Congenital Intestinal Atresias and Obstructions of Genetic Cause (including Prenatal Volvulus)

Genetic approach to duodenal, jejunoileal, multiple and colonic atresias, apple-peel atresia, meconium ileus and meconium peritonitis, fetal volvulus and intestinal perforation: trisomy 21, cystic fibrosis, TTC7A deficiency, PI4KA-related disorder, Strømme syndrome, GUCY2C deficiency and other syndromic causes.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

The table brings together the entities within scope. Some appear only to guide the work-up.

Abbreviations used in the table: EBMT, European Society for Blood and Marrow Transplantation; CID, combined immunodeficiency; CNV, copy-number variation; IBD, inflammatory bowel disease; CF, cystic fibrosis; GIDID, gastrointestinal defects and immunodeficiency syndrome; HMIA, hereditary multiple intestinal atresia; MIA, multiple intestinal atresia; PN, parenteral nutrition; QF-PCR, quantitative fluorescent polymerase chain reaction; HSCT, haematopoietic stem cell transplantation; ERN, European Reference Network.

1. Introduction

1.1. Definitions and scope

The word atresia comes from Greek and means "not perforated": it denotes loss of continuity of the intestinal lumen, through absence of a segment or complete occlusion, with obstruction upstream. Stenosis is a localised narrowing that produces partial obstruction [35, 36]. For congenital gastrointestinal obstructions as a whole, the birth frequency is around 1 in 2000, and duodenal atresia is the most frequent form of intestinal atresia in the series of the Oxford Desk Reference [35]. In European registries, duodenal and jejunoileal atresia have prevalences of the same order of magnitude, 0.9 and 0.7 per 10,000 births with a normal karyotype [2], and OMIM describes jejunal atresia as the most frequent cause of neonatal intestinal obstruction [5], so the sources diverge as to the most frequent form.

Prenatal volvulus, intestinal atresia and intestinal perforation are three clinical designations that overlap in practice. Intrauterine volvulus and perforation can give rise to atresia, and prenatal perforation, by spilling meconium into the peritoneal cavity, produces meconium peritonitis [37–39]. This article treats congenital intestinal atresias and obstructions as a class of malformations with heterogeneous aetiology. Most are sporadic and non-genetic, but a fraction has a chromosomal cause (above all trisomy 21 in duodenal atresia), a recessive monogenic cause (cystic fibrosis, TTC7A deficiency, PI4KA-related disorder, Strømme syndrome, GUCY2C deficiency, Mitchell-Riley syndrome) or a dominant one (Feingold syndrome). The geneticist's task is to distinguish these groups, because recurrence risk, prognosis and management differ [35].

Some entities are covered here only insofar as they present as intestinal obstruction: cystic fibrosis, Down syndrome, Feingold syndrome, VACTERL association, CHARGE syndrome, Hirschsprung disease, biliary atresia, severe combined immunodeficiency, junctional epidermolysis bullosa with pyloric atresia and Fanconi anaemia.

1.2. Founding descriptions and historical milestones

The vascular theory of jejunoileal atresias rests on animal models, among which the Oxford Desk Reference highlights the work of Louw and Barnard (1955), and the book itself stresses that direct evidence of a vascular aetiology in humans remains scarce [35]. The presence of fetal squames and lanugo in the lumen distal to the atresia shows that, in jejunoileal forms, the lesion arises after the bowel has become patent and peristalsis has been established, which is compatible with a late vascular accident [36]. In duodenal atresia, by contrast, the dominant hypothesis is failure of recanalisation of the lumen after the phase of epithelial proliferation, around the eighth week [36].

Martin and Zerella proposed an anatomical classification of jejunoileal atresias in 1976 (types I, II, IIIa, IIIb and IV) [5], Grosfeld and colleagues systematised it in 1979 in the form still used today [36], and the Indianapolis series of 277 newborns treated between 1972 and 1997 established the reference clinical associations for each level of obstruction [40]. In epidemiology, the EUROCAT network study of 1133 cases in 20 European registries (1990–2006) measured for the first time the population prevalence and the proportion of cases with chromosomal and structural anomalies [2].

Hereditary multiple intestinal atresia was described by Winter and Zeltzer in 1956; autosomal recessive transmission was postulated by Guttman and colleagues in 1973, and the association with combined immunodeficiency emerged in the following years [41]. Between 2013 and 2014, three groups independently identified biallelic variants in TTC7A: Samuels and colleagues in French-Canadian families from Quebec, by exome sequencing [42], Chen and colleagues in eight unrelated patients with combined immunodeficiency and atresias [43], and Bigorgne and colleagues, who demonstrated inversion of the apicobasal polarity of the epithelium in patient organoids [44].

Strømme and colleagues described in 1993 two sisters, daughters of healthy unrelated parents, with apple-peel jejunal atresia, severe microcephaly and ocular anomalies [16]; in 2016, Filges and colleagues reassessed them in early adulthood (IQ of 70 and 83, mainstream schooling, employment, persistent malabsorption and good vision in one eye), identified compound heterozygous truncating CENPF variants in this and another sibship and classified the syndrome as a recessive ciliopathy [16, 45]. In 2012, Romi and colleagues described recessive meconium ileus without cystic fibrosis caused by GUCY2C variants in two consanguineous Bedouin families [46]. PI4KA-related disorder, which includes the multiple intestinal atresia of the Ohio Amish, received a GeneReviews chapter in 2022 [15].

1.3. Current nomenclature and classifications

The Grosfeld classification describes the morphology of the atresia and has aetiological and prognostic implications [36]:

In duodenal obstruction, the British study distinguished types I (38%), II (5%) and III (36%) and a pre-ampullary (24%) or post-ampullary (44%) location, which determines whether the vomiting is bilious [3, 36]. Meconium ileus is classified as simple, when thick meconium obstructs the terminal ileum without any other lesion, and complex, when complicated by atresia, necrosis, volvulus or perforation; prenatal perforation produces sterile meconium peritonitis, with calcifications and sometimes a pseudocyst [37, 39]. Neonatal volvulus may be complete, of the midgut on a malrotation, or segmental, a mainly prenatal entity that frequently occurs without malrotation [47]. Spontaneous intestinal perforation is a single focal perforation, usually in the terminal ileum, of the very low birth weight newborn, distinct from necrotising enterocolitis [48].

In genetic nomenclature, TTC7A deficiency corresponds in OMIM to gastrointestinal defects and immunodeficiency syndrome 1 (GIDID1, 243150) and the PI4KA form to GIDID2 (619708); Orphanet uses "isolated multiple intestinal atresia" (ORPHA:2300) and "combined immunodeficiency-multiple intestinal atresia" (ORPHA:436252) [9, 10, 15]. Strømme syndrome has also been designated primary ciliary dyskinesia 31 (CILD31) [19], and Orphanet keeps a separate entry for the lethal fetal form with duodenal atresia and renal hypoplasia (ORPHA:444069), now integrated into the CENPF spectrum [49].

1.4. Entities within scope and organisation of the class

2. Molecular Genetics and Pathophysiology

2.1. Gut development and general mechanisms of atresia

The bowel develops as a hollow tube. The midgut, connected to the umbilical cord by the vitelline duct, grows faster than the abdominal cavity, herniates physiologically into the base of the cord and returns to the abdomen around the tenth week, after a sequence of rotations; the caecum and ascending colon then become fixed to the posterior wall [35, 36]. Rotation takes place between the fourth and twelfth weeks, and the left-right patterning genes (SHH, activin, NODAL, FOXF1, PITX2, BAPX1, FGF8) are the most conserved across species; defects in this pathway are associated with malrotation and heterotaxy [36].

The mechanisms of atresia fall into four groups: monogenic disease, teratogens, vascular disruption and deformation, such as constriction of the duodenum by an annular pancreas [35]. Duodenal atresia results, under the most widely accepted hypothesis, from a defect of embryogenesis (failure of recanalisation) and is frequently associated with other malformations, whereas jejunoileal atresia results mainly from a localised intrauterine vascular accident with necrosis and resorption of the segment [36]. In a Japanese series of 48 jejunoileal atresias, intrauterine intussusception accounted for 25% of gap or cord atresias and volvulus was present in 13 cases; neither was observed in high jejunal, apple-peel or multiple atresias, which suggests different mechanisms for these forms [38]. Volvulus can be a cause or a consequence: in some cases it results from the anatomical changes that follow the atresia [38].

Vascular disruption also explains the atresias associated with gastroschisis and those occurring in monozygotic twins. In gastroschisis, intestinal atresia is a recognised complication, and the association of amyoplasia, gastroschisis and intestinal atresia was described by Reid and colleagues [50]. In amyoplasia, a disruptive sequence, Smith's includes non-duodenal intestinal atresia, gastroschisis and defects of the trunk musculature among the associated anomalies; among patients with involvement of the lower limbs only there is an excess of boys with intestinal atresia, and among those with involvement of the upper limbs only an excess of girls with gastroschisis [51]. In monozygotic twins, placental vascular anastomoses and the intrauterine death of a co-twin can cause disruptive defects in the survivor, including intestinal atresia, gastroschisis, porencephaly and limb amputation; in the Collaborative Perinatal Project (50,000 deliveries), about 3% of monozygotic twins near term had a dead co-twin [52, 53].

2.2. Chromosomal causes

Trisomy 21 is the main cause to exclude in duodenal atresia: it accounts for 30–50% of cases according to the Oxford Desk Reference estimate [35], 32% in the British population study [3] and 24% in the Indianapolis series [40]; in cases with a prenatal double bubble, the proportion lies at 15–20% [54]. In Down syndrome, the overall incidence of congenital anomalies is more than twice that of the population, notably duodenal atresia or stenosis and Hirschsprung disease [55]. In the EUROCAT registries, 20.6% of small-bowel atresias in singleton fetuses were associated with a chromosomal anomaly [2]. Malrotation is associated with trisomies 9, 13, 18 and 21 and with triploidy [36]. In the Johns Hopkins double-bubble cohort, one of the seven isolated cases had a likely pathogenic microdeletion, and the authors point to the 4q22.3 microdeletion as an aetiology to consider [56].

2.3. TTC7A: multiple intestinal atresia with combined immunodeficiency

TTC7A (2p21) encodes a protein with nine tetratricopeptide repeat (TPR) domains that functions as an adaptor: it links phosphatidylinositol 4-kinase alpha (PI4KIIIα, encoded by PI4KA) to EFR3 and HYCC1 (FAM126A), recruits the complex to the plasma membrane and regulates the synthesis of phosphatidylinositol 4-phosphate [15, 57, 58]. This function sustains apicobasal polarity, growth and differentiation of the intestinal epithelium and the integrity of the thymic epithelium [57]. The protein is expressed in the cytoplasm of epithelial cells of the bowel, thymus and pancreas and in thymocytes [41, 43].

The mechanism was clarified in patient intestinal organoids: loss of TTC7A increases Rho kinase activity, which inverts apicobasal polarity and disturbs epithelial growth and differentiation; pharmacological inhibition of Rho kinase normalised polarity in vitro [44]. The same epithelial defect in the thymus explains the immunodeficiency: patients have a hypoplastic thymus with abnormal distribution of epithelial cells, lymphoid depletion in the thymus and lymph nodes and profound lymphocytopenia [43, 44]. The French-Canadian autopsies also showed changes in the lung, spleen and liver, which defines a multiorgan disease [41]. Mice with variants in the orthologue Ttc7 (flaky skin and hereditary erythroblastic anaemia strains) have cutaneous, haematological and immune changes, but not intestinal ones, which limits the animal model [42].

Inheritance is autosomal recessive. The French-Canadian founder variant is a four-nucleotide deletion (AAGT) in the splice donor of exon 7, which causes skipping of that exon; in current nomenclature it corresponds to NM_020458.4:c.1001+3_1001+6del, classified as pathogenic in ClinVar [42, 59]. In a review of 98 alleles, variants clustered in exons 2 (40 alleles), 7 (12) and 20 (10), with two recurrent variants: c.211G>A p.(Glu71Lys), in 26 alleles, and the exon 7 AAGT deletion, in 10 [60, 61].

