%, compared with 0.7% in situs solitus [17, 26]. Between these two extremes lies situs ambiguus, or visceral heterotaxy, in which the situs of the different asymmetrical organs is discordant [18, 26].

The Nomenclature Working Group of the International Society for Nomenclature of Paediatric and Congenital Heart Disease, responsible for the International Paediatric and Congenital Cardiac Code (IPCCC), defined heterotaxy as synonymous with «visceral heterotaxy» and «heterotaxy syndrome» and characterised it as an abnormality in which the internal thoracoabdominal organs show an abnormal arrangement across the left–right axis of the body, excluding by definition situs solitus and situs inversus [3]. In the same document, situs ambiguus is defined as the coexistence, in the same person, of components of situs solitus and situs inversus [3]. The 2022 North American multidisciplinary consensus uses the term heterotaxy (HTX) for all laterality defects except situs inversus totalis, including abdominal situs inversus, polysplenia with interrupted inferior vena cava and isolated laterality defects in diseases that affect the axis, such as polysplenia or malrotation in primary ciliary dyskinesia (PCD) [18]. The PCD GeneReviews emphasises that «heterotaxy» and «situs ambiguus» are not always used as synonyms and that the clinical classification distinguishes asplenia, polysplenia, predominant right bilateralism (right isomerism) and predominant left bilateralism (left isomerism) [17].

1.2. Right isomerism and left isomerism

The term isomerism designates the presence of morphologically right, or morphologically left, structures on both sides of the body [18]. In the heart, isomerism is identified by the atrial appendages: the left appendage is narrow and tubular, the right is triangular and broad-based [18]. Right isomerism (asplenia syndrome, Ivemark syndrome, right bilateralism sequence) reflects bilaterally «right» signalling in early development and is associated with two morphologically right atria, two trilobed lungs with eparterial bronchi, an absent or hypoplastic spleen and invariably complex heart disease [6, 18, 26]. Left isomerism (polysplenia syndrome, left bilateralism sequence) reflects bilaterally «left» signalling, with two morphologically left atria, two bilobed lungs with hyparterial bronchi, multiple spleens and generally less severe heart disease; absence of the sinoatrial node may cause complete heart block [18, 26]. The atrial appendages are frequently discordant with the thoracoabdominal situs, so the appendages, liver, spleen and lungs must be assessed independently; classification into right or left isomerism describes tendencies and not watertight categories [18, 19]. Pulmonary isomerism is usually asymptomatic [17].

Two schools of nomenclature coexist in paediatric cardiology: the Boston school, with Van Praagh's segmental notation, and the European school, with sequential segmental analysis, which favours description of the morphology of the atrial appendages; the IPCCC document compares the two and proposes correspondences [3]. In clinical practice, a complete description of each segment (atrial situs, systemic and pulmonary venous connections, atrioventricular and ventriculoarterial connections, splenic, hepatic, gastric and bronchial anatomy) is preferable to the isolated use of a syndromic label [18].

1.3. Historical and molecular discovery milestones

The association between splenic agenesis and cardiac malformations was analysed by Biörn Ivemark in 1955, in a monograph on the pathogenesis of conotruncal anomalies in the «splenic agenesis syndrome», with 14 new cases; hence the eponym Ivemark syndrome for asplenia with right isomerism [33]. Smith's Recognizable Patterns of Human Malformation (Smith) records as a historical synonym the «triad of splenic agenesis, defects of the heart and vessels and situs inversus» and cites the series of Freedom (1972) and Van Mierop (1972) on the asplenia and polysplenia syndromes [6]. The observation, in 1977, of abnormal cilia in Kartagener syndrome first linked ciliary function to laterality, and the description, in 1987, of an X-linked laterality sequence opened the genetic route [6].

Positional cloning of ZIC3 in 1997, at a locus previously mapped to Xq26.2 by familial linkage and by a deletion in a man with situs ambiguus, identified the first gene unequivocally associated with human situs anomalies; the same frameshift allele was associated with situs inversus in some heterozygous women [34]. There followed variants in LEFTY A, now LEFTY2 in HUGO Gene Nomenclature Committee (HGNC) nomenclature, in 1999 [13, 35], in ACVR2B in the same year [36], in CFC1 in 2000 [37] and in NODAL in 2009 [38]. Exome sequencing enabled the description of MMP21 in 2015 [39, 40], PKD1L1 in 2016 [41] and, in 2022, a genetic module of the left–right organiser with CIROP, DAND5, PKD1L1 and MMP21, lost during the evolution of species whose organiser lacks motile cilia [42]. In 2025 CIROZ (formerly C1orf127) joined this module [43] and, in 2026, DAW1 was associated with heterotaxy without PCD in a single proband with a functional study [44].

1.4. Scope of the article

The article covers visceral heterotaxy in its right and left isomerism forms, the Orphanet entities ORPHA:137628, ORPHA:423712, ORPHA:649029 and ORPHA:244283, and the monogenic forms HTX1–HTX13, with the genetics, associated heart defects, asplenia and polysplenia with the respective prophylaxis, intestinal malrotation, biliary atresia and prenatal diagnosis [1, 4, 5]. Situs inversus totalis and isolated congenital asplenia (RPSA) are included as differential diagnoses [11, 12]. PCD, which also causes situs inversus and heterotaxy, congenital heart disease in general and the ZIC3-linked VACTERL phenotype are included in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Embryology of the left–right axis

In the human embryo, the left–right organiser (LRO), equivalent to the mouse node, appears in the third week of gestation [18]. It is formed by central cells («pit cells») with motile cilia lacking the central pair and radial spokes, surrounded by peripheral cells («crown cells») with immotile cilia [18]. This architecture explains a clinical observation: defects of the radial spokes or the central apparatus cause PCD without laterality defects, because these components do not exist in the cilia of the organiser [17, 18]. In the mouse, motile cilia generate a directional flow of extraembryonic fluid around the node, which concentrates left–right determinants on one side and activates asymmetrical gene expression [6]. The «two-cilia» model proposes that leftward flow is sensed by peripheral mechanosensory cilia, by a still unknown mechanism (calcium or mechanical force) [18]. The ciliary PKD1L1–PKD2 complex participates in this sensing and restricts NODAL signalling to the left lateral plate mesoderm [21].

The downstream molecular cascade is well characterised. Flow increases degradation of DAND5 mRNA (a NODAL antagonist, also called Cerl2 or Coco) on the left side, which releases the activity of NODAL, a ligand of the transforming growth factor beta (TGF-β) superfamily, in the organiser [13, 18]. NODAL activates its own expression in the left lateral plate mesoderm through the co-receptor CRIPTO (TDGF1) and the CRYPTIC protein (encoded by CFC1), with phosphorylation of SMAD2 and entry into the nucleus; LEFTY1 and LEFTY2 restrict NODAL activity; the homeobox factor PITX2, induced by NODAL on the left side, mediates asymmetrical morphogenesis, including cardiac looping [18, 20, 45]. The Wnt, planar cell polarity and hedgehog pathways also participate, and the posterior position of the cilia in the organiser depends on the non-canonical Wnt pathway and planar cell polarity [18]. In the chick embryo, activin on the right side of the primitive streak represses sonic hedgehog, whose residual expression on the left induces NODAL [6].

In 2022, analysis of genes lost during evolution in species whose organiser lacks motile cilia identified five genes for extracellular proteins, including CIROP (ciliated left–right organiser metallopeptidase), expressed specifically in ciliated organisers; in zebrafish and Xenopus, CIROP is required only on the left side, downstream of the flow and upstream of DAND5 [42]. The same group showed that DAND5, PKD1L1, MMP21 and CIROP form a module specific to vertebrates with motile cilia in the organiser, joined by CIROZ, an extracellular protein with a signal peptide and three ZP-N domains; inactivation of CIROZ in the mouse causes situs anomalies, but in zebrafish and Xenopus it produces no observable abnormalities [43]. This divergence between species has practical consequences: the absence of a phenotype in a non-human model does not exclude a role for a gene in human laterality [43].

Disruption of this cascade can have three outcomes: randomisation of laterality (half of cases with situs solitus and half with situs inversus, as in PCD with absent flow), consistent inversion or discordance between organs, that is, heterotaxy [19, 20]. Right bilateralism and left bilateralism have been documented in different members of the same family, indicating that both are manifestations of the same primary defect of lateralisation [6].

2.2. Genetic architecture and diagnostic yield

Heterotaxy is most frequently sporadic and without an identified cause [18]. Smith estimates that only 20% of cases are due to variants in known genes [6], and the 2022 consensus refers to at least 33 genes implicated in human situs defects, with overlap with the genes of tetralogy of Fallot, double outlet right ventricle (DORV), transposition of the great arteries (TGA) and atrioventricular septal defect (AVSD) [45]. The 2018 American Heart Association (AHA) scientific statement describes clinically relevant copy number variants (CNVs) in 15–26% of patients with heterotaxy, states that heterotaxy has the highest relative recurrence risk among the classes of congenital heart disease and that, unlike other heart defects, de novo variants are not major contributors [19]. The yield of testing depends on the population and the method, as the following table shows.

The figures are not comparable with each other. The 7.1% value of Li 2019 corresponds to a non-consanguineous cohort analysed with candidate genes, and the authors conclude that variants in established genes explain fewer than 20% of cases, with extensive locus heterogeneity and complex genetic models; they found no de novo variants [47]. Yields above 40% come from consanguineous populations, in which autosomal recessive ciliary forms predominate [50, 51]. In the French series, consanguinity was unexpectedly present in 20% of positive cases [48]. The authors of Ho 2026 place the yield of NGS between 20% and 30% [52]. A 2026 meta-analysis on genome sequencing in congenital heart disease (14 studies, 933 patients, 2000–2024) found 17.83% pathogenic or likely pathogenic single nucleotide variants, 9.83% in isolated heart disease, 22.36% in syndromic heart disease and 20% additional diagnoses after a negative microarray; this study is not specific to heterotaxy [53].

2.3. Genes, nomenclature and transcripts

The table brings together genes with an established or emerging relationship with heterotaxy. The MANE Select transcripts (Matched Annotation from NCBI and EMBL-EBI) and cytobands are those of the HGNC consulted in October 2026 [13]; for genes not included in that consultation, the data come from GeneGuidance [14–16].

2.4. ZIC3 and X-linked heterotaxy

ZIC3 encodes a C2H2-type zinc-finger transcription factor of the ZIC family, which binds to a GLI-like consensus site and is required in the early stages of axial midline development and left–right specification, in the primitive streak and the node [54]. The 2022 consensus adds that ZIC3 is critical for morphogenesis of the organiser and for posterior positioning of cilia mediated by planar cell polarity [18]. Loss of function randomises the position of the thoracoabdominal organs and causes X-linked heterotaxy with complex heart disease [54]. The spectrum includes TGA, atrial septal defect, ventricular septal defect, AVSD, pulmonary and aortic stenosis and patent ductus arteriosus, that is, also heart defects that are not typical of heterotaxy; the same loss-of-function variant can produce anything from classic heterotaxy to isolated heart disease [19, 54].

In the first study, in 1997, one frameshift, two missense and two nonsense variants were described in familial and sporadic situs ambiguus [34]. Screening of 194 patients (61 with classic heterotaxy, 93 with heart defects characteristic of heterotaxy and 11 with situs inversus totalis) found five new variants and estimated that ZIC3 explains about 1% of sporadic heterotaxy; variants in the zinc-finger domain and the N-terminal region reduce transactivation, and variants between amino acids 253 and 323 cause aberrant cytoplasmic localisation [46]. Later estimates place ZIC3 in fewer than 3–5% of males with heterotaxy [18] or in up to 5% of males, with a lower percentage in females, and find pathogenic variants in about 75% of families with possible X-linked inheritance [19]. Penetrance in males is high, with at least one case of non-penetrance described [19]. Heterozygous females are not reliably unaffected: some have situs inversus, and systematic screening concluded that the spectrum includes affected females, probably owing to variable X inactivation [34, 46, 54]. There is no established male lethality in utero [54].