Genotype-phenotype correlation has prognostic value. In the systematic review of 87 patients, biallelic loss-of-function variants were associated with multiple atresia with severe combined immunodeficiency and parenteral nutrition dependence, whereas biallelic missense variants were associated more with mild phenotypes, above all very early-onset inflammatory bowel disease (IBD); the presence of at least one loss-of-function variant reduced median survival to 9 months, against 33.5 months with biallelic missense variants [62]. In earlier Kaplan-Meier analyses, prognosis was better with biallelic missense variants, with intact TPR domains and, paradoxically, in patients who developed autoimmunity [60]. In the international EBMT cohort, multiple atresia was associated with double nonsense variants in 77.8% and IBD with double missense variants in 73.7% [11]. The correlation is not absolute: the homozygous missense variant p.(Leu69Pro) caused severe multiple atresia with combined immunodeficiency in a consanguineous Chinese family [58].

2.4. PI4KA: the other component of the complex

PI4KA (22q11.21) encodes PI4KIIIα, a ubiquitous kinase essential for the production of membrane phosphatidylinositides. Its stability depends on the formation of a heterotrimeric complex with TTC7A or TTC7B and HYCC1, anchored by EFR3; the complex with TTC7A predominates in the digestive tract and the complex with TTC7B in nervous tissue, which explains why variants that differentially affect binding to each partner produce predominantly gastrointestinal or neurological phenotypes [15]. The Amish founder variant NM_058004.4:c.4867T>G p.(Tyr1623Asp) has normal catalytic activity in vitro but loses the interaction with TTC7A, which destabilises the complex; as TTC7A is expressed more in the bowel than in the brain, homozygosity produces extensive multiple atresia without apparent neurological disease [13, 15, 61]. The recurrent variant c.5560G>A p.(Asp1854Asn), in the catalytic domain, reduces activity to almost undetectable levels and is associated with severe early neurological disease, with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis in fetuses compound heterozygous with p.(Arg796Ter) [15].

The mechanisms described are nonsense-mediated messenger RNA decay, loss of catalytic activity and loss of protein stability through failure of the complex. No patients with complete biallelic loss of function have been described, which suggests that it is incompatible with life [15]. Two partial non-processed pseudogenes (PI4KAP1 and PI4KAP2), located less than 1 Mb away, hamper sequencing and alignment [15].

2.5. CENPF: Strømme syndrome as a ciliopathy

CENPF (1q41) encodes centromere protein F (mitosin), a large nuclear matrix protein that assembles at the kinetochore between late G2 and early anaphase, recruits dynein, LIS1, NDE1 and NDEL1 and is required for chromosome segregation; outside mitosis it takes part in ciliogenesis and primary cilium function, which is why its loss produces a ciliopathy-type malformative picture [19, 63]. The mechanism is biallelic loss of function [19]. In the review of 32 published cases, the great majority of variants alter the reading frame (nonsense, frameshift and, more rarely, canonical splice-site); missense variants are rare, always homozygous, and only one has functional evidence [20]. Patient fibroblasts have shortened primary cilia [64]. There are no known genotype-phenotype correlations or allelic disorders [19].

2.6. CFTR, GUCY2C and meconium ileus

Meconium ileus results from dehydration of meconium due to deficient chloride and water secretion by the intestinal epithelium, together with slow transit [21, 65]. In cystic fibrosis, the probability of meconium ileus depends on the CFTR genotype: F508del homozygosity is strongly associated with meconium ileus, and the meconium ileus prevalence (MIP) score, calculated in 2492 Canadian patients and compared with registries in the USA, Italy and Germany, ranks severe variants, with G542X (historical designation, = NM_000492.4:c.1624G>T p.(Gly542Ter); 0.31) above F508del (0.22) and G551D (historical designation, = NM_000492.4:c.1652G>A p.(Gly551Asp); 0.08) [22, 65]. Monozygotic twins are more concordant than dizygotic twins, which demonstrates the contribution of modifier genes (ADIPOR2, SLC4A4 and a CLCA1 variant have been associated; linkage to the CFM1 locus was not replicated) [65]. Modifiers explain about 17% of phenotypic variability [66].

GUCY2C (12p12.3) encodes guanylate cyclase 2C, a transmembrane receptor activated by guanylin, uroguanylin and the heat-stable enterotoxin of Escherichia coli; the cGMP it produces activates CFTR in the intestinal mucosa [46]. The gene causes two opposite disorders by opposite mechanisms: biallelic loss of function causes autosomal recessive meconium ileus without cystic fibrosis (OMIM 614665), described in two consanguineous Bedouin families and later in families of other origins; heterozygous gain of function causes autosomal dominant familial diarrhoea (diarrhoea 6, OMIM 614616), described in a Norwegian family with the activating variant NM_004963.4:c.2519G>T p.(Ser840Ile) [46, 61, 67]. De novo activating variants can present in the newborn as secretory diarrhoea with prenatal bowel dilatation and functional obstruction [67]. Penetrance of the recessive form is partial: in the large original Bedouin family (4 of 12 siblings with meconium ileus and normal sweat electrolytes), 11 of 15 homozygotes had postnatal meconium ileus (73%), and in one of the unaffected homozygotes late ultrasound showed meconium ileus that resolved with spontaneous passage of stool after birth; the variant was found in the heterozygous state in 3 of 240 Bedouin controls [23, 25].

2.7. Other genes of syndromes with atresia

Mitchell-Riley syndrome is caused by biallelic variants in RFX6 (6q22.1), which encodes the DNA-binding protein RFX6; heterozygous truncating variants cause a MODY-type monogenic diabetes, with reduced penetrance and without malformations, so the same gene has two inheritance patterns [28, 68]. Martínez-Frías syndrome, autosomal recessive, overlaps with Mitchell-Riley [35]. Feingold syndrome type 1 results from haploinsufficiency of MYCN (2p24.3) [32, 35]. Alveolar capillary dysplasia with misalignment of the pulmonary veins, caused by heterozygous FOXF1 variants, includes duodenal atresia, anal atresia and malrotation [35, 36]. X-linked laterality disorders due to ZIC3 variants combine atresias of the oesophagus, duodenum and anus, and heterotaxy occurred in three of 15 non-trisomic cases with a prenatal double bubble [35, 56].

2.8. Advances in the genetics of malrotation

Two 2026 studies explored the genetics of isolated malrotation, a cause of volvulus and short bowel. In a Swedish genome study of ten children with volvulus due to isolated malrotation, one boy had two TTC7A variants in cis, NM_020458.4:c.433G>A p.(Ala145Thr) and c.1057G>A p.(Glu353Lys), inherited from his mother, who had a mild rotation anomaly; two others had inherited variants in ROCK2 and LIMK2, genes of the same Rho kinase signalling pathway whose inhibition causes malrotation in Xenopus [61, 69]. In a North American trio genome study (21 families) of children with short bowel due to volvulus, variants emerged in GSTT4, CCDC175, WBP4 (de novo) and likely pathogenic de novo variants in TFRC in three patients [70]. Both are discovery studies, without functional validation, and do not change diagnostic practice.

2.9. Normalised reference variants

The conversions below were confirmed in VariantValidator (GRCh38, MANE Select transcripts) or in ClinVar [59, 61].

2.10. Penetrance, expressivity and modifiers

In the recessive forms (TTC7A, PI4KA, CENPF, RFX6), heterozygotes are asymptomatic [15, 19]. Expressivity is highly variable: Strømme syndrome ranges from mid-gestation lethality to isolated microcephaly with developmental delay, and atresia, initially regarded as pathognomonic, is absent in about half of cases [19, 64]; TTC7A deficiency ranges from lethal multiple atresia to IBD without atresia [11, 60]. In cystic fibrosis, the CFTR genotype and modifiers determine who has meconium ileus [22, 65].

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts and what each one measures

The figures in this article come from studies with different designs, which are not directly comparable. The table indicates what each one measures.

3.2. Congenital duodenal obstruction

Duodenal atresia is estimated at 1/6000–10,000 live births and is associated with polyhydramnios in up to 80% of cases, with frequent preterm delivery [36]. In the British study, median gestational age at birth was 36 weeks (26–42) and weight 2475 g; 59% of cases were suspected prenatally and 83% had a double bubble on radiograph [3]. Vomiting is non-bilious when the obstruction is pre-ampullary and bilious when it is post-ampullary, and without replacement dehydration, weight loss and electrolyte disturbances ensue [36].

Associated anomalies define the prognosis. In the United Kingdom, 69% of infants had at least one: heart disease in 48% (ductus arteriosus with another anomaly 19%, ventricular septal defect 17%, foramen ovale 15%, atrial septal defect 10%, atrioventricular canal 4%, tetralogy of Fallot 3%), abnormal rotation in 21%, annular pancreas in 13%, oesophageal atresia in about 10%, anorectal malformation in 6%, renal anomalies in 5% and trisomy 21 in 32% [3]. In Indianapolis, duodenal atresia was associated with prematurity (46%), polyhydramnios (33%), Down syndrome (24%), annular pancreas (33%) and malrotation (28%) [40]. In 3% there was a family history of duodenal obstruction [3].

3.3. Jejunoileal atresia

In the German cohort, the coded location was jejunal in 43% and ileal in 50%. The most frequent associations were prematurity (64%), heart disease (21%), abdominal wall defects (16%; mainly gastroschisis), volvulus (12%), central nervous system malformations (8%), urogenital malformations (7%) and cystic fibrosis (6.7%); trisomy 21 occurred in only two of 435 patients [6]. In the Indianapolis series, jejunoileal atresia was associated with intrauterine volvulus (27%), gastroschisis (16%) and meconium ileus (11.7%) [40]. Unlike the duodenal form, there is no sex predominance or relevant association with Down syndrome, and more than one third of children are born preterm [36].

The bowel proximal to the atresia is bulbous, with frequently compromised vascular supply and a risk of perforation; the distal bowel is collapsed. Prenatal ultrasound shows polyhydramnios and distended loops, and at birth there is abdominal distension, bilious vomiting and failure to pass meconium in the first 24–48 hours; the radiograph shows dilated loops with air-fluid levels and absence of distal gas [36].

Cystic fibrosis is the most relevant genetic association. In a North American population study by Roberts and colleagues (1998), cited in the Oxford Desk Reference, 4 of 38 Caucasian newborns with jejunoileal atresia had cystic fibrosis, which corresponds to a risk 210 times that of the population [35]; other series found 8% (114 cases over 35 years; 50 cases in Groningen) [72]. In the German cohort, 72% of patients with cystic fibrosis needed an initial stoma, but they had shorter admissions and no deaths in the first year [6].

3.4. Type IIIb atresia (apple peel)

Apple-peel atresia is located in the proximal jejunum near the ligament of Treitz and ends blindly; the distal segment, supplied by branches of the right colic or ileocolic artery, coils in a spiral around its pedicle and is associated with an extensive mesenteric defect [19, 36]. The distal bowel is short, the blood supply is precarious and the need to preserve bowel makes surgery difficult, with a greater risk of short bowel and of prolonged parenteral nutrition complicated by cholestasis, sepsis and multiorgan failure [19]. In a South African series of this form, 82.4% of the children were preterm [6]. The form has been described in families [36] and is highly suggestive, though not obligatory, of Strømme syndrome; in a 2026 case with prenatal diagnosis, laparotomy showed duodenal and jejunal atresia with apple-peel configuration and a hypoplastic superior mesenteric artery [19, 71].

3.5. Colonic atresia

Isolated colonic atresia or stenosis, without imperforate anus or cloacal exstrophy, is rare, located mainly in the ascending and transverse colon, has a slight male predominance and is occasionally associated with Hirschsprung disease [36]. It can coexist with small-bowel atresias in cystic fibrosis, Martínez-Frías syndrome and hereditary multiple atresias, and occur in caudal regression and the OEIS complex (omphalocele, cloacal exstrophy, imperforate anus and spinal defect) [35]. In the Indianapolis series there were 21 cases, all long-term survivors [40].