ZIC3 is also associated with an X-linked VACTERL phenotype, with or without hydrocephalus, which combines vertebral anomalies, anal atresia, heart disease, tracheo-oesophageal fistula, renal anomalies (such as urethral atresia with hydronephrosis) and limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia, proximally placed thumb) [54, 65]. A polyalanine expansion of ZIC3 has been described with X-linked heterotaxy and VACTERL [66], and some people have deletions detectable by microarray [66]. The X-linked laterality sequence may be combined with sacral agenesis or neural tube defects [26], and oesophageal, duodenal and anal atresias, as well as biliary tract and renal malformations, have been reported in ZIC3 laterality disorders; Oxford Desk Reference considers digestive atresias a possibly underappreciated component of these disorders [67]. X-linked hydrocephalus with VACTERL features has two known genes, FANCB and ZIC3, and only ZIC3 is accompanied by heterotaxy [65]. VACTERL is frequent in children of diabetic mothers, and some cases have a ZIC3 variant or deletion [68].

The cytoband of ZIC3 appears differently in the books: Xq26 in the 2017 Oxford Desk Reference (p. 58), Xq26.2 in Smith, which follows the 1997 mapping, and Xq28 on another page of Oxford Desk Reference [6, 26, 66]. The HGNC gives Xq26.3, which is the location adopted in this article [13].

2.5. The NODAL pathway: NODAL, CFC1, LEFTY, ACVR2B, GDF1 and susceptibility genes

NODAL, a secreted ligand of the TGF-β superfamily, signals through the co-receptor CRIPTO, with phosphorylation of SMAD2 and nuclear entry, and is essential in mesoderm formation, axial patterning and the left–right axis [45]. In a study of 269 unrelated cases of classic heterotaxy or «looping» cardiovascular malformation, four missense variants, one in-frame indel and two conserved splicing variants were found in 14 patients (5.2%); carriers had more pulmonary valve atresia (p = 0.001), and the missense proteins were hypomorphic, with reduced CRIPTO-mediated activation, SMAD2 phosphorylation and nuclear import [38]. Inheritance is autosomal dominant with reduced penetrance, and isolated «looping» cardiac malformation is part of the spectrum [45].

CFC1 encodes CRYPTIC, a member of the EGF-CFC family and an obligatory NODAL co-receptor; the mutant proteins described in 2000 had aberrant cellular localisation and were defective in the zebrafish oep mutant rescue assay [37]. The phenotype described includes heterotaxy with conotruncal heart disease (TGA, DORV), AVSD, anomalous venous drainage, asplenia or polysplenia, malrotation and biliary anomalies, and there are reports in biliary atresia with polysplenia [20]. The contribution of CFC1 is small and controversial. Two variants were found in 86 patients with TGA or DORV, no convincing excess in 167 patients with heart disease, and three non-synonymous variants (NM_032545.4:c.61A>C p.(Asn21His), c.140G>A p.(Arg47Gln) and c.232C>T p.(Arg78Trp)) at significant frequency in unaffected African Americans, transmitted by unaffected parents [20]. These three variants are now classified in ClinVar as benign or likely benign [56]. In 2026, aggregate variant calling in paralogous genes, applied to case and control exomes, concluded that CFC1 loss-of-function variants are probably not associated with heterotaxy in people with congenital heart disease [55]. CFC1 has an almost identical paralogue, CFC1B, in the same band; with short reads mapping is ambiguous and standard diploid calling is unreliable, so any CFC1 variant detected by short-read sequencing should be validated by a paralogue-aware method [20, 55]. The mapping of HTX2 to ORPHA:99042 (congenitally corrected transposition with coarctation) that appears in some databases is incorrect; the corresponding entity is ORPHA:450 [20].

In 1999, two human genes homologous to the murine Lefty genes, LEFTY A and LEFTY B, separated by about 50 kb at 1q42, with four exons each, were characterised; in 126 cases of left–right axis malformation, one nonsense and one missense variant were found in LEFTY A, in the cysteine knot region [35]. The abstract states that LEFTY A is identical to EBAF, which is a previous symbol of LEFTY2 in the HGNC; the 1999 variants are therefore in LEFTY2 [13, 35]. The 2000 article on CFC1 uses the expression «LEFTB (formerly LEFTY2)», a historical nomenclature that does not correspond to the current one, because LEFTB is now a previous symbol of LEFTY1 [13, 37].

ACVR2B encodes the activin type IIB receptor. The Acvr2b-null mouse has atrial and ventricular septal defects, right morphology of the left atrium and lung and splenic hypoplasia; in the screening of 112 sporadic and 14 familial cases of left–right axis malformation, two heterozygous missense substitutions were found (one of them in two unrelated individuals), absent from 200 control chromosomes, and the authors concluded that ACVR2B variants are rare [36]. The phenotype described includes dextrocardia, right aortic arch, right-sided spleen and inferior vena cava anomalies; OMIM assigns no mode of inheritance and penetrance is not established [16].

GDF1 is associated with two distinct phenotypes. Autosomal recessive right atrial isomerism (OMIM 208530) results from biallelic truncating variants and manifests as complete AVSD with common atrium, univentricular atrioventricular connection, anomalous pulmonary venous drainage, transposition or malposition of the great arteries, bilateral trilobed lungs, midline liver, asplenia and severe heart failure at birth [57]. The first description was a Finnish sibship of five compound heterozygotes with healthy heterozygous parents, and confirmation came from a homozygous truncating founder variant, p.(Trp203Ter), in consanguineous Arab families with more than 15 affected individuals; by 2020 about 23 individuals with GDF1 variants had been described [57]. In ClinVar, the change p.(Trp203Ter) exists under two distinct nucleotide descriptions, NM_001492.6:c.608G>A (pathogenic or likely pathogenic, several submitters) and NM_001492.6:c.609G>A (pathogenic, one submitter); the source consulted does not state which of them corresponds to the founder families [56, 57]. Congenital heart defects, multiple types, 6 (OMIM 613854), dominant, is based on heterozygous loss-of-function variants in tetralogy of Fallot, TGA and DORV, but the evidence is disputed and the heterozygous variant should be regarded at most as a susceptibility factor [57]. In the 2026 Franco-Vietnamese series, MMP21 and GDF1 correlated with severe conotruncal malformations [52].

Other genes of the pathway contribute as rare or susceptibility factors. SMAD2 is associated, besides Loeys–Dietz syndrome type 6 (OMIM 619656), with congenital heart defects, multiple types, 8, with or without heterotaxy (OMIM 619657), autosomal dominant, described in 2 of 362 individuals with severe heart disease [63]. Heterozygous CRELD1 missense variants occur in almost 6% of people with AVSD without trisomy 21, including AVSD with heterotaxy, and OMIM treats them as susceptibility [64]. Reduced NODAL signalling strength in several members of the pathway, including FOXH1, is associated with heart defects and holoprosencephaly [20]. Orphanet records CITED2 as a major susceptibility factor for situs inversus totalis [11], a gene that the Clinical Genome Resource (ClinGen) associates with moderate evidence (2023) with atrial and ventricular septal defects [69], and the 2018 AHA statement mentions SHROOM3, GRK5 and ANKS3 as associated non-ciliary genes [19].

2.6. Left–right organiser genes: MMP21, PKD1L1, CIROP, CIROZ and DAND5

MMP21 encodes a matrix metallopeptidase that may modulate cell proliferation and migration through remodelling of the extracellular matrix [26]. In 2015, recessive variants were described in nine index cases with heterotaxy, with Mmp21 mutant mice with heterotaxy and morphant zebrafish with abnormal cardiac looping [39], and, independently, a homozygous 2 bp deletion in a consanguineous family, the only coding variant with cosegregation, with looping defects and altered Notch signalling in zebrafish [40]. The 2025 Italian review brought together 18 missense variants in 26 patients with biallelic missense variants: 94% had congenital heart disease and 64% variable extracardiac manifestations, the variants were distributed without clustering, there was no phenotypic difference between homozygotes and compound heterozygotes, and the probable mechanism is loss of function, particularly in the catalytic domain [58]. The variant MMP21 NM_147191.1:c.903G>A p.(Met301Ile), described in two unrelated patients with heterotaxy, is classified in ClinVar as of uncertain significance by a single submitter [56, 58]. In 2025, the first intronic MMP21 variant with an effect on splicing, c.980-16T>A, was described in a fetus, in compound heterozygosity with c.414del p.(Arg139Glufs*38); the abstract does not state the transcript [70].

PKD1L1 encodes a polycystin-1-like protein. In 2016 two families were described: in the first, a fetus and a deceased child with heterotaxy and complex heart disease were homozygous for NM_138295.5:c.6473+2_6473+3del (intron 42 splice donor); in the second, a patient with situs inversus totalis and heart disease was homozygous for NM_138295.5:c.5072G>C p.(Cys1691Ser), at a conserved cysteine of the GPS motif [41, 71]. The spectrum ranges from situs inversus totalis to situs ambiguus, with predominant complex heart disease and intra- and interfamilial variability, and includes congenital asplenia, non-immune fetal hydrops with heart disease and situs inversus in two fetuses of the same family, and situs inversus with sideroblastic anaemia; several cases are fetal or neonatal lethal, diagnosed at fetal pathology [21]. GenCC classifies the relationship as Definitive by two submitters and Strong by another two, and 11 families had been described by 2021 [21].

CIROP was associated in 2022 with recessive situs anomalies in 21 patients with loss-of-function variants [42], and CIROZ in 2025 with heterotaxy with heart disease in 16 individuals from 10 families with biallelic inactivation [43]. They are different genes: CIROP is located at 14q11.2 (previous symbol LMLN2) and CIROZ at 1p36.22 (previous symbol C1orf127) [13]. In the 2025 consanguineous Saudi cohort, both are among the genes with a diagnosis [51].

DAND5 is the NODAL antagonist in the organiser. By 2026, at most four probands with biallelic variants had been described: one homozygote in a cohort of 30 Arab-Muslim probands [50], a child with heterotaxy homozygous for NM_152654.3:c.197del p.(Leu66ArgfsTer22), whose protein did not inhibit NODAL signalling in vitro [59, 71], and two unrelated Arab-Muslim probands with dextrocardia, heart disease and heterotaxy homozygous for NM_152654.3:c.396_397dup p.(Tyr133SerfsTer11), in the last exon, with predicted escape from nonsense-mediated decay and a truncated protein lacking the DAN domain [60, 71]. This last report may overlap with the 2022 proband [23]. The hypothesis of dominant heterotaxy due to DAND5 rests on the heterozygous variant NM_152654.3:c.455G>A p.(Arg152His), found in a Portuguese study in 2 of 38 patients (one with left isomerism, ventricular septal defect with overriding aorta and pulmonary atresia; the other with extreme tetralogy of Fallot) and with reduced activity in a NODAL-dependent luciferase assay [72]. The allele frequency of this variant, about 1% in gnomAD v2 with 37 homozygotes, and the absence of loss-of-function constraint in DAND5 (pLI index of 0) make this evidence weak [59]. The ClinVar search found no entry for p.(Arg152His) [56].

2.7. Laterality ciliopathies without classic PCD: CFAP53, CFAP52, CFAP45, MNS1 and DAW1

CFAP53 (formerly CCDC11) is essential for the rotation of the organiser cilia, but dispensable for the structure and motility of respiratory cilia, so it causes laterality defects without classic PCD [61]. The spectrum includes situs inversus totalis in healthy people, dextrocardia and heterotaxy with complex heart disease, with marked intrafamilial variability: in the first family, one sibling had isolated situs inversus totalis and another heterotaxy [61]. GenCC classifies the recessive relationship as Strong, whereas Orphanet submits situs inversus as dominant, a discordance between databases [61]. In 2025, a second fetus with situs inversus totalis due to CFAP53 was reported [61].

CFAP52 (WDR16) causes situs inversus totalis or heterotaxy, with possible heart disease and male infertility; in a series of people with situs inversus without PCD, one in nine had CFAP52 variants, and a Chinese family with male infertility was successful with intracytoplasmic sperm injection (ICSI) [14]. CFAP45 was described in three individuals with biallelic loss of function: two with situs inversus totalis and mild upper respiratory symptoms and one with a prenatal diagnosis of heterotaxy and operated heart disease; the adult had asthenospermia, with about 80% of spermatozoa in non-progressive or circular movement, and none met PCD criteria, with normal respiratory ciliary ultrastructure and beat frequency [15]. MNS1 causes a motile ciliopathy with a laterality defect and male infertility; an extended Amish family has a founder frameshift variant with randomisation of laterality in homozygotes and unaffected heterozygous carriers [22]. The 2025 French series extended the phenotype to a female patient with complete situs inversus, severe myopia and agenesis of 10 permanent teeth and to two sibling fetuses with a complex malformation syndrome (with a second homozygous variant in GLDN) [62]. In a proband with oligoasthenoteratozoospermia, three ICSI cycles failed [22].

DAW1 encodes a dynein arm assembly factor. In 2026, a proband with heterotaxy and complex heart disease, without extracardiac malposition and without PCD, was described, compound heterozygous for NM_178821.3:c.648+1G>A (NC_000002.12:g.227903110G>A, maternal) and NM_178821.3:c.341G>A p.(Arg114Gln) (NC_000002.12:g.227893818G>A, paternal), both classified as of uncertain significance according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [44, 71]. In Xenopus tropicalis, depletion of Daw1 altered left–right patterning, cardiac looping and mucociliary flow, with rescue by human DAW1; p.(Arg114Gln) rescued mucociliary flow but not left–right patterning, behaving as a tissue-dependent hypomorphic allele, and c.648+1G>A was a complete loss of function, which led the authors to propose reclassification as likely pathogenic [44]. This is a single-case human study with an animal model, without replication.

2.8. Primary ciliary dyskinesia genes and situs anomalies

In PCD, situs inversus totalis occurs in 40–50% of patients and heterotaxy in about 9–12%, a proportion possibly underestimated owing to the lack of systematic screening [17]. PCD involves more than 50 genes, autosomal recessive except FOXJ1 and TUBB4B (dominant) and DNAAF6, OFD1 and RPGR (X-linked), and 20–30% of patients remain without an identified variant [17]. GeneReviews separates the genes with reported situs anomalies (approximate frequency in PCD in brackets) — CCDC39 (5%), CCDC40 (9%), CCDC103/DNAAF19 (less than 2%), CFAP298, CFAP300 (less than 2%), CLXN/ODAD5, DNAAF1 (less than 2%), DNAAF2, DNAAF3 (2%), DNAAF4 (3%), DNAAF5, DNAAF6, DNAAF11/LRRC6 (less than 4%), DNAH1, DNAH5 (22%), DNAH9, DNAH10, DNAH11 (11%), DNAI1 (6%), DNAI2 (less than 2%), DNAL1, FOXJ1, LRRC56, NME8, ODAD1 (3%), ODAD2 (1%), ODAD3, ODAD4, OFD1, SPAG1, TTC12 and ZMYND10 — from the genes without reported situs anomalies, which encode the central pair, radial spokes or multiciliogenesis: CCDC65/DRC2, CCNO, CFAP54, CFAP57, CFAP74, CFAP221, DNAJB13, DRC1, GAS2L2, GAS8, HYDIN, IFT74, KIAA0586, MCIDAS, NEK10, NME5, RSPH1, RSPH3, RSPH4A, RSPH9, SPEF2, STK36 and TP73 [17]. The gene table of the 2022 consensus includes in the list of heterotaxy-associated PCD genes radial spoke and central pair genes (RSPH1, RSPH4A, RSPH9, HYDIN) and ciliary aplasia genes (CCNO, MCIDAS), which, according to the consensus text itself, cause PCD without laterality defects [18]. The interpretation of a variant in these genes in a patient with heterotaxy should take this distinction into account.

2.9. Reinterpreted historical variants

Several variants described as causal in the first studies are now classified as benign, which requires old reports to be reinterpreted.

The ZIC3 polyalanine expansion described in 2010 was not normalised in the sources consulted [66]. DAND5 numbering is identical in versions NM_152654.2 and NM_152654.3 of the transcript [71].

2.10. Chromosomal, syndromic and environmental causes

Heterotaxy may arise in aneuploidies, complex rearrangements and microdeletions; the syndromic minority includes trisomy 13, 22q11.2 deletion syndrome, CHARGE syndrome and syndromic ciliopathies, whereas most patients are non-syndromic and usually have normal intellectual development [19]. The 2022 consensus lists the syndromes with heterotaxy in the phenotype: 22q11.2 deletion, aglossia with situs inversus, agnathia–otocephaly complex, Bardet–Biedl, cardiourogenital syndrome (MYRF), cardiofacioneurodevelopmental syndrome (CCDC32), Carpenter, DK phocomelia, Ellis–van Creveld, galactosialidosis, Hennekam (lymphangiectasia–lymphoedema), Johanson–Blizzard, Marden–Walker, nephronophthisis, oculo-auriculo-vertebral spectrum, polycystic kidney disease, PCD, renal–hepatic–pancreatic dysplasia, Sandestig–Stefanova and short-rib thoracic dysplasia 3 [18].

Maternal diabetes is the main known environmental factor. In the 1999 study by Splitt and colleagues, 50% of cases of left isomerism occurred in children of diabetic mothers [26]. In a Northern England cohort with pregestational diabetes, the relative risk of laterality disturbance compared with children of women without diabetes was 57, compared with 170 for the caudal dysplasia sequence, 5 for neural tube defects and 3 for congenital heart disease in general [73]. In the Texas registry, maternal diabetes was associated with a crude prevalence ratio for heterotaxy of 3.13 (95% confidence interval, 95% CI, 2.12–4.45) [25]. Diabetic embryopathy enters the differential diagnosis. Monozygotic twinning is another modifier [19]: in dicephalic conjoined twins, the right twin almost always has situs inversus [74]. Asplenia is among the occasional anomalies of warfarin embryopathy [75].

2.11. Penetrance, expressivity and allelic disorders

Expressivity is highly variable: the same variant may produce classic heterotaxy, situs inversus totalis or isolated heart disease [19, 61]. In the dominant forms of the NODAL pathway, penetrance is reduced and carriers may be asymptomatic, which has led several associations to be interpreted as susceptibility rather than as a Mendelian cause [20, 45, 57]. The 2022 consensus emphasises the role of environmental and genetic modifiers in the final phenotype [18, 37].

There are allelic overlaps with other malformations. Variants in FOXH1, NODAL and CRIPTO (formerly TDGF1) have been reported rarely in non-syndromic holoprosencephaly, without replication in large cohorts, so their role is uncertain [76, 77]. GDF1 and SMAD2 are associated with congenital heart defects without heterotaxy [57, 63], and ZIC3 with X-linked VACTERL [54]. The left ventricular non-compaction chapter of the book Clinical Cardiogenetics (CARDIO) describes left atrial appendage isomerism in 4 of 66 patients (6%) with non-compaction and congenital heart disease, and a locus at 6p24.3–21.1 associated with non-compaction, bradycardia, pulmonary valve stenosis, atrial septal defect, left bronchial isomerism, azygos continuation of the inferior vena cava, polysplenia and intestinal malrotation [78].

3. Clinical Spectrum and Manifestations by System

3.1. A spectrum with tendencies by subtype

Heterotaxy is a systemic disease that may involve the heart, great vessels, spleen, liver and biliary tract, intestine, lungs and bronchi, central nervous system and kidneys [18, 19]. The patterns associated with right isomerism and left isomerism overlap substantially and the AHA emphasises that there is no absolutely defined pattern [19]. The following table brings together the most frequent features of each subtype according to the 2022 consensus and Oxford Desk Reference.

Sources: 2022 consensus, Table 5, and Oxford Desk Reference, Table 2.22 [18, 26].

Smith adds that right bilateralism is two to three times more frequent in males and that left bilateralism has a sex ratio close to 1; that complex heart defects, with cyanosis and early heart failure, are the main cause of early death; that renal anomalies are more frequent (25%) in right isomerism; and that occasional anomalies include malrotation, biliary atresia, anomalous portal and hepatic vessels, intestinal obstruction, anal atresia or stenosis, renal agenesis or hypoplasia, ureteral malformations, myelomeningocele, cerebellar hypoplasia and arhinencephaly [6]. The Smith summary figure (p. 869) gives percentages by finding for each form of bilateralism, but the assignment of values to each finding is not legible in the version consulted, so they are not transcribed [6].

3.2. Congenital heart disease

Congenital heart disease is present in 50–95% of people with heterotaxy; most of the right isomerism spectrum, isolated levocardia (with abdominal situs inversus) and isolated dextrocardia (with abdominal situs solitus) have significant heart disease, whereas left isomerism does not always have a relevant intracardiac defect [19]. The 2022 consensus reports complex cardiovascular malformations in more than 80% [18]. The most prominent finding is atrioventricular canal defect, frequently unbalanced, with malposed great vessels; right ventricular obstruction and anomalous pulmonary venous return predominate in right isomerism, and left ventricular obstruction, interrupted inferior vena cava and rhythm disturbances due to absence of the sinus node predominate in left isomerism [19]. Anatomical assessment includes situs, heart position, atrial situs, ventricular loop, atrioventricular and ventriculoarterial connections, infundibulum, relationship of the semilunar valves, septa and systemic and pulmonary venous returns; non-compacted myocardium may cause early or late cardiomyopathy [18].

Oxford Desk Reference reproduces a classic series of heart defect frequencies by subtype (Burn and Goodship, 2001):

Source: Oxford Desk Reference, Table 2.21 [26]. The same table prints a value of 35% for TAPVD in the left isomerism column, with the right isomerism column empty; Table 2.22 of the same book, the 2022 consensus and the AHA associate TAPVD with right isomerism, so this value is not reproduced as a left isomerism datum [18, 19, 26]. Recent surgical series give an order of magnitude: in a Los Angeles cohort of 217 operated patients, 46% had TAPVD (supracardiac in 40, intracardiac in 34, infracardiac in 18 and mixed in 7), obstructed in 19 [79]; in a state-wide series from Western Australia, 91% of patients with right isomerism had AVSD and 71% a univentricular circulation [80].

In the meta-analysis of 647 fetuses with prenatally diagnosed isomerism (16 studies), pooled proportions of AVSD were 59.3% (95% CI 44.0–73.7) in left isomerism and 72.9% (95% CI 60.4–83.7) in right isomerism, and right outflow tract obstruction occurred in 35.5% of left isomerism [81]. In the Vienna series with fetal magnetic resonance imaging (MRI), 7 of 19 fetuses (37%) with left isomerism had normal intracardiac anatomy, whereas all fetuses with right isomerism had a cardiac malformation [82]. In a two-centre London study of 182 patients, heart disease was present in 100% of right isomerism and 61.7% of left isomerism [83].