3.6. Hereditary multiple atresias: TTC7A and PI4KA

TTC7A deficiency presents at birth or shortly afterwards. At the severe end, multiple intestinal atresia with combined immunodeficiency (MIA-CID) produces obstructions at several levels, from pylorus to rectum, with homogeneous intraluminal calcifications, cholestasis and liver failure, a hypoplastic thymus and susceptibility to bacteria and viruses; the immune profile includes profound T lymphopenia, milder B and NK lymphopenia and low IgG, IgA and IgM with raised IgE [10, 57]. At the mild end there is very early-onset IBD with apoptotic enterocolitis and loss of intestinal architecture, with or without immunodeficiency, and skin and hair manifestations [57, 75]. In the review of 49 patients published up to 2017, phenotypes were distributed as follows: multiple atresia with combined immunodeficiency (16), IBD with immunodeficiency (14), isolated multiple atresia (8), atresia-IBD-immunodeficiency complex (8) and isolated IBD (3); 20 survived [60].

The EBMT cohort (61 patients, 31 with multiple atresia and 30 with IBD) adds data on treated disease. Surgery at presentation was needed by 90% of patients with atresia, almost always with multiple resections and stomas from duodenum to colon, and 97% required parenteral nutrition from birth; T lymphopenia affected 92% of patients with atresia and 66% of patients with IBD, and immunoglobulin replacement was needed in 71% and 43%, respectively [11]. Infections with cytomegalovirus, Gram-negative organisms, Pneumocystis and Aspergillus were frequent; autoimmunity (cytopenias, thyroiditis, alopecia) occurred in 28% and neoplasms in 6.5% (myelodysplastic syndrome, gastric carcinoma, lymphoblastic lymphoma after transplantation and Langerhans cell histiocytosis) [11].

Histology has characteristic but not diagnostic features: multifocal atresia with multiple "sieve-like" lumina due to mucosal adhesions, "cord-like" segments without a lumen, calcifications, neutrophilic colitis, eosinophilia of the lamina propria throughout the digestive tract, hypertrophy and disorganisation of the colonic muscularis mucosae and atrophic gastritis [41, 57]. In the French-Canadian families, pregnancies were accompanied by polyhydramnios and bowel dilatation from 22–25 weeks, and several patients developed new atresias (pyloric, jejunal) after the first operation [41, 42].

PI4KA-related disorder has four overlapping phenotypes: hypomyelinating leukodystrophy with pyramidal signs, developmental delay and intellectual disability, with or without IBD (the most common); multiple intestinal atresia at birth, with or without immunodeficiency; and late-onset hereditary spastic paraplegia (SPG84) [15]. Multiple atresia occurred in 5 of 24 patients, IBD in 4 of 24 and immunodeficiency in 6 of 21 [15]. In the 13 Amish newborns with atresia (five with molecular confirmation of p.(Tyr1623Asp)), the atresias extended from pylorus to anus; only one had enough patent bowel to attempt resection, but inflammation, restenosis and a new antral atresia prevented enteral feeding, and all died in the first month [15]. The immunodeficiency is combined and variable (hypo- or agammaglobulinaemia, T lymphopenia with CD8 predominance) and, in one patient homozygous for p.(Asp1854Asn), follicular lymphoma developed at 10 years [15].

3.7. Strømme syndrome

The frequencies reported in GeneReviews (25 individuals with clinical data) are as follows [19]:

In the review of 32 cases published in 2026, neurological manifestations (mainly microcephaly) occurred in 91%, gastrointestinal ones in 69% and ocular ones in 44%, and facial dysmorphism had no common pattern [20]. Four individuals with biallelic variants had microcephaly (−2.9 to −5.6 standard deviations) and developmental delay without the combination of atresia and ocular anomaly, and only one had duodenal atresia [64]. Most patients are born preterm, and atresia worsens the malabsorption and poor weight gain, which also occur without atresia [19]. Prognosis ranges from mid-gestation lethality, corresponding to the Orphanet entry of lethal brain malformation with duodenal atresia and bilateral renal hypoplasia, to isolated microcephaly [19, 49].

3.8. Meconium ileus

Meconium ileus is obstruction of the terminal ileum by thick meconium; it presents with failure to pass meconium, distension and vomiting [37]. It occurs in 13–17% of people with cystic fibrosis in the van der Doef review, in about 20% in other reviews and in 13–21% in the registries of Canada, the USA, Italy and Germany, and is often the first manifestation of the disease [22, 65, 66, 76]; the Brazilian book Síndromes Genéticas: Reconhecer para Tratar includes it, together with low birth weight and failure to thrive, among the gastrointestinal manifestations of cystic fibrosis [77]. Meconium ileus also occurs without cystic fibrosis: in Amsterdam, 23 of 43 patients (53.5%) had cystic fibrosis; complex forms were more frequent in patients without cystic fibrosis, who had lower gestational age and weight, and all patients with cystic fibrosis and complex ileus were F508del homozygotes [73]. GUCY2C deficiency explains part of the cases without cystic fibrosis, without pulmonary or pancreatic involvement, and two patients had chronic diarrhoea in childhood [25, 46].

In the Italian series of 85 infants with cystic fibrosis and meconium ileus (2009–2015), 24% were preterm, about 25% had obstruction diagnosed prenatally, 39% had complex ileus and 71 underwent surgery, 82% of whom received postoperative intensive care; cholestasis occurred in 21% [74]. After the neonatal period, the obstructive spectrum of cystic fibrosis continues with distal intestinal obstruction syndrome (DIOS), formerly called "meconium ileus equivalent", with a lifetime prevalence of 7–8% in childhood and 14–16% in adulthood, and with constipation [65]. Patients with cystic fibrosis also have a higher prevalence of coeliac disease and IBD and a lifetime risk of gastrointestinal cancer 23 times that of the population [21].

3.9. Meconium peritonitis, fetal volvulus and perforation

Meconium peritonitis results from a prenatal intestinal perforation. In the meta-analysis of 244 prenatally diagnosed cases, the most common cause of perforation was small-bowel atresia (52.2%) and cystic fibrosis was diagnosed in 9.8% [39]. In a Taiwanese series, 64.9% of the 37 cases had a prenatal diagnosis, 59.5% were born preterm, the most common prenatal findings were ascites and dilated loops, and volvulus was the most frequent anatomical anomaly [78].

Segmental volvulus is a mainly prenatal entity: of 17 newborns operated on at the Necker hospital, 94% had anomalies on prenatal ultrasound (more than in complete volvulus), only 23% had intestinal malposition, 88% needed resection and all required parenteral nutrition, for a median of 50 days (5–251) [47]. In complete midgut volvulus, on a malrotation, twisting of the mesentery interrupts the blood supply and produces distension, pain, vomiting, constipation and bloody stools, with shock and peritonitis within a few hours [36]. In a German series from 2005–2022, seven of 45 volvulus cases were fetal; diagnosis rested on bowel distension and the whirlpool sign, and the outcome depended mainly on gestational age and the morbidity of prematurity [33].

3.10. Natural history and treated disease

Intestinal atresias are incompatible with survival without surgery, and the available data describe treated disease. In isolated forms, survival is high: 86% in duodenal atresia, 84% in jejunoileal atresia and 100% in colonic atresia in Indianapolis (1972–1997) [40]; 1-year mortality of 5.1% in jejunoileal atresia in Germany (2007–2016) [6]; and survival of all infants without an associated anomaly at 28 days in British duodenal obstruction [3]. The main causes of morbidity and mortality are the associated heart defects, in duodenal atresia, and ultrashort bowel (less than 40 cm) with prolonged parenteral nutrition and liver disease, in jejunoileal atresia [40]. In genetic forms with multiple atresia, the prognosis is different: in TTC7A deficiency, survival was 48% in the multiple atresia phenotype, against 80% in the IBD phenotype (median follow-up 4.2 years), and among the Amish with PI4KA atresia all newborns died in the first month, with most families opting for palliative care [11, 15]. In cystic fibrosis meconium ileus, first-year survival rose from 55% (born 1958–1972) to 96% (1973–1987), and recent series show no difference in survival compared with patients without meconium ileus [65].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

Pregnancy. Fetal intestinal obstruction is suspected in the presence of polyhydramnios, a dilated stomach and duodenum (double bubble), dilated bowel loops, hyperechogenic bowel, ascites, peritoneal calcifications or a pseudocyst [36, 39, 54]. Polyhydramnios (deepest vertical pocket greater than 8 cm) occurs in 1–2% of pregnancies; about 8% have additional fetal anomalies on ultrasound, and the dominant structural causes are high gastrointestinal obstruction and brainstem anomalies [54]. The double bubble is highly suggestive of duodenal obstruction: all live-born infants with a prenatal double bubble had confirmed duodenal atresia in a cohort of 21 cases, and 25 of 27 operated infants in another cohort of 29 fetuses [56, 79]. Hyperechogenic bowel, with echogenicity equal to that of the iliac crest, occurs in about 0.8% of pregnancies in the second and third trimesters and is associated with aneuploidy, cystic fibrosis, congenital infection, digestive anomaly, growth restriction and fetal death [80]. In atresias, prenatal detection is incomplete: about one third of cases were detected in 18 European registries (40% of these before 24 weeks) [35], and 59% of duodenal obstructions in the United Kingdom [3].

Newborn. The cardinal signs are bilious vomiting, abdominal distension, excessive gastric aspirate and failure to pass meconium in the first 24–48 hours [35, 36]. Duodenal obstruction should be considered in any newborn with signs of high obstruction in the first hours, because in almost half there is no prenatal suspicion [3].

Family and exposure context. The history should record affected siblings or parents, consanguinity, maternal age, maternal diabetes, exposure to teratogens (thalidomide embryopathy, with a teratogenic window between days 20 and 36 after fertilisation, includes intestinal atresia, anorectal stenosis and pyloric stenosis [81]), twinning or early loss of a co-twin [35]. In consanguineous families with neonatal deaths from intestinal obstruction, as in the Chinese family described by Mou and colleagues, recurrence suggests TTC7A deficiency [58]. In people of Ohio Amish origin with multiple atresia, the PI4KA founder variant should be tested first [15].

4.2. Clues pointing to a genetic cause

4.3. Warning and emergency signs

In the presence of bilious vomiting in the newborn, midgut volvulus must be excluded immediately, because twisting of the mesentery interrupts the blood supply and progresses within a few hours to necrosis, shock and peritonitis [36]. In meconium ileus, the complex form is a surgical emergency; intra-abdominal calcifications and marked air-fluid levels help to distinguish it from the simple form, but the distinction is not always easy [37]. In prenatal meconium peritonitis, pseudocyst (odds ratio [OR] 6.75), bowel dilatation (OR 4.17) and ascites (OR 2.57) predict neonatal surgery, and these fetuses should be delivered in centres with paediatric surgery [39]. When associated oesophageal atresia is suspected, an experienced paediatrician should be present at delivery to reduce the risk of aspiration pneumonia [35]. In an infant operated on for multiple atresia, recurrent sepsis refractory to antibiotics should prompt investigation of immunity [58].

4.4. Newborn screening

Newborn screening for cystic fibrosis by immunoreactive trypsinogen (IRT) in dried blood spots collected at 24–72 hours has been universal in the USA since 2010; an abnormal result requires a sweat test [21]. In the United Kingdom, the Oxford Desk Reference describes IRT measurement followed by two-tier CFTR analysis in samples above the 99.5th percentile, which detects affected individuals and also some carriers, in a number roughly equal to that of affected individuals [82]. In Brazil, the algorithm uses two IRT measurements, the second by 30 days, followed by a sweat test [83]. In the Italian meconium ileus series, a higher initial IRT was associated with a worse outcome at 12 months [74]. A newborn with jejunoileal atresia or meconium ileus should be investigated for cystic fibrosis regardless of screening, because the atresia alone justifies the investigation [35, 72].