3.3. Conduction and arrhythmias

In left isomerism, absence of the sinoatrial node may cause bradycardia and complete atrioventricular block (AVB); in right isomerism, duplicated sinus and atrioventricular nodes predispose to supraventricular tachycardias [18, 26]. In the fetal meta-analysis, arrhythmias occurred in 36.7% (95% CI 26.9–47.2) of fetuses with left isomerism, mainly complete AVB, compared with 1.3% (95% CI 0.2–3.2) in right isomerism [81]. In the Western Australia series, 3 of 16 patients (19%) with left isomerism had complete AVB [80], and in the 2026 neonatal surgical series a permanent pacemaker was more frequent in left isomerism [84]. Some newborns with polysplenia and complete AVB need an urgent pacemaker [18]. A 2025 review describes arrhythmias as a major contributor to morbidity and mortality, with bradyarrhythmic and tachyarrhythmic substrates and the need for individualised and prolonged rhythm surveillance [85]. AVB of genetic origin outside heterotaxy belongs to the group of genetic atrioventricular blocks and progressive cardiac conduction disease.

3.4. Spleen and infectious risk

Splenic anomalies occur in up to 90% of people with heterotaxy and cardiovascular malformation, and any structural variation, including polysplenia and an anatomically normal spleen, may be accompanied by functional hyposplenism [18]. Asplenia is associated with fewer IgM memory B lymphocytes [18]. In a systematic review, 42 episodes of bacteraemia were documented in 32 patients with heterotaxy; about 79% were asplenic and the mean age at bacteraemia was 17 months, and the authors concluded that the risk of fatal bacteraemia is high regardless of anatomical splenic type [86]. According to the 2022 consensus, which cites that work, 21% of patients with proven bacteraemia had polysplenia or an anatomically normal spleen [18]. In a single-centre cohort of 83 patients with isomerism and heart disease, 17 (20%) had 21 episodes of bacteraemia, 86% nosocomial, at a median age of 4 months; splenic anatomy was significant in univariable but not in multivariable analysis, and neither the type of atrial isomerism nor antibiotic prophylaxis was associated with risk [87].

The 2022 consensus, attributing the data to other studies, reports an annual rate of infection by encapsulated organisms of 4.2% in asplenia or hyposplenism, hospital admission for infection in 50% in anatomical asplenia versus 8% in polysplenia or normal spleen, and high infection-related mortality in both groups; in asplenia of other causes, the lifetime risk of bacteraemia approaches 5% and the mortality risk may reach 600 times that of the general population [18]. The Canadian Paediatric Society (CPS) adds that infants with congenital asplenia have a higher risk of fulminant sepsis than adults, greatest in the first three years of life, with 50–70% mortality in sepsis due to encapsulated organisms, highest before 2 years [88]. In the British Society for Haematology (BSH) guideline, post-splenectomy sepsis is most frequent between 0 and 2 years and above 60 years, and infections may arise decades later and even with vaccination and prophylaxis [27]. Survivors with heterotaxy have more skin, respiratory and other infections, which Smith attributes possibly to asplenia [6].

3.5. Intestine: malrotation and volvulus

The incidence of malrotation in patients with heterotaxy who are screened is 58–72% [18]. In a prospective study of seven institutions in Canada and the USA (2012–2016), 21 of 29 infants assessed (72%) had a rotational anomaly; the median age at symptoms was 46 days (5–171) [89]. In heterotaxy, the distance between the fixation points and the width of the mesenteric root vary, and the risk of volvulus is lower than in classic malrotation: 5.8% in unscreened patients with heterotaxy, compared with 37% in infants, 22% in children and 12% in adults with malrotation without heterotaxy [18]. In the London series, 20.9% of patients required abdominal surgery, mainly in the first year of life, with similar proportions in the two subtypes (20.4% and 21%) [83]. Prenatally, malrotation was detected in 14.2% (95% CI 2.5–33.1) of fetuses with left isomerism and 27.1% (95% CI 7.9–52.0) of those with right isomerism [81]. Digestive atresias (oesophagus, duodenum, anus) also occur, particularly with ZIC3 [67].

3.6. Liver and biliary tract

The liver may be midline or transverse, and the position of the gallbladder and stomach is frequently abnormal [19]. Extrahepatic biliary atresia occurs in about 6% of children with heterotaxy and cardiovascular malformation, about 1000 times the frequency in the general population (0.5–0.8 per 10,000), is associated mainly with left isomerism and has a worse prognosis when diagnosis or surgery occurs after 3 months of age; abdominal ultrasound has low sensitivity for detecting it [18, 26]. Orphanet individualises biliary atresia splenic malformation syndrome (ORPHA:244283), in which CFC1 was tested as a candidate gene [10]. Alagille syndrome is another differential diagnosis with biliary atresia and heart disease.

3.7. Airway, lungs and ciliary function

About 50% of people with PCD have laterality defects, of whom 9–25% have heterotaxy; the converse prevalence, of PCD or milder ciliary dysfunction in people with heterotaxy, is unknown [18]. In an online survey of people with heterotaxy, 37% reported bronchiectasis, chronic respiratory symptoms or previous detection of PCD-associated organisms, and in a group of 43 patients with heterotaxy, 42% had an abnormal ciliary beat pattern on high-speed videomicroscopy and nasal nitric oxide (nNO) below or near the threshold of 77 nL/min, without genetically confirmed PCD [18]. In a cohort of 337 patients with PCD, heterotaxy was present in 6.3% (21 patients), most with heart disease, a prevalence of heart disease with heterotaxy about 200 times higher than in the general population, and situs defects were associated more with outer dynein arm defects [90]. Estimates of the proportion of heterotaxy in PCD vary with era and method: about 6% in the 2017 Oxford Desk Reference and the 2007 cohort, 9–12% in the 2025 GeneReviews [17, 90, 91]. In PCD, heterotaxy is associated with poorer growth and poorer lung function [17]. Isolated left bronchial isomerism constitutes the entity ORPHA:649029 [9].

3.8. Central nervous system, kidneys and neurodevelopment

Brain malformations were found in 46% of autopsies of children with right isomerism and in none with left isomerism; imaging screening is not routinely recommended [18]. Children with heterotaxy are at risk of developmental delay, attention deficit hyperactivity disorder (ADHD), learning and executive function difficulties, and feeding disorders [18]. In the clinical case in section 10, the child had language and fine motor delay [59]. Renal anomalies are more frequent in right isomerism [6].

3.9. Grouped forms and Orphanet entities

«Cardiac anomalies-heterotaxy syndrome» (ORPHA:137628) is a malformation syndrome without an associated gene in Orphanet [7]. DORV with AVSD, pulmonary stenosis and heterotaxy (ORPHA:423712) is a clinical subtype corresponding to the typical profile of right isomerism [8, 18]. Isolated left bronchial isomerism (ORPHA:649029) and biliary atresia splenic malformation syndrome (ORPHA:244283) represent partial forms of the spectrum [9, 10]. The heterotaxy of laterality ciliopathies without PCD (CFAP53, CFAP52, CFAP45, MNS1) is accompanied in several cases by male infertility due to asthenospermia [14, 15, 22]. Carpenter syndrome type 2 (MEGF8) has laterality defects in almost half of patients [92]. These forms are described in the differential diagnosis.

3.10. Fetal natural history and natural history under treatment

The most frequent neonatal surgical indications are obstructed TAPVD and severe cyanosis due to valvular or subvalvular pulmonary stenosis, both more common in right isomerism, and complex heart defects are the main cause of early death [6, 18]. In the Texas registry (1999–2006), first-year mortality of live births with heterotaxy was 30.9% [25]. In the fetal period, about a quarter of fetuses with heterotaxy died in the 2018 meta-analysis, hydrops occurred in 11.8% (95% CI 2.9–25.6) of fetuses with left isomerism, and the predictors of fetal death in a Philadelphia cohort were complete AVB and ventricular dysfunction [81, 93]. Survival data after surgical treatment, which describe treated patients and not natural history, are in section 11.

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Heterotaxy is frequently identified on obstetric ultrasound, followed by detailed fetal echocardiography [18]. The 2023 guidelines of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) include in routine fetal cardiac screening the determination of fetal laterality, confirmation that the stomach and heart are on the left, the position of the descending aorta (left) and inferior vena cava (right) of the spine on the abdominal circumference view, and the cardiac axis, normally 45 ± 20° to the left; situs anomalies should be suspected when the heart or stomach is not on the left side [94]. The ultrasound signs that led to diagnosis in the first trimester in a Chinese series were abnormal position of the stomach and heart, stomach and umbilical vein on different sides, complete AVSD and DORV; left isomerism was associated with bradycardia and a reversed «a» wave in the ductus venosus [95]. Persistent fetal bradycardia, particularly with complete AVB, hydrops and ventricular dysfunction are signs of severity [81, 93]. Left isomerism without complex intracardiac malformation is the most easily missed [95].

4.2. Newborn and infant

In the newborn, heterotaxy should be suspected in the presence of complex congenital heart disease, particularly unbalanced AVSD with malposed great vessels, dextrocardia or mesocardia, TAPVD or interrupted inferior vena cava [19]. Severe cyanosis and respiratory distress due to obstructed TAPVD are surgical emergencies [18]. Bradycardia or complete AVB in a newborn with polysplenia may require an urgent pacemaker [18]. A blood smear with unexpected Howell–Jolly bodies, a severe infection by an encapsulated organism or a spleen not visualised on routine ultrasound may reveal a previously unknown asplenia [27]. Neonatal respiratory distress without apparent cause is one of the clinical criteria for PCD [18].

4.3. Warning signs requiring immediate assessment

4.4. Child, adolescent and adult

Heterotaxy may be recognised late when left isomerism has no significant heart disease, for example when azygos continuation of the inferior vena cava is discovered on imaging, incidental polysplenia, malrotation discovered at abdominal surgery or sinus bradycardia [19, 82]. Prevalence may be underestimated because of subtle findings, such as a bilateral superior vena cava [19]. Heterotaxy should also be considered in the presence of abdominal situs inversus with levocardia or dextrocardia with abdominal situs solitus, because these discordances are frequently accompanied by significant heart disease [19]. In adults with congenital heart disease, the 2025 North American guideline reports high rates of comorbidity, heart transplantation and early death in heterotaxy, and recommends considering referral for genetic evaluation, particularly with a family history or syndromic features [96]. In PCD with respiratory symptoms, the presence of situs inversus or heterotaxy should lead to echocardiography and abdominal ultrasound [17].

4.5. Family and maternal contexts

Suspicion of a monogenic form increases with parental consanguinity, recurrence in the sibship, affected males related through the maternal line (X-linked inheritance) or the coexistence of situs inversus totalis and heterotaxy in the same family [19, 26, 61]. Pregestational maternal diabetes should always be asked about, particularly in left isomerism [26, 73]. Male infertility in a man with situs inversus or heterotaxy points towards laterality ciliopathies or PCD [15, 22, 97].

4.6. Newborn screening

The sources consulted do not describe biochemical or genetic newborn screening for heterotaxy; detection is based on prenatal ultrasound screening and clinical and echocardiographic assessment after birth [18, 94].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no consensus diagnostic criteria in universal clinical use. For epidemiological purposes, the US National Birth Defects Prevention Study (NBDPS) defines heterotaxy as abnormal symmetry of the viscera in at least three categories (cardiac, vascular, abdominal), and the 2022 consensus reproduces the operational version, modified from Lin 2014 and Foerster 2007, which classically requires 3 of 8 features [18, 24].

Source: 2022 consensus, Table 2 [18]. In clinical practice, diagnosis rests on the IPCCC definition (abnormal arrangement of organs across the left–right axis, excluding situs solitus and situs inversus) and on a complete segmental description of each organ [3, 18].

5.2. Cardiac and anatomical assessment

Transthoracic echocardiography is the basis of postnatal assessment; transoesophageal echocardiography is used perioperatively; cardiac MRI provides volumes, function and three-dimensional anatomy, with the limitations of anaesthesia, gadolinium and pacemakers; cardiac computed tomography (CT) defines vascular anatomy with a modest radiation dose; catheterisation is used for haemodynamic assessment and interventions [18]. A baseline electrocardiogram is mandatory, Holter monitoring of at least 24 hours should be considered, and electrophysiological study is indicated in complex arrhythmias; intraoperative conduction mapping is increasingly used [18]. In abdominal and general assessment, abdominal ultrasound or CT defines visceral situs and the number and position of the spleen; chest radiography shows bronchial situs; liver function tests and hepatobiliary assessment look for biliary atresia; if there is a VACTERL phenotype, renal ultrasound, spine and limb radiographs and cranial imaging are added [20, 26, 54]. No non-molecular test identifies the causal gene [54].

5.3. Assessment of splenic function

Anatomical asplenia implies presumed hyposplenism; in polysplenia or an anatomically normal spleen, assessment is individualised with immunology or infectious diseases, and the 2022 consensus recommends presuming hyposplenism and starting prophylaxis until the assessment is complete [18]. The table summarises the available tests.

Smith also mentions Heinz bodies on the smear [6].

5.4. Assessment of respiratory ciliary dysfunction

The diagnosis of PCD requires at least two of four clinical criteria (unexplained neonatal respiratory distress, year-round wet cough, year-round nasal congestion, laterality defect), plus nNO repeatedly below 77 nL/min, or diagnostic genetics or transmission electron microscopy (TEM) [18]. As heterotaxy fulfils one of the criteria by itself, mechanical application of these criteria requires caution. nNO is unreliable before 2 years, and genetics and TEM are negative in up to 30% of people with PCD [18, 19]. GeneReviews considers PCD unlikely in a person with visceral heterotaxy without respiratory manifestations [17]. The 2022 consensus recommends screening for signs of PCD in all patients and, in the presence of suggestive symptoms, referring to respiratory medicine for nNO and/or PCD genes, with TEM or a PCD Foundation centre if these tests are unavailable or inconclusive [18].

5.5. Malrotation and biliary atresia

The upper gastrointestinal contrast study remains the diagnostic standard for malrotation and volvulus, with a sensitivity of 96% for volvulus according to the 2022 consensus; ultrasound is useful in screening and laparoscopy is safe for diagnosis and treatment, distinguishing a narrow mesentery, low-risk non-rotation and atypical anatomy [18, 98]. In a prospective cohort of 18 patients with heterotaxy and a rotational anomaly, the need for surgery did not correlate with the findings of ultrasound or the contrast study [99]. Routine screening for malrotation in asymptomatic patients is not recommended by the 2022 consensus (section 7.5) [18]. For biliary atresia, abdominal ultrasound has low sensitivity, and clinical suspicion (jaundice, acholia, choluria) requires urgent assessment [18].

5.6. Genetic testing

There are no formal guidelines for genetic evaluation in heterotaxy; the 2022 consensus recommends assessment by a geneticist in all patients, study of CNVs and sequence variants, with commercial multigene panels (heterotaxy, laterality, heart disease, PCD, non-motile ciliopathies, situs inversus), and genome sequencing when panels do not explain the phenotype; karyotyping is unnecessary unless trisomy 13 is suspected [18]. Oxford Desk Reference suggests storing DNA or studying ZIC3 when the pedigree suggests X-linked inheritance, and using genomic analysis (microarray, panel, exome or genome) according to availability [26]. The practical order is as follows: chromosomal microarray (CNV in 15–26%) [19]; panel or exome with laterality genes, situs-associated PCD genes and ciliopathy genes, ideally as a trio [17, 18]; genome if negative [18]. In heterotaxy, molecular testing is what changes counselling, by distinguishing a 25% autosomal recessive risk from a sporadic case [100].

The limitations of the tests condition interpretation. A negative result does not exclude a genetic cause: locus heterogeneity is extensive, established genes explain fewer than 20% of cases and part of PCD has no identifiable variant [17, 47, 54]. CFC1 variants obtained from short reads must be confirmed by a method sensitive to the CFC1B paralogue [20]. Deep intronic or splicing variants, such as MMP21 c.980-16T>A, require functional studies (minigene) [70]. ZIC3 deletions are detected by microarray [66]. Heterozygous variants in dominant genes with reduced penetrance (NODAL, CFC1, ACVR2B, GDF1, DAND5) should be interpreted as susceptibility until there is segregation, and several historical variants are now classified as benign (section 2.9) [56, 57, 59]. Variants of uncertain significance (VUS) in recent genes, such as DAW1, CIROZ or DAND5, benefit from segregation studies, consanguinity data and functional assays [44, 59].

The report should state the gene, the transcript with version (preferably MANE Select), the variant in Human Genome Variation Society (HGVS) nomenclature at c. and p. levels, zygosity (hemizygosity, heterozygosity, homozygosity, compound heterozygosity with phase determined), the ACMG/AMP class and the technical limitations of the region [13, 71]. In the case in section 10, the DAND5 variant was initially classified by the laboratory as a VUS «in a gene of uncertain significance», which illustrates how classification depends on the state of knowledge about the gene [59].

5.7. Prenatal diagnosis

Fetal echocardiography confirms the ultrasound suspicion and enables counselling and perinatal planning [18]. In the Chinese series of 31 fetuses with heterotaxy, 23 were diagnosed between 11+0 and 13+6 weeks, with a sensitivity of 74.19%, specificity of 100%, positive predictive value of 100% and negative predictive value of 99.98%; most of the cases diagnosed early ended in termination of pregnancy [95]. Fetal MRI, in Vienna, identified non-cardiac anomalies (situs and spleen) in all 27 fetuses, a specific liver configuration in 12 of 19 (63%) with left isomerism, signs of TAPVD obstruction in three and a suspected abnormal bronchial tree in 6 of 19 (32%) with left isomerism and 3 of 8 (38%) with right isomerism [82]. The accuracy of fetal echocardiography in a North American series of 102 pregnancies was 91% for predicting a univentricular or biventricular strategy, 75% for ductal dependence and 69% for the timing of the first intervention, lower for venous anatomy, and the main error was the severity of pulmonary stenosis [101]. In the meta-analysis of 647 fetuses, abnormal stomach position was found in 59.4% of cases of left isomerism and 54.5% of right isomerism, and abnormal liver position in 32.5% and 45.9% [81]. Oxford Desk Reference mentions ultrasound scans at 14, 19 and 22 weeks for the prenatal diagnosis of most laterality disorders in at-risk pregnancies [26]. Prenatal exome sequencing has been used in fetuses with laterality defects for counselling [48, 49, 61]. The 2014 AHA statement on fetal cardiac disease could only be consulted in abstract form, so its specific recommendations are not reproduced [102].

Molecular prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing (PGT-M) are possible when the familial variant is known and classified as pathogenic or likely pathogenic (section 8) [18, 100].

5.8. Practical algorithm

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differential diagnoses

The first differential diagnosis is situs inversus totalis, in which all organs are inverted concordantly. The distinction is anatomical: in situs inversus totalis there is no isomerism of the atrial appendages or spleen, and heart disease, when present (3–9%), is less complex; in heterotaxy, discordance between organs is the rule [3, 26]. The two conditions are part of a continuum, because the NBDPS showed differences in the pattern of associated defects (more DORV, atrioventricular canal, pulmonary stenosis and atresia and anomalous venous drainage in heterotaxy; more Dandy–Walker, anotia or microtia and limb defects in situs inversus totalis), but also overlap, and the same genotype may produce both in the same family [24, 61].

The second is PCD, which should be sought in any person with heterotaxy and chronic respiratory symptoms; the absence of respiratory manifestations makes it unlikely [17]. The 5p deletion of cri-du-chat syndrome may cause PCD when the remaining DNAH5 allele carries a pathogenic variant [17]. Other sinopulmonary diseases, such as cystic fibrosis or immunodeficiencies, are not accompanied by situs anomalies [17].

Isolated congenital asplenia is distinguished by the absence of heart disease and other laterality anomalies; the risk of fulminant infection is high (45% mortality in the French series), but this figure should not be transposed to heterotaxy [103]. In syndromic heterotaxy, extracardiac signs (craniosynostosis in Carpenter type 2, cataracts and dental anomalies in oculofaciocardiodental dysplasia, intellectual disability and haemoglobin H in ATR-X, polydactyly and retinal dystrophy in Bardet–Biedl) guide genetic testing [92, 107–109]. Diabetic embryopathy should be systematically considered in left isomerism [26, 73].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

There is no gene-directed therapy or drug specifically licensed for heterotaxy by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) [18, 54]. Management has three critical fronts: cardiac, with complete anatomical definition and staged surgical or percutaneous repair by a congenital heart disease team, in which the complexity of the lesions, and not the genotype, determines prognosis; splenic and infectious, with assessment of splenic anatomy and function and prevention of sepsis regardless of splenic type; and gastrointestinal, with clinical surveillance for malrotation and biliary atresia [18, 54]. The reference document is the 2022 North American multidisciplinary consensus, an expert consensus without formal grading of evidence, which proposes a «medical home» in a tertiary centre with cardiology, genetics and immunology, and a primary care physician who coordinates immunisations, the response to fever and surveillance for volvulus and biliary atresia [18]. The care organisation table of that consensus is as follows.

Source: 2022 consensus, Table 1 [18].

7.2. Cardiovascular treatment

The most frequent neonatal indications are obstructed TAPVD and severe cyanosis due to valvular or subvalvular pulmonary stenosis, both more common in right isomerism; mortality of urgent surgery for obstructed TAPVD in heterotaxy was 38%, and 1-year mortality after neonatal repair of pulmonary atresia or stenosis was above 12% [18]. In more than half of patients a univentricular strategy is chosen: cavopulmonary anastomosis (Glenn) at 3–6 months, with a single or bilateral superior vena cava, and the Fontan operation at 2–3 years; when the inferior vena cava is interrupted, the azygos drains the lower half of the body into the superior vena cava, which alters the surgical sequence [18]. Biventricular repair may be achieved with staged ventricular recruitment, restricting the atrial septal defect without closing the ventricular septal defect [18]. Immediate mortality after Fontan is higher than in similar malformations without heterotaxy, but long-term mortality is similar, and surgical outcomes have improved [18]. Heart transplantation has a 1-year survival of 77.2% in heterotaxy, compared with 85.1% without heterotaxy [18].