Screening for severe combined immunodeficiency by TREC count can detect TTC7A deficiency, but sensitivity is incomplete. In the EBMT cohort, neonatal TREC was available in eight patients and was abnormal in one; of the six patients with severe T lymphopenia and TREC available, only one had a low TREC [11]. In the case of Mou and colleagues, TREC measured at 80 days was 29.4 copies/µL, against 123–455 copies/µL in controls [58]. A normal neonatal TREC therefore does not exclude TTC7A deficiency in an infant with multiple atresias.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal published diagnostic criteria for intestinal atresias, TTC7A deficiency or Strømme syndrome; the anatomical diagnosis is made by imaging and surgery, and the aetiological diagnosis rests on identifying a chromosomal anomaly, biallelic variants in the causal gene or criteria for cystic fibrosis [19, 57]. In cystic fibrosis, the Cystic Fibrosis Foundation consensus (2017) requires demonstration of CFTR dysfunction, preferably by sweat test, in those with a positive screen, compatible signs (including meconium ileus) or a family history; sweat chloride ≥60 mmol/L or two cystic fibrosis-causing variants confirm the diagnosis [21, 84]. In Strømme syndrome, identification of biallelic variants of uncertain significance, or of one pathogenic variant and one uncertain variant, neither establishes nor excludes the diagnosis [19].

5.2. Prenatal imaging diagnosis

Duodenal obstruction produces the double bubble (dilated stomach and proximal duodenum), almost always with polyhydramnios; a prenatal double bubble had a high positive predictive value for duodenal atresia in two North American cohorts [56, 79]. The presence of fluid in the distal bowel on fetal magnetic resonance imaging was not associated with malrotation with volvulus in a cohort of 29 fetuses with a double bubble, in which there were five asymptomatic malrotations and no volvulus [79]. Jejunoileal atresias present with polyhydramnios and distended loops, with a differential diagnosis of meconium ileus and Hirschsprung disease [36]. Fetal volvulus is suspected in the presence of bowel distension and the whirlpool sign [33], and meconium peritonitis in the presence of ascites, calcifications, pseudocyst and dilated loops [39, 78]. In hereditary multiple atresia, intraluminal calcifications may allow prenatal detection, and in Quebec prenatal suspicion arose in 6 of 13 patients with ultrasound, on the basis of polyhydramnios, calcifications or distension [7].

Hyperechogenic bowel deserves a separate approach. In a French multicentre study of 682 fetuses (outcome known in 91%), 65.5% had a normal outcome, 3.5% a chromosomal anomaly, 3% cystic fibrosis, 2.8% viral infection (15 cytomegalovirus, 4 parvovirus), 6.2% preterm delivery, 4.1% growth restriction and 1.9% intrauterine death [80]. In a St. Louis cohort of 64,048 pregnancies, after excluding aneuploidy and cytomegalovirus infection, hyperechogenic bowel was associated with fetal death (7.3% versus 0.9%; adjusted OR 9.6) and growth restriction (19.5% versus 12.9%; adjusted OR 2.1), even when isolated [85]. The risk of cystic fibrosis in a fetus with hyperechogenic bowel ranges from 0.5% to 9.9% in the series cited by GeneReviews, and non-visualisation of the gallbladder with other anomalies multiplies it by 16; fewer than 7% of low-risk fetuses with hyperechogenic bowel will have meconium ileus [21, 66]. GUCY2C deficiency can also first manifest as hyperechogenic bowel in the second trimester, as in the Lebanese family described by Smith and colleagues [86].

Source: table 6.5 of the Oxford Desk Reference [80].

5.3. Guidelines for isolated hyperechogenic bowel

The Society for Maternal-Fetal Medicine (SMFM), in Consult Series No. 57 (2021), which replaced the 2011 document on isolated hyperechogenic bowel, recommends: not offering diagnostic testing for aneuploidy solely for an isolated marker when serum or cell-free DNA screening was negative (GRADE 1B); without prior screening, counselling on the probability of trisomy 21 and offering cell-free DNA screening (1B); and, with isolated hyperechogenic bowel, evaluating for cystic fibrosis and fetal cytomegalovirus infection and repeating ultrasound in the third trimester to reassess the bowel and growth (1C) [87]. The Oxford Desk Reference proposes the same investigation (cystic fibrosis carrier testing of the parents, maternal serology for congenital infection, biometry, detailed anomaly scan and Doppler) and adds serial growth surveillance when pregnancy-associated plasma protein A (PAPP-A) is low or the Doppler abnormal, because the risk of early growth restriction and adverse outcome persists after a negative investigation [80]. The two sources converge; the difference lies in the level of detail of surveillance.

Chromosomal microarray has a higher yield in non-isolated hyperechogenic bowel, when diagnosed in the second trimester and when there are other markers, according to a Chinese cohort of 446 pregnancies [88].

5.4. Postnatal diagnosis

The plain radiograph shows the double bubble in duodenal obstruction (83% of British cases) and dilated loops with air-fluid levels and absent distal gas in jejunoileal atresias; the upper contrast study was reserved, in the United Kingdom, for diagnostic doubt and bilious vomiting (34% of cases) [3, 36]. In Amsterdam, a contrast enema under fluoroscopy was the first diagnostic and therapeutic step in simple meconium ileus [37]. In meconium ileus, calcifications and marked air-fluid levels suggest the complex form [37]. Laparotomy defines the anatomical diagnosis, and the findings should be recorded for counselling: site, number of atresias, malrotation, volvulus, apple-peel configuration, vascular anatomy and pancreatic anomalies [35].

5.5. Aetiological investigation and algorithm

The Oxford Desk Reference proposes the following investigation: echocardiogram (VACTERL, CHARGE), renal ultrasound, spinal radiograph in oesophageal atresias, radiograph of the lumbar spine and sacrum in infants of diabetic mothers, chromosome breakage study if there are bilateral upper limb anomalies (Fanconi anaemia), ophthalmological examination, genomic analysis (microarray, panel, exome or genome) in the presence of syndromic signs, cystic fibrosis investigation in jejunoileal and colonic atresias, and DNA storage [35]. The British authors recommend an echocardiogram in all infants with duodenal obstruction before discharge, given the frequency of heart disease [3].

In TTC7A deficiency, no non-molecular test is confirmatory: histology is characteristic but not diagnostic, and demonstration of polarity inversion in organoids is a research tool [57]. Immunological testing nevertheless guides urgency: profound lymphocytopenia with low proliferation, with normal superoxide function and IL-10 signalling, helped to exclude chronic granulomatous disease and IL-10 receptor deficiency, important differentials of very early-onset IBD [57, 60]. Chen and colleagues observed profound CD8 T lymphopenia in all seven patients tested, frequent severe hypogammaglobulinaemia and more bacteraemias with intestinal organisms than viral infections, unlike typical severe combined immunodeficiency [7].

5.6. Limitations of tests

Negative results do not exclude a genetic cause, and each test has its own limitations:

The American College of Medical Genetics and Genomics published in 2020 a points-to-consider document on the use of fetal exome sequencing in prenatal diagnosis [90].

The molecular report should state the gene, the versioned reference transcript (MANE Select: TTC7A NM_020458.4, PI4KA NM_058004.4, CENPF NM_016343.4, GUCY2C NM_004963.4), the HGVS nomenclature, zygosity, the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) classification and the segregation study in the parents [19, 61]. Articles on TTC7A sometimes use transcript NM_001288951, and the old genomic numbering of the French-Canadian variant does not correspond to current c. nomenclature, which requires confirmation in ClinVar before variants are compared [42, 59, 62].

5.7. Prenatal and preimplantation diagnosis

When the family variants are known, prenatal diagnosis (chorionic villus sampling or amniocentesis) and preimplantation genetic testing are possible for TTC7A, PI4KA, CENPF and CFTR [19, 21, 91]. In cystic fibrosis, diagnosis by chorionic villus sampling is possible at 11 weeks, and non-invasive detection of the paternal allele, where available, can halve the need for an invasive procedure [91]; non-invasive prenatal testing for cystic fibrosis is expanding [21]. Without known variants, prenatal diagnosis rests on ultrasound, whose sensitivity is limited (about one third of atresias detected in European registries) [35]. In the 2026 Strømme case, suspicion of atresia at 20 weeks led to amniocentesis and exome sequencing, which identified the homozygous CENPF variant before birth [71]. Measurement of disaccharidases in amniotic fluid between 15 and 19 weeks was used historically in hereditary multiple atresia, before the molecular era [7].

6. Differential Diagnosis

6.1. Comparative table

Sources for the table: [15, 19, 28, 32, 35, 36, 46, 48, 50, 53, 54, 57, 92–94].

6.2. Main differentials

The first step is to distinguish mechanical from functional obstruction. Hirschsprung disease, MMIHS, hypothyroidism, sepsis and prenatal or intrapartum exposure to magnesium sulphate or opioids cause distension, bilious vomiting and failure to pass meconium without atresia; MMIHS is distinguished by non-obstructive megacystis and microcolon, and isolated colonic atresia has no megacystis [93]. In MMIHS, ACTG2 accounts for 44.1% of cases (autosomal dominant, more severe when de novo, with parental mosaicism described), and about 55% remain without an identified cause; prenatal suspicion arose in 26% of cases in a systematic review, mainly because of megacystis [93]. Congenital chloride diarrhoea can mimic obstruction in the fetus, with multiple dilated loops and polyhydramnios [54].

Among multiple atresias, TTC7A deficiency and PI4KA-related disorder share the mechanism and the intestinal phenotype; they are distinguished by origin (Ohio Amish in the case of PI4KA with atresia), by neurological disease (hypomyelinating leukodystrophy and polymicrogyria, specific to PI4KA) and by the hepatic manifestations and omphalocele described in TTC7A deficiency [15, 19]. Strømme syndrome differs from both by microcephaly, ocular anomalies and the absence of immunodeficiency [19].

Among syndromes with duodenal atresia and anomalies of the pancreas and biliary tract, Mitchell-Riley syndrome has neonatal diabetes and no tracheo-oesophageal fistula, and Martínez-Frías syndrome has tracheo-oesophageal fistula without diabetes; both are autosomal recessive, and no RFX6 variants were found in one patient with Martínez-Frías [35, 92]. Feingold syndrome 2 has the hand and foot phenotype of Feingold syndrome 1 without gastrointestinal anomalies, and Fanconi anaemia, which can also have intestinal or anal atresia, has neither brachymesophalangy nor toe syndactyly and carries a tumour risk [32].

In neonatal perforation, spontaneous intestinal perforation is distinguished from necrotising enterocolitis by occurring in healthy bowel, without pneumatosis or prodrome, mainly in the first week in newborns weighing less than 1500 g [48]. In the USA (Vermont Oxford Network, 2006–2010), it affected 1.1% of newborns weighing 401–1500 g, with in-hospital mortality of 19%, half that of necrotising enterocolitis confirmed at laparotomy (38%) [34]. Treatment of the ductus arteriosus with indomethacin was associated with a higher risk of spontaneous perforation (adjusted OR 1.61), and perforation was associated with death or neurodevelopmental impairment at 18–22 months (adjusted OR 1.85) [95]. In extremely low birth weight newborns born in 2000–2005, death before discharge was 39.1% with spontaneous perforation, 53.5% with surgical necrotising enterocolitis and 22.1% with neither, and death or neurodevelopmental impairment 79.3%, 82.3% and 53.3%, respectively [96]. Spontaneous perforation is not a genetic disease and does not by itself justify genetic investigation; prenatal perforation with meconium peritonitis, by contrast, requires exclusion of cystic fibrosis [39].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

Management of intestinal atresias is surgical, and delivery should be planned in a hospital with neonatal intensive care and a link to a paediatric surgical team [35]. Reality falls short of this principle: in the United Kingdom, 59% of duodenal obstructions were suspected prenatally, but only 46% of newborns were born in a centre with neonatal surgery, which the authors attribute mainly to the physical separation between maternity units and children's hospitals [3]. In Germany, 20.5% of children with jejunoileal atresia were transferred before surgery, and 69.7% of these needed an initial stoma [6]. In meconium peritonitis, survival was 100% in newborns born at the centre and 80% in those transferred, a difference without statistical significance in a series of 37 patients [78]. The European Reference Network for rare inherited and congenital digestive and gastrointestinal diseases (ERNICA) brings together multidisciplinary European centres [4], and ERN RITA covers rare immunological diseases, including TTC7A and PI4KA deficiencies [12].