The 2025–2026 series detail the risk factors. In a series of 41 newborns operated on at a North American centre, 30 (73%) followed the univentricular pathway, with Glenn in 28 (93.3%) and Fontan in 14 (46.7%) at a median follow-up of 2.3 years, operative mortality of 9.8% and interstage mortality of 10%, with no deaths after Fontan, and obstructed TAPVD was associated with overall mortality (hazard ratio, HR, 6.0; 95% CI 1.2–31.2) [84]. In Los Angeles, among 217 patients, TAPVD repair with control of pulmonary blood flow and coarctation were early predictors of mortality, tricuspid atresia, Fontan revision and atrioventricular valve repair or replacement were late predictors, and reaching Glenn reduced the risk [79]. In Toronto, in patients with Fontan, the extracardiac conduit technique was used in 66%, and connection of the inferior vena cava to the contralateral pulmonary artery had 100% survival, compared with 67% (95% CI 34–87) at 20 years when the connection was ipsilateral to the apex; in-hospital mortality was 9.8% in heterotaxy compared with 1.3% in tricuspid atresia [119]. In Japan, in 151 patients with asplenia syndrome on univentricular palliation, the independent mortality factors were TAPVD, pulmonary atresia and moderate or greater atrioventricular regurgitation, and, in the TAPVD subcohort, pulmonary atresia, infracardiac TAPVD and neonatal TAPVD repair [120].

Patients with complete AVB or sinus node disease need a pacemaker, sometimes urgently in the neonatal period, and tachyarrhythmias due to duplicated nodes require surveillance and, when complex, electrophysiological study [18, 85]. Pulmonary hypertension may complicate the course: in the clinical case in section 10, it was treated with sildenafil at 13 months, with no dose stated in the report; paediatric use of sildenafil in pulmonary hypertension associated with congenital heart disease is not described in the sources consulted as a specific indication in heterotaxy [59]. The sources consulted do not provide heterotaxy-specific cardiovascular drug doses; medical therapy of heart failure and arrhythmias follows the general rules for congenital heart disease.

7.3. Infection prevention: antibiotic prophylaxis

Continuous antibiotic prophylaxis is the central preventive measure in asplenia and functional hyposplenism, but the evidence of efficacy comes from sickle cell disease. The only prospective controlled study showed an 84% reduction in infections in sickle cell disease [88], and the 2022 consensus reports reductions of 50–80% in invasive pneumococcal infections in some populations [18]. In heterotaxy, the cohort of 83 patients with isomerism found no association between prophylaxis and absence of bacteraemia, with 86% of episodes nosocomial, so prophylaxis is a reasonable practice whose efficacy in this population has not been demonstrated [87]. The 2022 consensus recommends starting it in anatomical asplenia and maintaining it in polysplenia or a normal spleen until hyposplenism has been excluded [18]. Doses differ between sources, as the table shows.

The grades in brackets are those of the GRADE classification used by the BSH (1 = strong, 2 = weak; A–D = quality of evidence) [27]. The differences have practical explanations. The fixed age-based doses of the 2022 consensus and the CPS reflect the formulations available in each country, and the CPS chooses amoxicillin because phenoxymethylpenicillin suspension is unavailable [18, 88]. Duration is the point of greatest divergence: the 2022 consensus relies on the National Heart, Lung, and Blood Institute recommendation for sickle cell disease (stop at 5 years, unless splenectomy or previous IPD) [18]; the CPS states that the 2018 American Academy of Pediatrics Red Book proposed prophylaxis until 5 years and for at least 1 year after splenectomy above that age, and that the 2011 British and 2017 Australian guidelines maintained it until 16 years, after IPD or in splenectomy for haematological malignancy [88]; the BSH 2024, acknowledging the lack of robust data, considers prophylaxis reasonable until 5 years and above 65 years and identifies as high-risk factors age under 5 or over 65, previous IPD, splenectomy for haematological malignancy and immunosuppression [27]. The CPS justifies the lifelong option by the occurrence of sepsis up to 65 years after splenectomy and the absence of emergence of resistant pneumococci under prolonged prophylaxis, weighing adherence, access to care, local resistance and previous sepsis [88]. In a patient on prophylaxis who develops a systemic infection, the BSH recommends immediately starting an antibiotic of another class [27]. The sources consulted do not describe the dosing of the BNF for Children, access to which is restricted to the United Kingdom, nor the adverse effect profile of these antibiotics, which are generic medicines without specific authorisation for this indication.

7.4. Infection prevention: vaccination

All people with heterotaxy and asplenia or hyposplenism should complete the national schedule and receive additional pneumococcal, meningococcal and annual influenza vaccination [18, 27, 121]. Schedules differ by country and have changed since 2022: the 2022 consensus followed the Centers for Disease Control and Prevention (CDC) and Advisory Committee on Immunization Practices (ACIP) recommendations of the time, with routine 13-valent pneumococcal conjugate vaccine (PCV13) and Haemophilus influenzae type b (Hib), 23-valent polysaccharide vaccine (PPSV23, PPV23 in the United Kingdom) at 2 years with a booster 5 years later, meningococcal conjugate vaccine for serogroups A, C, W and Y (MenACWY) at 11–12 years with a booster at 16 and meningococcal B vaccine (MenB) from 10 years [18]. These schedules were superseded by the following recommendations.

United Kingdom (BSH 2024), children up to 10 years:

Source: BSH 2024, Table 2 [27]. Above 10 years and in adults, the BSH does not recommend Hib, recommends 1 dose of PPV23 repeated every 5 years, 1 dose of MenACWY, 2 doses of 4CMenB at least 4 weeks apart if never vaccinated, annual influenza and COVID-19 vaccine; the 20-valent conjugate vaccine (PCV20) is licensed in adults, but in May 2023 it was not part of the British programme and is an alternative to PPV23 in hyposplenic adults, without evidence on boosters (2D); MenB-fHbp (Trumenba®) is an alternative from 10 years, in 2 doses 6 months apart or 3 doses (0, at least 1 month and at least 4 months after the 2nd) (2C), without evidence on MenB boosters (2D) [27]. The BSH no longer recommends the additional Hib dose outside the infant schedule (1B) or MenACWY boosters, owing to herd immunity in the United Kingdom (1C) [27]. The 2020 Green Book, which predates the BSH guideline, provided at diagnosis before 1 year for 2 doses of MenACWY at least 4 weeks apart in the 1st year, an additional dose of PCV13 (2 primary doses 8 weeks apart), a MenACWY booster 8 weeks after the 1-year vaccines, an additional PCV13 booster at least 8 weeks after the 1-year booster and PPV23 after the 2nd birthday and at least 8 weeks after the last PCV13 [121]. The BSH 2024 no longer requires the additional PCV13 and indicates 2 doses of MenACWY at least 8 weeks apart before 6 months [27].

USA (CDC, schedule of 2 July 2025), anatomical or functional asplenia:

The regulatory status of the US schedule requires a note. The official CDC page states that, by preliminary order of 16 March 2026 in the case American Academy of Pediatrics et al. v. Kennedy et al. (No. 1:25-cv-11916, District Court of Massachusetts), all ACIP votes from the June, September and December 2025 meetings and the decision memorandum of the acting CDC Director of 5 January 2026 revising the childhood schedule were stayed, and that the schedule of 2 July 2025 is the schedule in force [122]. This description is based on the notice on the official page; the text of the court decision was not consulted, and the outcome of the case may change the applicable schedule in the USA.

Canada (CPS 2019, Canadian schedule of the time): PCV13 in 4 doses (2, 4, 6 and 12–15 months), 2 doses at least 8 weeks apart between 12 and 24 months if unvaccinated and 1 dose above 24 months; PPV23 about 8 weeks after PCV13, with a booster 5 years later; quadrivalent meningococcal conjugate vaccine (MCV4) at 2, 4, 6 and 12–15 months (or 2, 4 and 12 months with Nimenrix®), 2 doses 8 weeks apart between 12 and 23 months and above 2 years; 4CMenB (Bexsero®) with 2 or 3 doses between 2 and 11 months, 2 doses at least 8 weeks apart between 12 months and 10 years and Bexsero® or Trumenba® in 2 doses 6 months apart between 11 and 18 years; revaccination with MCV4 every 5 years, as long as there are no data on the duration of immunity; Hib at 2, 4, 6 and 18 months, with 1 dose above 5 years if unvaccinated or incomplete, and some experts give an additional dose to all; annual influenza from 6 months and vaccination of household contacts [88]. The CPS therefore maintains the additional Hib and two doses of MCV4, which the BSH no longer recommends [27, 88].

France (HAS, recommendation validated on 23 July 2026): the 20-valent pneumococcal conjugate vaccine (PCV20) replaces the others at all paediatric ages: in infants, from 8 weeks, in a 3+1 schedule (2, 4 and 6 months and booster at 11 months), completing with PCV20 schedules started with PCV13 or PCV15; in at-risk children from 15 months to 18 years, a single dose of PCV20 at least 8 weeks after the last pneumococcal vaccine. The HAS no longer recommends PCV13, PCV15 and the 23-valent polysaccharide vaccine in at-risk children, and in at-risk adults aged 18 to 64 years and all adults aged 65 years or more prefers the 21-valent conjugate vaccine (PCV21) as a single dose, without addressing repeat doses [123]. The French position thus departs from the 5-yearly PPV23 boosters maintained in the United Kingdom and from the CDC's PCV20 or PPSV23 option, which in immunocompromised people with PPSV23 provides for a further dose of PCV20 or PPSV23 at least 5 years later [27, 124].

7.5. Infection prevention: fever, education and travel

Fever in a child with heterotaxy is an emergency. The 2022 consensus sets the threshold of 38.5 °C (101.3 °F) for immediate sepsis assessment and empirical antibiotic; if the child looks unwell or the tests are concerning, the child is admitted, and if the child looks well and follow-up is reliable, discharge with reassessment at 24–48 hours is possible, according to an algorithm modified from Loomba 2016 [18]. The CPS recommends immediate medical review for sudden fever, blood culture without delaying the antibiotic and ceftriaxone 100 mg/kg/dose (maximum 2 g per dose) for all patients; where pneumococci with intermediate or high resistance are prevalent, ceftriaxone with vancomycin 60 mg/kg/day in divided doses every 6 hours; in severe penicillin or cephalosporin allergy, vancomycin with ciprofloxacin [88]. The BSH recommends that all patients have a rescue antibiotic at home (1A) and that an infection despite these measures lead to parenteral antibiotic and urgent admission (1A) [27]. The 2022 consensus suggests a home supply of antibiotic for those living far from healthcare [18].

The BSH further recommends an alert card and written information (1A), education about travel, malaria and animal bites (1B), clinical records flagged with documented vaccination status (1A) and, ideally, a local or national register of at-risk patients (2C) [27]. The British health agency provides a leaflet and a card for people with an absent or dysfunctional spleen [125]. For animal bites, because of the risk of Capnocytophaga canimorsus, the CPS indicates amoxicillin with clavulanic acid; for travel to malaria areas, asplenia severely increases the risk, and chemoprophylaxis and barrier measures are recommended [88].

7.6. Intestinal malrotation and Ladd procedure

Management of asymptomatic malrotation is the area in which practice has changed most in the last decade. The 2022 consensus does not recommend routine screening or prophylactic Ladd procedure in heterotaxy: 30-day complications of the Ladd procedure were 14–57% (adhesive obstruction, renal failure, respiratory arrest, sepsis), procedural mortality in heterotaxy was 13–22%, higher than in patients without heterotaxy owing to cardiovascular complications, and the lifetime risk of adhesive obstruction after Ladd is 3–15% [18]. Volvulus confirmed on the contrast study requires an emergency Ladd procedure [18]. Surgery in an asymptomatic patient may be considered when there is no rapid access to care, as in remote communities, and, if elective surgery is chosen, it should be postponed until after the cavopulmonary connection or complete cardiac repair, in a centre with paediatric cardiac anaesthesia; postponement is associated with fewer days of ventilation, parenteral nutrition and hospital stay, without changing in-hospital mortality [18]. Laparoscopy has a low recurrence rate, but may prolong ischaemia [18].

The 2015 American Pediatric Surgical Association (APSA) systematic review, of the literature from 1980 to January 2013, found minimal evidence for screening asymptomatic patients, suggested considering surgery in younger patients and observation in older ones, allowed observation of atypical malrotation with a broad-based mesentery and considered it reasonable to postpone the Ladd procedure until after palliation in patients with severe heart disease, with extensive education and close follow-up, emphasising the poor quality of the data [98]. In the 2018 prospective study, of the 7 Ladd procedures performed, 4 were prophylactic (3 of them combined with other surgery) and 3 emergency, and no child under surveillance had acute midgut volvulus at a median follow-up of 1.6 years (0.06–4.93) [89]. In a prospective clinical pathway at a North American centre (2016–2019), with quarterly symptom screening in the first 2 years and annually thereafter, 72.2% of the 18 patients with a rotational anomaly remained asymptomatic without intestinal surgery at a median follow-up of 5 years, 16.7% had feeding intolerance or faltering growth and underwent gastrostomy and diagnostic laparoscopy with Ladd, and 11.1% had urgent exploration for suspected volvulus [99]. In the US national readmissions database (2010–2014), among 4797 newborns with malrotation, 16% had heterotaxy; the Ladd procedure was performed in 56% of those with heterotaxy and in 73% of the others, and heterotaxy was associated with more wound dehiscence (8% vs 1%), sepsis (9% vs 2%), infections (19% vs 11%), venous thrombosis (9% vs 1%) and prolonged ventilation (39% vs 22%), with no readmissions for volvulus in either group; identification of cases by administrative codes limits interpretation [126]. In the London series, 86% of patients were free of Ladd at 10 years and 79% free of any gastrointestinal surgery [83].

7.7. Biliary atresia

Biliary atresia should be actively sought on clinical grounds: parents are taught to recognise jaundice, acholic stools and dark urine, and suspicion leads to urgent assessment by paediatric gastroenterology or surgery, particularly in the first 8 weeks, because diagnosis or surgery after 3 months worsens the prognosis [16, 18]. Routine abdominal ultrasound is not sufficient to exclude it [18].

7.8. Respiratory and perioperative treatment

In patients with respiratory ciliary dysfunction, a series of 27 patients had more postoperative respiratory complications, with no difference in length of stay or mortality [18]. Pre-existing PCD does not preclude cardiac surgery, but elevated pulmonary vascular resistance may make univentricular palliation less favourable, and perioperative optimisation includes antibiotics and airway clearance [18]. The 2025 North American guideline for adults with congenital heart disease states that patients with heterotaxy and ciliary dysfunction had more postoperative respiratory complications and greater use of inhaled beta-agonists, which improve ciliary function, and that identifying ciliary dysfunction beforehand allows, in collaboration with respiratory medicine, the use of preoperative airway clearance protocols and potentially improved recovery [96]. In confirmed PCD, treatment rests on regular airway clearance, proactive antibiotic therapy, respiratory vaccines and attention to otitis and rhinosinusitis [18].

7.9. Neurodevelopment, mental health and other areas

The 2022 consensus recommends annual developmental and psychological screening of the patient and parents, given the frequency of developmental delay, ADHD, learning and executive function difficulties and feeding disorders [18]. In the clinical case in section 10, the child needed speech and occupational therapy [59]. In men with laterality ciliopathies (CFAP45, CFAP52, MNS1), andrological assessment is recommended; ICSI was successful in one family with CFAP52 and failed in 3 cycles in a patient with MNS1 [14, 15, 22]. In Carpenter syndrome type 2, management includes early suture release with fronto-orbital advancement, correction of polysyndactyly, cardiological assessment, orchidopexy and weight control [92].

7.10. Comparative regulatory status

The sources consulted do not include the European summaries of product characteristics of the vaccines or the marketing status of Penbraya® in the European Union; the European regulatory information above reflects the British guidelines.

7.11. Intervention studies, management cohorts and registered trials

There are no randomised clinical treatment trials specific to heterotaxy [127]. The evidence supporting decisions comes from observational cohorts and extrapolation from sickle cell disease.

The registry also includes completed observational studies on the genetics of the left–right axis (NCT00341133, n = 900), intestinal rotation (NCT01591928, n = 40, probably corresponding to the 2018 study), dyskinesia in heterotaxy (NCT00608556, n = 3) and the racial distribution of heterotaxy (NCT00485654, terminated, n = 65), a phase 2 study on PPSV23 after splenic injury (NCT02232191) and a French national cohort of asplenic people (NCT04199403, 6000 planned) [127]. These studies have limitations that condition their reading. None is randomised in heterotaxy; the series are small, single-centre or administrative, with short follow-up for a rare event such as volvulus, and do not allow indirect comparisons between them. The 84% relative reduction in sickle cell disease applies to a disease with a different baseline infection rate and spectrum of organisms, and the absence of a prophylaxis effect in the 2017 cohort results from a study with few events, mostly nosocomial, which does not exclude a benefit in community-acquired infection [87, 88]. A negative registry search for therapeutic trials does not prove their non-existence outside it [127].

7.12. Developments in the last 12 months (October 2025 to October 2026)

There are no regulatory authorisations or agency opinions concerning heterotaxy in this period in the sources consulted.

7.13. Special situations: pregnancy, lactation, perioperative care and transition

Pregnancy in a woman with heterotaxy is mainly a matter of adult congenital heart disease, with preconception assessment of cardiovascular risk and genetic counselling [96]. The CDC makes no recommendation on PCV or PPSV23 in pregnancy owing to lack of data, which makes it desirable to complete vaccination before conception [122]. The sources consulted do not describe the use of prophylactic antibiotics during lactation. Perioperatively, the specific points are respiratory optimisation when there is ciliary dysfunction, postponement of elective abdominal surgery until after the cavopulmonary connection and performance in a centre with paediatric cardiac anaesthesia [18, 96]. In the transition to adult care, the 2025 guideline emphasises that most adults with congenital heart disease did not have access to genetic evaluation in childhood and recommends considering referral for genetic evaluation when there is a family history or syndromic features (class 2a, level of evidence C-EO) [96].

7.14. Guideline recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

Heterotaxy has the highest relative recurrence risk among the classes of congenital heart disease, which reflects a strong genetic component [19]. The actual risk depends on whether or not there is a molecular diagnosis.

The type of isomerism does not necessarily recur: left and right bilateralism have been observed in different members of the same family, and a sibling with isolated situs inversus totalis does not exclude heterotaxy in a subsequent pregnancy [6, 61]. In the general context of congenital heart disease, a Danish study of more than 18,000 patients found sibling recurrence of 1.4% for the same defect and 1% for a different defect, with relative risks of 15.17 in monozygotic twins and 3.33 in dizygotic twins; these figures are not specific to heterotaxy [128]. The online sources consulted do not provide updated numerical empirical risks for non-syndromic heterotaxy or estimates of the frequency of germline mosaicism; when a variant in ZIC3 or a dominant gene is not found in the parents, the recurrence risk is not zero, because undetected parental mosaicism cannot be excluded by a blood test [54].

8.2. Cascade testing and carriers

When a pathogenic variant has been identified, testing of the parents clarifies phase and mode of inheritance and allows testing to be offered to at-risk relatives [100]. In X-linked heterotaxy, heterozygous ZIC3 women should have echocardiography and abdominal imaging, because they may have manifestations [54]. In dominant forms with reduced penetrance (NODAL), cascade assessment of relatives is implicit in practice but not codified in a guideline [45]. In recessive forms in founder populations, carrier screening in the extended family is useful: GDF1 p.(Trp203Ter) in Arab-Muslim families, the MNS1 frameshift in the Amish community and DAND5 c.396_397dup in Arab-Muslim families [22, 57, 60]. Heterozygous MNS1 carriers are unaffected [22].

8.3. Prenatal and preimplantation diagnosis

The 2022 consensus recommends fetal echocardiography in all future pregnancies of the parents of a child with heterotaxy [18]. Oxford Desk Reference suggests ultrasound scans at 14, 19 and 22 weeks, which allow prenatal diagnosis of most laterality disorders [26]. When the familial variant is known and classified as pathogenic, molecular prenatal diagnosis and preimplantation genetic testing are options to be discussed in a genetics clinic [18, 100]. Without a molecular diagnosis, ultrasound surveillance is the only option; fetal echocardiography more frequently misses left isomerism without complex heart disease and venous anatomy [95, 101]. Termination of pregnancy was the outcome of most cases diagnosed in the first trimester in a Chinese series and of 21 of 102 pregnancies in a North American series, which shows the importance of counselling informed by the variability of prognosis [95, 101].

8.4. Fertility and reproductive options for patients themselves

In men with laterality ciliopathies (CFAP45, CFAP52, MNS1) or with PCD, infertility due to asthenospermia is frequent; PCD is associated with infertility in about 50% of men according to Oxford Desk Reference [14, 15, 22, 91]. ICSI has had variable results: successful in one family with CFAP52 and failed in 3 cycles in a patient with MNS1 [14, 22]. Women with PCD may have subfertility or a higher risk of ectopic pregnancy, according to the PCD Foundation [129]. In adults with congenital heart disease, the genetics clinic offers preconception counselling on the mechanism and risks to offspring [96].

8.5. Counselling of minors and content of the consultation

Testing of asymptomatic minors is only justified when the result changes immediate surveillance, as in the case of cardiac and abdominal imaging of a heterozygous ZIC3 sister [54]. The counselling consultation should address the aetiology, variability of expression, the possibility that a negative test does not exclude a genetic cause, the meaning of susceptibility variants, recurrence risks, the role of maternal diabetes and the options in the next pregnancy [18, 19, 26].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Estimates vary with the definition (isolated heterotaxy or all laterality defects), the source (population-based registry, case–control study, single centre), the denominator (total births or live births) and the inclusion of terminations of pregnancy. None of them is a validated national prevalence.

The Western Australia estimate of 0.48 per 10,000 is lower than the North American ones because it counts only live births followed up in a cardiology service, whereas the NBDPS and the Texas registry include cases identified by active birth defects surveillance [24, 25, 80]. Structural heart defects, for reference, occur in about 7 per 1000 live births [130].

9.2. Sex, ancestry and maternal factors

In the Texas registry, prevalence was about 70% higher in children of Hispanic and non-Hispanic Black mothers, 28% higher in females (crude prevalence ratio 1.28; 95% CI 1.04–1.59) and 3.13 times higher with maternal diabetes (95% CI 2.12–4.45) [25]. In the NBDPS, laterality defects were more frequent in preterm newborns and in children of non-white mothers or mothers under 20 years [24]. Smith describes a two- to three-fold male predominance in right isomerism and a sex ratio close to 1 in left isomerism [6]; in Western Australia, 53% of patients were male [80]. These sex differences between sources reflect different definitions and populations and do not allow a single conclusion. A registered study on the racial distribution of heterotaxy (NCT00485654) was terminated with 65 participants [127].

9.3. Founder and consanguineous populations

In populations with high consanguinity, autosomal recessive forms predominate and the exome yield exceeds 40% [50, 51]. In Israel, 17 of 30 Arab-Muslim probands (56.7%) had a molecular diagnosis, with homozygous variants in ciliary genes and in GDF1, PKD1L1 and DAND5 [50]. The GDF1 variant p.(Trp203Ter) is a founder variant in consanguineous Arab families with more than 15 affected individuals [57], and DAND5 c.396_397dup was found in the homozygous state in unrelated Arab-Muslim probands [60]. In Saudi Arabia, 7 of 9 diagnostic variants were homozygous [51]. In the Amish community, a founder MNS1 frameshift variant causes randomisation of laterality in homozygotes [22]. The first description of recessive GDF1 was a Finnish sibship of compound heterozygotes, with no indication of a founder effect [57]. The child in the clinical case, of Gambian ancestry with first-cousin parents, had multiple regions of homozygosity, and the DAND5 variant was in one of them [59].