7.2. Prenatal management

In fetal intestinal obstruction, ultrasound surveillance follows the polyhydramnios, bowel dilatation and signs of perforation. Fetuses with a meconium pseudocyst, bowel dilatation or ascites are more likely to need neonatal surgery and should be delivered in centres with paediatric surgery [39]. In fetal volvulus, a German series of seven cases shows that, in stable fetuses with extreme prematurity, conservative observation with close surveillance may be considered (two cases regressed spontaneously), whereas at more advanced gestational ages signs of fetal deterioration may lead to consideration of delivery and postnatal surgery; the authors stress that the size of the series does not allow standardised recommendations [33]. Severe polyhydramnios may require amnioreduction, as in the Italian case of meconium ileus treated with CFTR modulators [97]. In gastroschisis with atresia, the Oxford Desk Reference refers to close surveillance and planned delivery around 37 weeks in a specialist perinatal centre [50].

7.3. Duodenal obstruction

Definitive treatment is surgical and aims to restore digestive continuity without injuring the bile and pancreatic ducts; no technique has shown superiority [3]. In the British study, surgery took place on day 2 of life (0–75), by laparotomy in 95% of cases, with duodenoduodenostomy in 76%, duodenojejunostomy in 15%, web resection in 4%, duodenoplasty in 3% and web incision in 1%; intestinal rotation was assessed in 87% and rotation anomalies corrected in 82% of the cases found (Ladd procedure in 13% of the total) [3]. In Indianapolis, duodenoduodenostomy was used in 86%, web excision in 7% and duodenojejunostomy in 5%, and three critically ill newborns received a duodenostomy tube [40].

After surgery, gastroduodenal dysmotility secondary to the intrauterine obstruction requires nutritional support. The two strategies, parenteral nutrition and distal feeding via a transanastomotic tube, have not been conclusively compared; in the United Kingdom, 42% of infants had a transanastomotic tube and 88% received parenteral nutrition (median 11 days), with variation between centres not explained by clinical factors [3]. Enteral feeding started on day 4 (1–35) and was full by day 12 (2–44); 21% of infants had central catheter complications, reoperation related to the initial surgery was 3% at 28 days, and the two deaths (2%) occurred in infants with trisomy 21 from causes unrelated to the obstruction [3]. Surgery is usually curative, but trisomy 21, heart defects and prematurity shape the outcome [3, 40].

7.4. Jejunoileal atresia and apple-peel atresia

The options are resection with primary anastomosis, tapering enteroplasty of the dilated proximal segment, temporary stoma (including the Bishop-Koop technique) and, in short bowel, bowel lengthening procedures (Bianchi and STEP, serial transverse enteroplasty) [6, 40]. In Indianapolis, 76% of patients had resection (anastomosis 46%, tapering 24%, temporary stoma 30%), 20% stoma alone and 4% web excision [40]. In the German cohort, an initial stoma was used in 59.8% (against 11–42% in other series) and a further 8.5% needed a secondary stoma; short bowel was coded in 22.3%, liver disease in 16.3% and bowel lengthening in 1.8% [6]. Patients with a stoma had more short bowel, surgical central catheters and longer admissions (median 81–86 days against 32 days without a stoma), without a difference in mortality, which indicates that the stoma was used in the most severe cases; the authors do not draw recommendations on the choice of technique from the data [6].

In apple-peel atresia, resection of the atretic segment with anastomosis has to reconcile the precarious blood supply of the distal segment with the need to preserve bowel; the risk of short bowel and of prolonged parenteral nutrition, complicated by cholestasis, sepsis and multiorgan failure, is higher [19].

7.5. Colonic atresia

In Indianapolis, 86% of the 21 colonic atresias were treated with an initial stoma and delayed anastomosis and 14% with resection and primary anastomosis, all with long-term survival [40]. An occasional association between colonic atresia and Hirschsprung disease has been described [36].

7.6. Meconium ileus

In simple meconium ileus, most authors use as initial treatment an enema of hyperosmolar contrast, saline or N-acetylcysteine [37]. Success rates of diatrizoate enema (Gastrografin®) in contemporary series are 36–39%, lower than historical rates [66]. In Amsterdam, the protocol used Gastrografin® diluted 1:1 in 0.9% sodium chloride (hyperosmolar solution), in a single attempt under fluoroscopy: it resolved 7 of 18 simple ileus cases (39%), all 4 patients without cystic fibrosis and 3 of 14 with cystic fibrosis (21%), without enema complications [37]. There are no guidelines on enema technique or on surgery for meconium ileus, and the dose and dilution cited are those of the Amsterdam centre protocol, not a society recommendation [37].

Complex ileus and simple ileus not responding to the enema require surgery: enterotomy with irrigation, T-tube ileostomy, resection with primary anastomosis, Bishop-Koop ileostomy or other diversions [37]. Primary anastomosis had 21–31% surgical complications, more than delayed anastomosis [66]; in Amsterdam, two of the four patients treated with purse-string enterotomy and irrigation had peritonitis, and there were adhesive obstructions after resection [37]. In the Italian series, the factors for poor outcome at 12 months were prenatal diagnosis of the obstruction, the need for intensive care and oxygen, raised IRT and early cholestasis; breastfeeding was associated with a better outcome (not being breastfed: OR 2.921) [74]. Meconium ileus with obstruction requires surgery, and without obstruction it is treated with laxatives [21]. Cystic fibrosis follow-up includes pancreatic enzymes, nutrition, fat-soluble vitamins and CFTR modulators. After the neonatal period, DIOS is treated with oral polyethylene glycol or bowel lavage with electrolyte solution and hydration, and surgery has become rare [65].

Meconium ileus due to GUCY2C deficiency is treated like any neonatal obstruction [67]. The FDA-approved guanylate cyclase C agonists for constipation (linaclotide, Linzess®; plecanatide, Trulance®) pharmacologically reproduce the effect of activating variants: they have no indication in this disease, are contraindicated in known or suspected mechanical obstruction and the labels carry a warning about severe dehydration in young children [67].

7.7. Meconium peritonitis and volvulus

In the meta-analysis of 244 prenatally diagnosed meconium peritonitis cases, two thirds (66.5%) needed postnatal abdominal surgery, postoperative mortality was 8.1% and all non-operated newborns survived [39]. In Taiwan, 91.9% of the 37 cases underwent surgery, morbidity (adhesive ileus, bacteraemia, short bowel) was 37.8% and survival 91.9%, with no difference between prenatal and postnatal diagnosis [78]. Midgut volvulus requires urgent surgery to prevent necrosis [36]. Perinatal segmental volvulus led to resection in 88% of cases and to parenteral nutrition in all (median 50 days) [47].

7.8. TTC7A deficiency

There is no standard treatment or society guideline, and the evidence is limited to series and reviews [11, 57]. Surgery for the atresias is palliative: obstructions occur at several levels, recur, and new atresias appear after resection [11, 42, 57]. In the EBMT cohort, 97% of patients with multiple atresia needed parenteral nutrition from birth, and all survivors with this phenotype remain dependent on it, with or without transplantation [11]. Immunosuppression for the inflammatory component (corticosteroids or infliximab first line; leflunomide in three patients) had a limited response, of 38% in the atresia phenotype and 50% in the IBD phenotype [11]. Laboratory and animal data suggest that leflunomide reduces epithelial apoptosis, but there is no evidence of clinical efficacy, and Rho kinase inhibition remains in the domain of organoids [11, 15, 44].

Haematopoietic stem cell transplantation corrects the immunodeficiency but not the epithelial disease. In one patient transplanted from a non-identical sibling, immunity was reconstituted at 22 months, but the bowel remained atretic and dependent on parenteral nutrition [41]. In the review of 49 patients, transplantation restored immunity and appeared to reduce infections, but refractory diarrhoea persisted [60]. In the EBMT cohort, 16 patients (10 with atresia, 6 with IBD) were transplanted at a median age of 1.16 years, with a matched donor in 71% and reduced-intensity or myeloablative conditioning; all engrafted, acute graft-versus-host disease occurred in 50%, transplant-related mortality was 44% and only four of the 16 came off parenteral nutrition [11]. The two solid organ transplants in the cohort (intestine with liver; isolated intestine), both after stem cell transplantation, ended in death [11]. The French-Canadian authors suggested, on the basis of the thymic pathology, considering intestinal transplantation combined with thymus transplantation; a combined liver and small-bowel transplant in a patient with multiple atresia had no hepatic or intestinal recurrence [41].

Supportive measures follow from the combined immunodeficiency: immunoglobulin replacement (71% of patients with atresia in the EBMT cohort), prolonged multidrug anti-infective prophylaxis, irradiated and cytomegalovirus-safe blood products and avoidance of live vaccines, as in any severe combined immunodeficiency [11, 57]. Classification of the deficiency among the primary immunodeficiencies affecting cellular and humoral immunity was proposed to enable this early recognition [60]. When no intestinal donor is available and the prognosis is unfavourable, palliative care is a legitimate option [42, 57].

7.9. PI4KA-related disorder, Strømme syndrome and other syndromic forms

In PI4KA-related multiple intestinal atresia there is no known treatment; parenteral nutrition and intestinal transplantation (with high mortality) are the options, and in patients with a poor prognosis a palliative approach may be considered; in one infant, IBD and small-bowel stricture recurred after resection [15]. IBD is treated with the usual immunosuppressants, corticosteroids, antibodies and diet, and surgery is reserved for refractory disease and obstructions [15]. Neurological disease requires physiotherapy, occupational and speech therapy, educational support and antiseizure medication when indicated [15].

In Strømme syndrome there are no guidelines; the atresia is treated surgically, and the remaining care (development, ophthalmology and low vision, kidney, heart, augmentative communication, social services and coordination) is supportive [19]. Mitchell-Riley syndrome requires insulin (no response to sulfonylureas), high caloric intake and pancreatic enzymes for exocrine insufficiency [68]. In Feingold syndrome, the atresia is treated surgically without delay [32].

7.10. Drugs with published data in the entities within scope

There is no targeted pharmacological therapy for atresias. The drugs with data in the entities within scope are as follows.

The elexacaftor/tezacaftor/ivacaftor dose used in the reports of fetal treatment corresponds to the adult dose on the labels: the FDA and the EMA specify, from 12 years, two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg in the morning and one tablet of ivacaftor 150 mg in the evening, about 12 hours apart and with fat-containing food [98, 99]. The labels diverge on hepatic monitoring (the FDA requires liver function tests monthly for the first six months, then every three months for the following year and annually; the EMA requires transaminases and bilirubin before treatment, every three months in the first year and annually thereafter) and on pregnancy: the FDA describes limited human data and animal studies without adverse developmental effects, and the EMA, with 300–1000 pregnancy outcomes without malformative toxicity, considers it preferable as a precaution to avoid the drug in pregnancy [98, 99]. Both labels are intended for people with cystic fibrosis; treatment of a healthy carrier mother for the benefit of the fetus falls outside the conditions of both and, in the Italian case, required approval by an ethics committee and informed consent [97]. No guideline recommends this use.

7.11. Comparative regulatory status

Sources: [98, 99, 103].

7.12. Interventional evidence

The studies are not comparable with one another. The meta-analysis of prenatal modulators rests on reports and small series, with probable publication bias and comparison with a historical cohort, and the authors call for prospective controlled studies; the outcome is surgery, not survival or long-term pancreatic function [100]. Failures are also published: a 2026 case with meconium ileus and volvulus did not respond, and the Metcalf case with shorter exposure ended in jejunostomy [104, 105]. In the Italian series of the Boni case, pancreatic insufficiency set in during the first month despite resolution of the ileus [97]. In TTC7A deficiency, the transplant data come from a retrospective registry with selection of the transplanted patients [11].