9.4. Europe, Portugal and Brazil

The European data available in the sources consulted come from clinical series and not from population-based registries: two London centres (182 patients with isomerism) [83], Vienna (27 fetuses with MRI) [82], France (80 fetuses with NGS panel; 2026 Franco-Vietnamese series; MNS1 patient) [48, 52, 62], Italy (MMP21 review) [58] and Turkey (62 fetuses from a tertiary centre, with extracardiac anomaly in 25% of right isomerism and 44% of left isomerism) [131]. European prevalence from the EUROCAT network was not specifically searched. In Portugal, a study by the group of J. A. Belo (Lisbon), with Portuguese paediatric cardiologists, studied 38 unrelated patients with heart defects possibly originating in left–right axis defects and 40 controls, and described the DAND5 variant p.(Arg152His) in two patients [72]; the same group, with funding from the Fundação para a Ciência e a Tecnologia, took part in the functional study of the clinical case in section 10 [59]. The sources consulted do not include epidemiological data from Portugal or Brazil; the lack of data in these sources does not demonstrate that no published data exist.

9.5. Special populations

Preterm newborns are over-represented among laterality defects [24]. Children under 2 years have the highest risk of sepsis due to asplenia and the lowest reliability of splenic function tests and nNO [18, 88]. People living far from healthcare justify a home supply of antibiotic and, in selected cases, a Ladd procedure in asymptomatic patients [18]. Adults with congenital heart disease and heterotaxy have high comorbidity and more frequent heart transplantation and early death [96]. People with heterotaxy travelling to areas of endemic meningitis or malaria need specific vaccination and prophylaxis [27, 88].

9.6. European reference networks and patient associations

In the European Union, ERN GUARD-Heart brings together centres for rare heart diseases, including complex congenital heart defects [28]; ERN-LUNG includes PCD [29]; ERN ITHACA covers rare malformation syndromes and intellectual disability [30]. In the USA, Heterotaxy Connection is the patient organisation that endorsed and funded the 2022 consensus and organised, with the Heterotaxy Research and Clinical Care Collaborative, the «Facing Heterotaxy Together 2024» conference [18, 31, 32]. The PCD Foundation, a patient organisation founded in 2001, maintains a network of clinical and research centres in the USA, Puerto Rico and Canada (29 adult and 40 paediatric centres) and a patient registry, and is the North American reference for PCD [18, 129]. In the United Kingdom, Oxford Desk Reference mentions the Children's Heart Federation and the Ciliopathy Alliance [26, 91], and the British health agency provides the leaflet and card for people without a functioning spleen [125].

10. Illustrative Clinical Case

Ganapathi and colleagues (Columbia University, New York, with the group of J. A. Belo in Lisbon) described in 2022 a 5-year-old girl, daughter of first-cousin parents of Gambian ancestry, with three healthy siblings [59]. The complex heart disease suggestive of heterotaxy was detected prenatally. The child was born at term, by vaginal delivery, weighing about 7 pounds (3.2 kg); echocardiography showed levocardia, unbalanced complete atrioventricular canal defect (Rastelli A), ductus arteriosus, bicuspid aortic valve, interrupted inferior vena cava with azygos continuation, bilateral superior vena cava without a bridging vein and partial anomalous pulmonary venous return, and she spent 4 weeks in neonatal intensive care [59].

At 7 months she had repeated admissions for fever and respiratory infections, with suspected PCD; immunological assessment showed no abnormalities apart from low T lymphocytes. She developed valvular pulmonary stenosis, moderate biventricular hypertrophy and left ventricular systolic dysfunction, and underwent surgery for correction of the atrioventricular canal and closure of the ductus arteriosus [59]. CT, radiography and ultrasound showed left isomerism, intestinal malrotation, transverse liver and polysplenia; the article's abstract mentions «asplenia», an internal discrepancy in the article, whereas the imaging description mentions polysplenia [59]. The thoracoabdominal radiograph at 8 months (Figure 1A of the article) shows the heterotaxy, the transverse liver, the right-sided stomach with a duodenal tube and cardiomegaly [59]. After surgery, weight and height fell below the 5th percentile and a nasogastric tube was needed; a laryngeal granuloma due to prolonged intubation was excised. At 11 months the malrotation was surgically corrected. At 13 months secondary pulmonary hypertension appeared, treated with sildenafil. She had language and fine motor delay, with normal hearing, and started speech and occupational therapy. At the genetic examination at 7 months she had coarse facial features, hypertelorism and bilateral epicanthus [59].

The karyotype was 46,XX and the microarray showed no CNV, but revealed multiple regions of homozygosity greater than 3 Mb, compatible with consanguinity. Singleton exome sequencing, performed in 2017, identified the homozygous variant DAND5 NM_152654.2:c.197del p.(Leu66ArgfsTer22), in the first of two coding exons, in a region of homozygosity on chromosome 19, confirmed by Sanger and absent from gnomAD v2 and v3, TOPMed Bravo and the Greater Middle East Variome; in the MANE transcript NM_152654.3, the numbering is the same (NC_000019.10:g.12969857del) [59, 71]. The laboratory classified it as a VUS in a gene of uncertain significance, and it was submitted to ClinVar (VCV001704287.1) [59]. In a luciferase assay in HEK293T cells, with NODAL, CRIPTO and FOXH1, the mutant protein did not inhibit NODAL signalling, indicating complete loss of function (Figure 1E of the article); Figure 1 also shows the pedigree (B), the Sanger sequencing (C) and the location of the two known frameshift variants in the DAND5 protein (D) [59]. The family was lost to follow-up, so no parental genotypes or imaging were obtained, a limitation the authors point out [59].

The case illustrates several points of the article: the coexistence of left isomerism with interrupted inferior vena cava, unbalanced AVSD and partially anomalous venous return; malrotation, surgically corrected at 11 months (the report does not state whether there were digestive symptoms); recurrent infections, which lead to consideration of functional hyposplenism and ciliary dysfunction; the value of consanguinity and regions of homozygosity in exome interpretation; and the change in classification of a gene as new cases emerge (the DAND5 gene, considered of uncertain significance in 2017, now has a recessive OMIM phenotype, HTX13) [23, 59, 60]. The sildenafil treatment and the surgical timeline reported are the management of this case and not general protocols; correction of the malrotation at 11 months, after cardiac repair, is consistent with the recommendation to postpone elective abdominal surgery until after cardiac repair [18]. Figure consulted: https://pmc.ncbi.nlm.nih.gov/articles/PMC9808554/figure/MCS006248GANF1/

11. Prognosis and Long-Term Follow-up

11.1. Fetal and neonatal prognosis

Prognosis is determined mainly by the heart disease. In the meta-analysis of 647 fetuses, about a quarter died; biventricular repair was possible in 78.2% (95% CI 64.3–89.4) of fetuses with left isomerism and the univentricular pathway or palliation in 17.0%, and death during or after surgery occurred in 26.8% (95% CI 4.6–58.7) in left isomerism and 27.8% (95% CI 15.5–42.1) in right isomerism, mainly in the univentricular pathway [81]. In the Philadelphia cohort of 197 fetuses with heterotaxy and heart disease (2005–2023; 97 with right isomerism and 100 with left isomerism), median survival was 71% (95% CI 64–80) at 5 years and 68% (95% CI 60–77) at 10 years, higher in left isomerism (p = 0.028); predictors of fetal death were complete AVB and ventricular dysfunction, those of postnatal mortality pulmonary venous obstruction and complete AVB, and major extracardiac anomalies did not influence postnatal survival [93]. In a North American series of 102 pregnancies, there were 21 terminations, 5 fetal losses and 76 live births, and 1-year survival of the 55 with significant heart disease was 62%, with no difference between the univentricular and biventricular pathways [101]. In Turkey, univentricular repair was associated with higher mortality in childhood (p = 0.031), conotruncal anomalies were an independent mortality factor (HR 5.09; 95% CI 1.09–23.71), and hydrops, univentricular physiology and conotruncal anomalies were associated with a worse prognosis [131].

11.2. Prognosis after treatment

Right isomerism has a worse prognosis in most series, owing to the greater frequency of functionally single ventricle, obstructed TAPVD and pulmonary atresia [80, 93, 120]. In the Toronto series, the difference in survival after Fontan between subtypes was not significant [119]. Adults with heterotaxy and congenital heart disease have high rates of comorbidity, heart transplantation and early death [96]. In PCD, heterotaxy is associated with poorer growth and lower lung function [17]. Biliary atresia diagnosed after 3 months has a worse outcome [18]. Most people with non-syndromic heterotaxy have normal intellectual development, but the risk of developmental and learning difficulties justifies screening [18, 19].

11.3. Surveillance

12. Summary and Concluding Remarks

Heterotaxy is a disorder of the left–right axis that sets in during the first weeks of gestation, when the left–right organiser, with its motile and sensory cilia, defines the side on which the NODAL–PITX2 cascade is activated. Failure of this process produces a discordant arrangement of organs, organised into two tendencies, right isomerism with asplenia and more severe heart disease and left isomerism with polysplenia, interrupted inferior vena cava and conduction abnormalities, without watertight boundaries between them. Birth prevalence is around 0.8–1.2 per 10,000 in North American registries, and heterotaxy accounts for about 3% of congenital heart defects.

The aetiology is heterogeneous. ZIC3 explains the X-linked form and a small fraction of affected males; NODAL pathway genes act mainly as susceptibility factors with reduced penetrance, and several historical CFC1 and ZIC3 variants are now benign; the recessive organiser genes (GDF1, MMP21, PKD1L1, CIROP, CIROZ, DAND5) and the genes of laterality ciliopathies and PCD predominate in consanguineous populations, where the exome yield exceeds 40%, whereas in non-consanguineous cohorts it remains below 20%. Pregestational maternal diabetes is the main environmental factor. Genetic evaluation includes microarray, trio panel or exome and genome, with attention to technical limitations, such as the CFC1 paralogue, and to cautious interpretation of heterozygous variants.

Management is anatomical and preventive and has no specific drugs. Staged cardiac surgery, frequently univentricular, determines the prognosis, with survival of about 60–70% at 10–15 years, worse in right isomerism with obstructed TAPVD or pulmonary atresia. Every child with heterotaxy should be treated as potentially hyposplenic until proven otherwise, with antibiotic prophylaxis at least until 5 years, pneumococcal, meningococcal and annual influenza vaccination according to the national schedule and a written fever plan; doses and duration differ between the North American consensus, the Canadian society and the British guideline. Malrotation, present in more than half of screened patients, no longer justifies routine screening or prophylactic surgery, but volvulus is an emergency; biliary atresia requires clinical surveillance in the first weeks. Respiratory ciliary dysfunction should be sought clinically and prepared for before surgery. Fetal echocardiography in subsequent pregnancies, genetic counselling with risks ranging from 5–10% without a diagnosis to 25% or 50% in monogenic forms, and organised transition to adult cardiology complete the follow-up. The univentricular pathway, the Fontan circulation, its complications and surveillance by physiological stage follow the 2021 French PNDS (French National Diagnosis and Care Protocol) on univentricular heart disease.

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