7.13. Developments in the last 6–12 months

Between October 2025 and October 2026 the following data were published, ordered by level of evidence. At the level of evidence synthesis, the individual-data meta-analysis by Menditto and colleagues (2026) estimated the need for surgery in fetuses with meconium ileus treated with maternal modulators at 12% [100]. At the level of observational studies, the EBMT cohort of 61 patients with TTC7A deficiency measured survival, transplant outcomes, autoimmunity and neoplasms [11], and the Cain-Trivette cohort showed that distal fluid on fetal MRI with a double bubble does not predict volvulus [79]. At the level of case reports, the first Italian case of fetal treatment with transplacental pharmacokinetics was published [97], a failure with volvulus [105], the 27th genetically confirmed case of Strømme syndrome, with prenatal diagnosis [71], and the review of the 32 CENPF cases [20]. At the level of genetic discovery, candidates emerged for isolated malrotation (TTC7A, ROCK2, LIMK2; TFRC, WBP4) [69, 70]. In ClinicalTrials.gov there were no trials of therapy targeted at genetic atresias or TTC7A deficiency; the registered studies evaluate surgical techniques (stapled versus hand-sewn anastomosis, laparoscopy in duodenal atresia), intestinal failure (GLP-2, completed phase 1/2 trial; distraction enterogenesis) and enemas in meconium obstruction of prematurity [106]. The observational MAYFLOWERS study (NCT04828382; 285 estimated participants, primary completion expected in June 2027) evaluates pregnancy in women with cystic fibrosis and does not include treatment of carrier mothers [107]. There were no new regulatory authorisations or opinions for the entities within scope.

7.14. Agents to avoid, pregnancy, perioperative care and transition

In TTC7A deficiency and in forms with combined immunodeficiency, live vaccines should be avoided and irradiated, cytomegalovirus-safe blood products used [57]. In GUCY2C deficiency, guanylate cyclase C agonists are contraindicated [67]. In the very low birth weight newborn, indomethacin used to treat the ductus arteriosus was associated with a higher risk of spontaneous intestinal perforation, whereas prophylactic indomethacin and antenatal corticosteroids were not [95]. The MMIHS GeneReviews chapter includes prenatal or intrapartum exposure to magnesium sulphate and opioids in the differential diagnosis of functional obstruction in the newborn [93].

In a pregnancy with a fetus with atresia, planning delivery in a centre with paediatric surgery is the measure with the greatest impact [3, 35]. Maternal use of CFTR modulators for the benefit of the fetus should be discussed in a multidisciplinary team (cystic fibrosis, maternal-fetal medicine, paediatric surgery and ethics), with informed consent and follow-up of the exposed child, including neurodevelopmental assessment, liver function and ophthalmological examination, as in the Italian case; an international Delphi consensus endorsed by the European Cystic Fibrosis Society (ECFS, 2026) defines 73 follow-up items for children exposed to modulators in utero or through breastfeeding [21, 97].

In the perioperative care of TTC7A deficiency, infections with intestinal organisms and central catheter infections are the main threat; bacteraemia was more frequent than viral infections in the Chen series [7, 11]. In patients with cystic fibrosis and a history of meconium ileus or laparotomy, DIOS is frequent after lung transplantation, and the authors suggest preventive laxatives in that setting [65]. Transition to adulthood is relevant mainly in cystic fibrosis, in TTC7A deficiency with IBD (autoimmunity and neoplasms appear in the second and third decades) and in Strømme syndrome with intellectual disability [11, 19].

7.15. Applicable guidelines and divergences

No specific scientific society guidelines were found for intestinal atresia, surgery for meconium ileus or TTC7A deficiency; the Strømme syndrome GeneReviews chapter states that there are no guidelines, and GeneGuidance did not locate any for TTC7A deficiency [19, 37, 57]. The applicable guidance is indirect:

The most relevant divergence is not between societies but between surgical series: the proportion of primary stoma in jejunoileal atresia ranges from 11–42% in the literature to 59.8% in Germany, and postoperative feeding in duodenal obstruction varies between centres without a clinical explanation [3, 6]. As for the recurrence risk of about 1/50 after duodenal atresia, the Oxford Desk Reference attributes it to the American Academy of Pediatrics survey, which OMIM describes as 503 patients with 13 occurrences of atresia in siblings, without stating the number of siblings exposed (section 8) [1, 35].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

Counselling begins by classifying the case: isolated or syndromic, with or without an identified cause. In non-syndromic cases a cause is rarely found, but the recurrence risk is low; in syndromic cases, the risk follows the mechanism [35].

In type IIIb jejunal atresia, OMIM describes several sibships with recurrence and transmission compatible with recessive inheritance: 4 affected among 18 children of first cousins, Arab siblings of consanguineous parents and other families with affected siblings; the IIIb form is the one that most often presents in families, although there are familial cases of types I, II and IV [5]. In duodenal atresia too there are consanguineous families with several affected individuals and one family with transmission from an affected man to his daughter [1]. These families predate the molecular era, and some may correspond to the monogenic disorders now known; in one apple-peel case with a maternal balanced translocation t(2;3), the association may have been coincidental [5, 16].

8.2. Parental testing, carriers and cascade testing

In recessive disorders, the parents should be tested to confirm heterozygosity and exclude a de novo variant, parental mosaicism, an undetected deletion or uniparental isodisomy [19]. Carrier detection is only possible when the family's disorder has been identified (cystic fibrosis, another monogenic disorder with known variants or a chromosomal rearrangement) [35]. In cystic fibrosis, carrier testing is offered to both parents and then cascade screening of the extended family [91]. In founder populations, the carrier frequency changes the calculation: the Amish PI4KA variant has an allele frequency of 0.0006 and all Amish carriers identified are from Ohio [15]; the TTC7A AAGT deletion was found in the homozygous state in all French-Canadian cases from Quebec studied, with no known genealogical relationship back to the great-grandparents [42]; the GUCY2C variant of the large Bedouin family was found in 3 of 240 Bedouin controls [23].

8.3. Prenatal and preimplantation diagnosis and subsequent pregnancies

With known variants, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible; the ideal time to discuss the risk and options is before pregnancy [15, 19]. In cystic fibrosis, chorionic villus sampling is possible at 11 weeks, and non-invasive testing for the paternal allele can reduce the need for invasive procedures [91]. In pregnancies following an atresia without a genetic cause, ultrasound in the second and third trimesters is the available tool, with prenatal detection of about one third of atresias in European registries and of 59% of duodenal obstructions in the United Kingdom [3, 35]. In Feingold syndrome, high-resolution ultrasound with fetal echocardiography is recommended in any pregnancy with a carrier fetus or with a 50% risk [32].

8.4. Counselling for hyperechogenic bowel and cystic fibrosis

With hyperechogenic bowel, cystic fibrosis carrier testing of both parents guides the risk. If both are carriers, the risk of fetal cystic fibrosis is very high, and confirmation can be made by amniocentesis or placental biopsy, if termination is being considered, or on cord blood at birth, if the pregnancy continues [80]. If only one parent is a carrier, Muller and colleagues found cystic fibrosis in 11% of fetuses with one variant and hyperechogenic bowel, and the Oxford Desk Reference calculates by Bayes' theorem a risk of about 16.7% when the variant has been identified in the fetus and about 9.5% without a fetal sample, with probabilities valid for European populations (carrier frequency varies with ethnicity) [80]:

The table reproduces table 6.6 of the Oxford Desk Reference; the joint probability cell without cystic fibrosis is printed in the book as 0.33756, but the final result of 16.7% corresponds to 0.033756 [80].

8.5. Twins, disruptions and psychosocial aspects

In monozygotic twins, intestinal atresia may be a vascular disruption, especially after the death of a co-twin, and the genetic recurrence risk is low [52, 53]. In severe recessive disorders with high neonatal mortality (PI4KA atresia, TTC7A deficiency with multiple atresia), counselling includes discussion of palliative care, chosen by most Amish families and by some French-Canadian families [15, 42]. The offer of an experimental prenatal therapy, such as CFTR modulators, can transform the parents' experience during diagnostic uncertainty, a psychological effect that has not yet been studied systematically [97]. Predictive testing of younger siblings of a child with cystic fibrosis is justified by the benefit of early treatment (prophylactic antibiotics, pancreatic enzymes and vitamins) [91].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Europe

The EUROCAT study (20 registries, 1990–2006) measured total prevalence, which includes live births, fetal deaths and terminations of pregnancy: with a normal karyotype, 1.6 per 10,000 births for small-bowel atresia, 0.9 for duodenal atresia and 0.7 for jejunoileal atresia, with no temporal trend, significant variation between registries and a slightly higher risk in mothers under 20 years (RR 1.3) [2]. The country values compiled by Orphanet from this study show the heterogeneity:

Source: Orphanet [109, 110], based on Best and colleagues [2]. The values by registry refer to the regions covered by each registry, not to the whole country.

The more recent national studies measure something else. In the United Kingdom, the prospective incidence of duodenal obstruction treated in surgical centres was 1.22 per 10,000 live births in 2016–2017 [3]. In Germany, the incidence of operated jejunoileal atresia was 2.1 per 10,000 live births (1.9 without necrotising enterocolitis) in 2007–2016, higher than in other series (0.3–1.6 per 10,000), which the authors attribute to the inclusion of cases with gastroschisis and volvulus and to the socioeconomic profile of AOK insured persons [6]. Orphanet estimates isolated multiple intestinal atresia at 4.05 per 100,000 births [9]. In gastroschisis, European prevalence rose from 0.54 to 2.12 per 10,000 births between 1980–1984 and 2000–2002, with a 12-fold higher risk in mothers under 20 years [50].

9.2. North America

The Indianapolis series (277 cases, 1972–1997) and the population study by Roberts and colleagues (1968–1995), which found cystic fibrosis in 4 of 38 (11%) Caucasian newborns with jejunoileal atresia, are the classic North American references [5, 40]. In the Vermont Oxford Network (2006–2010), spontaneous intestinal perforation affected 1.1% of very low birth weight newborns [34]. The Johns Hopkins double-bubble cohort found trisomy 21 in 6 of 21 cases [56].

9.3. Founder populations and consanguinity

TTC7A deficiency has a French-Canadian founder effect in Quebec: Bilodeau and colleagues reviewed 16 multiple atresias over 30 years in the region (4 probands from Saguenay-Lac-Saint-Jean), all operated on, none recovered intestinal function and all died, with a mean survival of 50 days [7]; Samuels and colleagues found the same AAGT deletion in the homozygous state in all cases studied, with no known genealogical relationship [42]. PI4KA-related disorder with multiple atresia is concentrated in the Ohio Amish community, with a founder variant allele frequency of 0.0006 [15]. Meconium ileus due to GUCY2C deficiency was first described in consanguineous Bedouin families, then in a Lebanese family (with fetal hyperechogenic bowel in the second trimester as the first manifestation), in three families from southern India and in a non-Middle Eastern infant, and the authors of the original description speculate about a selective advantage (resistance to diarrhoea caused by E. coli enterotoxin) [46, 67, 86]. Recessive forms of atresia are more frequent in consanguineous populations, and the mild phenotype of TTC7A deficiency is recognised only by sequencing, so the true frequency is probably higher than the count of severe cases [57]. Mitchell-Riley syndrome has been described in Pakistani, Spanish Roma and French families [26], and Martínez-Frías syndrome in a sibship of consanguineous Spanish Roma parents [92].

9.4. Portugal and Brazil

The Portuguese registry took part in the EUROCAT study: the birth prevalence compiled by Orphanet is 10.0 per 100,000 for small-bowel atresia and 3.0 per 100,000 for duodenal atresia, the latter among the lowest values in Europe [2, 109, 110]. No Portuguese data on the monogenic forms were found in the sources consulted. In Brazil, the cystic fibrosis guidelines estimate the incidence at 1 in 7576 live births, higher in the southern states, with broad-coverage newborn screening based on two IRT measurements [83]; Brazilian data on intestinal atresias do not appear in the sources consulted, which does not demonstrate their absence.

9.5. European networks and associations

ERNICA is the European Reference Network for rare inherited and congenital digestive and gastrointestinal diseases, with multidisciplinary centres in several countries [4]. ERN RITA covers rare immunological diseases, which include TTC7A and PI4KA deficiencies with immunodeficiency [12]. The TOFS association supports families with oesophageal atresia and tracheo-oesophageal fistula [35]. Cystic fibrosis associations play a role in access to modulators; in the Italian case of fetal treatment, a local patient association supported the decision [97].

10. Illustrative Clinical Case

10.1. Multiple intestinal atresia with combined immunodeficiency due to a homozygous TTC7A missense variant

Mou and colleagues (Beijing Children's Hospital, 2021) described a boy, the fifth child of consanguineous Chinese parents [58]. The couple's first child had multiple intestinal atresia and died in the first month from postoperative sepsis and multiorgan failure; the second and fourth children had vomiting due to digestive obstruction and died in the neonatal period; the third, aged 11, was healthy; there had also been one termination of pregnancy. The pedigree, histology and chromatogram can be seen in figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC8714664/figure/f1/).

The patient was born by vaginal delivery at 34 weeks. Soon after birth, intestinal perforation and meconium peritonitis due to obstruction were suspected, and three operations revealed multiple atresias: a pyloric diaphragm, ileal atresia and colonic stenosis. Histology of the ileum adjacent to the atresias showed mucosal erosion, epithelial depolarisation, vascular hyperplasia, dense immune infiltrate of the lamina propria, dilated and tortuous glands and lymphoproliferative changes in the submucosa [58].

During the admission he had seven episodes of sepsis with high fever and raised C-reactive protein; at 21 days, two blood cultures from different sites grew Klebsiella oxytoca and methicillin-resistant Staphylococcus epidermidis, with a poor response to aztreonam, amikacin, meropenem and fluconazole. Immunophenotyping at 80 days showed normal total lymphocytes (3020/µL), but CD3 T lymphocytes of 182/µL (reference 2179–4424), CD4 of 47/µL, CD8 of 123/µL and markedly reduced naïve T cells (naïve CD4 13/µL; naïve CD8 31/µL); TREC was 29.4 copies/µL (controls 123–455), KREC (kappa-deleting recombination excision circles) was reduced, double-negative T cells and transitional B cells were increased and the thymus was small on radiograph, in a profile of low T and NK lymphocytes with B cells present (figure 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC8714664/figure/f3/) [58].

Trio exome sequencing identified the homozygous variant NM_020458.4:c.206T>C p.(Leu69Pro) in exon 2 of TTC7A, inherited from both heterozygous parents and absent from ClinVar and the Human Gene Mutation Database (HGMD); the residue is conserved and the substitution breaks a hydrogen bond between Gly65 and Leu69 [58, 61]. TTC7A expression was reduced in lymphocytes and in the bowel (figure 4, https://pmc.ncbi.nlm.nih.gov/articles/PMC8714664/figure/f4/), and expression of PI4KA, FAM126A and EFR3A was decreased in the colon. The patient died at 3 months from respiratory and circulatory failure, electrolyte disturbance and severe infection [58].

10.2. Lessons from the case

The case illustrates three points. First, recurrence of neonatal deaths from obstruction in a consanguineous family points to a recessive cause and should have led to genetic investigation and counselling before the subsequent pregnancies [19, 58]. Second, the variant is missense, yet the phenotype was the most severe, which shows that the genotype-phenotype correlation of TTC7A deficiency, useful on average, is not absolute [58, 62]. Third, the diagnosis of immunodeficiency emerged only after repeated sepsis; T lymphopenia and low TREC, which would have allowed earlier recognition of a combined immunodeficiency, justify early immunological investigation of any infant with multiple atresias, with severe combined immunodeficiency precautions while the result is awaited [11, 57]. The measures described (repeated operations, broad-spectrum antibiotics) reflect the individual case and do not constitute a protocol; the supportive guidance and the discussion of transplantation and palliative care are found in section 7.8.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by entity

In isolated atresias, long-term morbidity depends on the length of remaining bowel. Ultrashort bowel (less than 40 cm) with prolonged parenteral nutrition and liver disease is the main cause of late morbidity and mortality in jejunoileal atresia, and bowel lengthening, modified diets and growth factors have reduced parenteral nutrition dependence in few patients [40]. In Germany, 25% of children had a single intestinal operation and 39% two, but some reached 11 procedures during a median follow-up of 4.6 years, and 60.8% of children with short bowel had a long-term central venous catheter [6]. In duodenal obstruction, the weight z-score fell on average by 0.95 standard deviations from birth to 28 days [3].

In cystic fibrosis meconium ileus, long-term survival, nutritional status and lung function (at 15 and 25 years) are now similar to those of patients without meconium ileus in most series, although some studies find worse lung function and weight and height percentiles may be lower [65, 66]. Higher meconium ileus prevalence scores are, however, associated with a lower forced expiratory volume in one second (FEV1) and lower body mass index [22].

In TTC7A deficiency, long-term survivors (39 of 61 in the EBMT cohort, with median follow-up of 5.47 years and median age of 7.5 years) fall into two groups: the 15 with multiple atresia remain dependent on parenteral nutrition, with progressive liver injury in four and immunoglobulins in almost all; of the 24 with IBD, most came off parenteral nutrition, but nine developed autoimmunity and T lymphocytes decline over time in some patients [11]. Autoimmunity (28%) and neoplasms (6.5%) appear mainly in the second and third decades [7, 11].

In Strømme syndrome, the sisters of the original description reached early adulthood with mild cognitive impairment (IQ 70 and 83), mainstream schooling and employment, but with malabsorption and unilateral visual impairment [16]; in other patients there is fetal or neonatal lethality [19, 71].

11.2. Surveillance table

12. Summary and Final Considerations

Congenital intestinal atresias and obstructions affect about 1 in 2000 births overall; in European registries with a normal karyotype, duodenal and jejunoileal atresia occur in 0.9 and 0.7 per 10,000 births [2, 35]. Most isolated single-site atresias result from intrauterine vascular disruption, intussusception or volvulus and carry a low recurrence risk, but a substantial fraction has a genetic cause, and the clue to recognising it lies in the level, number and context of the atresia.

Duodenal atresia is associated with trisomy 21 in about one third of cases and with heart disease in almost half, so karyotype and echocardiogram are part of the routine assessment [3]. Jejunoileal and colonic atresia, meconium ileus and meconium peritonitis require investigation for cystic fibrosis, present in 7–11% of jejunoileal atresias and in about 10% of prenatal meconium peritonitis cases [6, 39, 72]; when meconium ileus occurs without cystic fibrosis, GUCY2C deficiency is a possible explanation [46]. Multiple atresias from pylorus to rectum, with calcifications and new atresias after surgery, point to TTC7A or PI4KA deficiency, recessive disorders with combined immunodeficiency in which surgery is palliative, stem cell transplantation corrects immunity but not the epithelium, and survival in the atresia phenotype is around 48% [11, 57]. Apple-peel atresia with microcephaly or ocular anomalies suggests Strømme syndrome, a CENPF ciliopathy with highly variable expressivity [19, 20].

In prenatal diagnosis, the double bubble predicts duodenal obstruction well, and isolated hyperechogenic bowel justifies, according to the SMFM, investigation for cystic fibrosis and cytomegalovirus and a third-trimester ultrasound, without invasive diagnosis of aneuploidy when screening was negative [56, 87]. Prenatal exome sequencing adds little in isolated gastrointestinal anomalies (2%) and much more in multisystem anomalies (29%) [89]. The technical limitations of each gene, such as the PI4KA pseudogenes, the CENPF exon 1 deletion and the negative immunodeficiency panels in TTC7A deficiency, require a negative result to be interpreted in the light of the phenotype [15, 60, 63].

The most relevant therapeutic development of recent months is maternal use of CFTR modulators to treat fetal meconium ileus, with postnatal surgery in 12% of the 42 fetuses pooled in an individual-data meta-analysis; the use is off-label, the evidence amounts to reports and small series, and failures have been published [100, 105]. For the genetic atresias proper there is no targeted therapy and no registered trials, and treatment remains surgical and supportive, ideally in centres within the European networks ERNICA and ERN RITA [4, 12, 106].

13. References

1. Online Mendelian Inheritance in Man (OMIM). Duodenal atresia. MIM 223400 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/223400
2. Best KE, Tennant PW, Addor MC, Bianchi F, Boyd P, Calzolari E, et al. Epidemiology of small intestinal atresia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed. 2012;97(5):F353-8. doi:10.1136/fetalneonatal-2011-300631 PMID: 22933095.
3. Bethell GS, Long AM, Knight M, Hall NJ. Congenital duodenal obstruction in the UK: a population-based study. Arch Dis Child Fetal Neonatal Ed. 2020;105(2):178-183. doi:10.1136/archdischild-2019-317085 PMID: 31229958. PMC7063389.
4. European Reference Network for rare Inherited and Congenital (digestive and gastrointestinal) Anomalies (ERNICA) [Internet]. [accessed 2026 Oct 29]. Available from: https://www.ern-ernica.eu/
5. Online Mendelian Inheritance in Man (OMIM). Jejunal atresia. MIM 243600 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/243600
6. Schmedding A, Hutter M, Gfroerer S, Rolle U. Jejunoileal Atresia: A National Cohort Study. Front Pediatr. 2021;9:665022. doi:10.3389/fped.2021.665022 PMID: 34136442. PMC8200531.
7. Online Mendelian Inheritance in Man (OMIM). Gastrointestinal defects and immunodeficiency syndrome 1; GIDID1. MIM 243150 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/243150
8. Online Mendelian Inheritance in Man (OMIM). Tetratricopeptide repeat domain-containing protein 7A; TTC7A. MIM 609332 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/609332
9. Orphanet. Isolated multiple intestinal atresia (ORPHA:2300) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/2300
10. Orphanet. Combined immunodeficiency-multiple intestinal atresia (ORPHA:436252) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/436252
11. Prunotto G, Parreillet M, Neven B, Moshous D, de Saint Basile G, Lindemans C, et al. TTC7A deficiency: A retrospective international study on treatment and outcomes from the Inborn Errors Working Party of EBMT. J Hum Immun. 2026;2(5):e20250271. doi:10.70962/jhi.20250271 PMID: 42421851. PMC13344125.
12. European Reference Network on Rare Immunological Disorders (ERN RITA) [Internet]. [accessed 2026 Oct 29]. Available from: https://ern-rita.org/
13. Online Mendelian Inheritance in Man (OMIM). Gastrointestinal defects and immunodeficiency syndrome 2; GIDID2. MIM 619708 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/619708
14. Online Mendelian Inheritance in Man (OMIM). Phosphatidylinositol 4-kinase, alpha; PI4KA. MIM 600286 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/600286
15. Baple EL, Salter C, Uhlig H, Wolf NI, Crosby AH. PI4KA-related disorder. 2022 Aug 11. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK583038/
16. Online Mendelian Inheritance in Man (OMIM). Stromme syndrome; STROMS. MIM 243605 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/243605
17. Online Mendelian Inheritance in Man (OMIM). Centromeric protein F; CENPF. MIM 600236 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/600236
18. Orphanet. Stromme syndrome (ORPHA:506307) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/506307
19. Ho SKL, Leung LT, Luk HM, Lo IFM. Strømme syndrome. 2022 Nov 10. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK586170/
20. Mulligan MR, Mulhall H, Hawarden SRA, Davies-Payne D, Heller R, Bicknell LS. Strømme syndrome: the clinical and molecular spectrum associated with variants in CENPF. Eur J Hum Genet. 2026;34(10):1486-1492. doi:10.1038/s41431-026-02187-7 PMID: 42471516. PMC13634044.
21. Savant A, Bojanowski CM, Upadia J. Cystic fibrosis. 2001 Mar 26 [updated 2026 Oct 1]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1250/
22. Dupuis A, Keenan K, Ooi CY, Dorfman R, Sontag MK, Naehrlich L, et al. Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Genet Med. 2016;18(4):333-340. doi:10.1038/gim.2015.79 PMID: 26087176.
23. Online Mendelian Inheritance in Man (OMIM). Meconium ileus. MIM 614665 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/614665
24. Online Mendelian Inheritance in Man (OMIM). Guanylate cyclase 2C; GUCY2C. MIM 601330 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/601330
25. Orphanet. Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency (ORPHA:314376) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/314376
26. Online Mendelian Inheritance in Man (OMIM). Mitchell-Riley syndrome; MTCHRS. MIM 615710 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/615710
27. Online Mendelian Inheritance in Man (OMIM). Regulatory factor X, 6; RFX6. MIM 612659 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/612659
28. De León DD, Pinney SE. Permanent neonatal diabetes mellitus. 2008 Feb 8 [updated 2024 Nov 14]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1447/
29. Orphanet. Hypoplastic pancreas-intestinal atresia-hypoplastic gallbladder syndrome (ORPHA:293864) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/293864
30. Online Mendelian Inheritance in Man (OMIM). Feingold syndrome 1; FGLDS1. MIM 164280 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/164280
31. Online Mendelian Inheritance in Man (OMIM). MYCN proto-oncogene, bHLH transcription factor; MYCN. MIM 164840 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/164840
32. Marcelis CLM, de Brouwer APM. Feingold syndrome 1. 2009 Jun 30 [updated 2019 Apr 4]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7050/
33. Holweg M, Lieber J, Kagan KO, Wiechers C, Haase B, Delbrück M, et al. Fetal volvulus: is emergency surgery the only option?-a single-center case series and management considerations. Arch Gynecol Obstet. 2026;313(1):158. doi:10.1007/s00404-025-08256-4 PMID: 41949628. PMC13061812.
34. Fisher JG, Jones BA, Gutierrez IM, Hull MA, Kang KH, Kenny M, et al. Mortality associated with laparotomy-confirmed neonatal spontaneous intestinal perforation: a prospective 5-year multicenter analysis. J Pediatr Surg. 2014;49(8):1215-1219. doi:10.1016/j.jpedsurg.2013.11.051 PMID: 25092079.
35. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 266–269 (Oesophageal and intestinal atresia (including tracheo-oesophageal fistula)).
36. Ludwig K, De Bartolo D, Salerno A, Ingravallo G, Cazzato G, Giacometti C, et al. Congenital anomalies of the tubular gastrointestinal tract. Pathologica. 2022;114(1):40-54. doi:10.32074/1591-951x-553 PMID: 35212315. PMC9040549.
37. Karimi A, Gorter RR, Sleeboom C, Kneepkens CM, Heij HA. Issues in the management of simple and complex meconium ileus. Pediatr Surg Int. 2011;27(9):963-968. doi:10.1007/s00383-011-2906-4 PMID: 21512809. PMC3156914.
38. Komuro H, Hori T, Amagai T, Hirai M, Yotsumoto K, Urita Y, et al. The etiologic role of intrauterine volvulus and intussusception in jejunoileal atresia. J Pediatr Surg. 2004;39(12):1812-1814. doi:10.1016/j.jpedsurg.2004.08.037 PMID: 15616938.
39. Shinar S, Agrawal S, Ryu M, Van Mieghem T, Daneman A, Ryan G, et al. Fetal Meconium Peritonitis - Prenatal Findings and Postnatal Outcome: A Case Series, Systematic Review, and Meta-Analysis. Ultraschall Med. 2022;43(2):194-203. doi:10.1055/a-1194-4363 PMID: 32575129.
40. Dalla Vecchia LK, Grosfeld JL, West KW, Rescorla FJ, Scherer LR, Engum SA. Intestinal atresia and stenosis: a 25-year experience with 277 cases. Arch Surg. 1998;133(5):490-6; discussion 496-7. doi:10.1001/archsurg.133.5.490 PMID: 9605910.
41. Fernandez I, Patey N, Marchand V, Birlea M, Maranda B, Haddad E, et al. Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort. Medicine (Baltimore). 2014;93(29):e327. doi:10.1097/md.0000000000000327 PMID: 25546680. PMC4602622.
42. Samuels ME, Majewski J, Alirezaie N, Fernandez I, Casals F, Patey N, et al. Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. J Med Genet. 2013;50(5):324-329. doi:10.1136/jmedgenet-2012-101483 PMID: 23423984. PMC3625823.
43. Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, et al. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol. 2013;132(3):656-664.e17. doi:10.1016/j.jaci.2013.06.013 PMID: 23830146. PMC3759618.
44. Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, et al. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clin Invest. 2014;124(1):328-337. doi:10.1172/jci71471 PMID: 24292712. PMC3871247.
45. Filges I, Bruder E, Brandal K, Meier S, Undlien DE, Waage TR, et al. Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF. Hum Mutat. 2016;37(4):359-363. doi:10.1002/humu.22960 PMID: 26820108.
46. Romi H, Cohen I, Landau D, Alkrinawi S, Yerushalmi B, Hershkovitz R, et al. Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. Am J Hum Genet. 2012;90(5):893-899. doi:10.1016/j.ajhg.2012.03.022 PMID: 22521417. PMC3376486.
47. Khen-Dunlop N, Beaudoin S, Marion B, Rousseau V, Giuseppi A, Nicloux M, et al. Segmental volvulus in the neonate: A particular clinical entity. J Pediatr Surg. 2017;52(3):454-457. doi:10.1016/j.jpedsurg.2016.10.002 PMID: 28443816.
48. Orphanet. Spontaneous intestinal perforation (ORPHA:645793) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/645793
49. Orphanet. Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome (ORPHA:444069) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/444069
50. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 704–705 (Anterior abdominal wall defects).
51. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 226–229 (Amyoplasia congenita disruptive sequence).
52. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 792–795 (Twins and twinning).
53. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 914–921 (Monozygotic twinning and structural defects).
54. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 774–775 (Polyhydramnios).
55. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 666–669 (Down's syndrome (trisomy 21)).
56. Bishop JC, McCormick B, Johnson CT, Miller J, Jelin E, Blakemore K, et al. The Double Bubble Sign: Duodenal Atresia and Associated Genetic Etiologies. Fetal Diagn Ther. 2020;47(2):98-103. doi:10.1159/000500471 PMID: 31167209. PMC6893095.
57. GeneGuidance. TTC7A — gastrointestinal defects and immunodeficiency syndrome 1 [local database, export 2026-09-26].
58. Mou W, Yang S, Guo R, Fu L, Zhang L, Guo W, et al. A Novel Homozygous TTC7A Missense Mutation Results in Familial Multiple Intestinal Atresia and Combined Immunodeficiency. Front Immunol. 2021;12:759308. doi:10.3389/fimmu.2021.759308 PMID: 34975848. PMC8714664.
59. National Center for Biotechnology Information. ClinVar: NM_020458.4(TTC7A) c.211G>A (VCV000190395), c.1001+3_1001+6del (VCV000050608), c.2468T>C (VCV000050609) [Internet]. Bethesda (MD): NCBI; [accessed 2026 Oct 29]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/50608/
60. Lien R, Lin YF, Lai MW, Weng HY, Wu RC, Jaing TH, et al. Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison. Front Immunol. 2017;8:1066. doi:10.3389/fimmu.2017.01066 PMID: 28936210. PMC5594067.
61. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348 PMID: 28967166.
62. Imhoff J, Schmidt HC, Belau MH, Hagens J, Lange M, Tegtmeyer D, et al. Genotype-Phenotype Correlation in TTC7A -Associated Gastrointestinal Defects and Immunodeficiency Syndrome 1. Am J Med Genet A. 2025;197(12):e64189. doi:10.1002/ajmg.a.64189 PMID: 40685546.
63. GeneGuidance. CENPF — Strømme syndrome [local database, export 2026-09-26].
64. Cappuccio G, Brillante S, Tammaro R, Pinelli M, De Bernardi ML, Gensini MG, et al. Biallelic variants in CENPF causing a phenotype distinct from Strømme syndrome. Am J Med Genet C Semin Med Genet. 2022;190(1):102-108. doi:10.1002/ajmg.c.31973 PMID: 35488810. PMC9322429.
65. van der Doef HP, Kokke FT, van der Ent CK, Houwen RH. Intestinal obstruction syndromes in cystic fibrosis: meconium ileus, distal intestinal obstruction syndrome, and constipation. Curr Gastroenterol Rep. 2011;13(3):265-270. doi:10.1007/s11894-011-0185-9 PMID: 21384135. PMC3085752.
66. Carlyle BE, Borowitz DS, Glick PL. A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon. J Pediatr Surg. 2012;47(4):772-781. doi:10.1016/j.jpedsurg.2012.02.019 PMID: 22498395.
67. GeneGuidance. GUCY2C — meconium ileus / familial diarrhea 6 [local database, export 2026-09-26].
68. GeneGuidance. RFX6 — Mitchell-Riley syndrome [local database, export of 2026-09-26].
69. Salehi Karlslätt K, Pettersson M, Lagerstedt-Robinson K, Ullberg U, Lindstrand A, Nordenskjöld A. Rare variants in TTC7A, ROCK2 and LIMK2 suggest a role for the ROCK-signaling pathway in isolated intestinal malrotation. Pediatr Surg Int. 2026;42(1):241. doi:10.1007/s00383-026-06442-2 PMID: 42185554. PMC13201279.
70. Salazar JA, Rockowitz S, French CE, Shao W, Elman DM, Carey AN, et al. Genetic sequencing of children with malrotation and midgut volvulus: A cross-sectional study. JPGN Rep. 2026. doi:10.1002/jpr3.70230 PMID: 42602198. PMC13473844.
71. Nawlakhe K, Bandiya P, Raghavendra P, Shivann N. Stromme syndrome presenting with classic microcephaly and apple-peel intestinal atresia in a neonate: a genetically confirmed case report. Matern Health Neonatol Perinatol. 2026;12(1):43. doi:10.1186/s40748-026-00287-2 PMID: 42608729. PMC13483490.
72. Siersma CL, Rottier BL, Hulscher JB, Bouman K, van Stuijvenberg M. Jejunoileal atresia and cystic fibrosis: don't miss it. BMC Res Notes. 2012;5:677. doi:10.1186/1756-0500-5-677 PMID: 23217263. PMC3532316.
73. Gorter RR, Karimi A, Sleeboom C, Kneepkens CM, Heij HA. Clinical and genetic characteristics of meconium ileus in newborns with and without cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50(5):569-572. doi:10.1097/mpg.0b013e3181bb3427 PMID: 20386322.
74. Padoan R, Cirilli N, Falchetti D, Cesana BM. Risk factors for adverse outcome in infancy in meconium ileus cystic fibrosis infants: A multicentre Italian study. J Cyst Fibros. 2019;18(6):863-868. doi:10.1016/j.jcf.2019.07.003 PMID: 31353045.
75. Jardine S, Dhingani N, Muise AM. TTC7A: Steward of Intestinal Health. Cell Mol Gastroenterol Hepatol. 2019;7(3):555-570. doi:10.1016/j.jcmgh.2018.12.001 PMID: 30553809. PMC6406079.
76. Sathe M, Houwen R. Meconium ileus in Cystic Fibrosis. J Cyst Fibros. 2017;16 Suppl 2:S32-S39. doi:10.1016/j.jcf.2017.06.007 PMID: 28986020.
77. Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 87–88 (Fibrose cística).
78. Chen CW, Peng CC, Hsu CH, Chang JH, Lin CY, Jim WT, et al. Value of prenatal diagnosis of meconium peritonitis: Comparison of outcomes of prenatal and postnatal diagnosis. Medicine (Baltimore). 2019;98(39):e17079. doi:10.1097/md.0000000000017079 PMID: 31574807. PMC6775423.
79. Cain-Trivette CJ, Nemeh C, Wu YS, Melnyk B, Park JP, Simpson LL, et al. Prenatal double bubble with distal fluid: Not a marker for malrotation with volvulus. J Neonatal Perinatal Med. 2026. doi:10.1177/19345798261475329 PMID: 42535476.
80. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 738–739 (Hyperechogenic bowel).
81. Correia LP, Almeida TP. Síndrome decorrente do uso da talidomida no pré-natal. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 187–188.
82. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 762–763 (Neonatal (newborn) screening (NS)).
83. Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43(3):219-245. doi:10.1590/s1806-37562017000000065 PMID: 28746534. PMC5687954.
84. Farrell PM, White TB, Ren CL, Hempstead SE, Accurso F, Derichs N, et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4-S15.e1. doi:10.1016/j.jpeds.2016.09.064 PMID: 28129811.
85. Goetzinger KR, Cahill AG, Macones GA, Odibo AO. Echogenic bowel on second-trimester ultrasonography: evaluating the risk of adverse pregnancy outcome. Obstet Gynecol. 2011;117(6):1341-1348. doi:10.1097/aog.0b013e31821aa739 PMID: 21606744. PMC3110147.
86. Smith A, Bulman DE, Goldsmith C, Bareke E, Majewski J, Boycott KM, et al. Meconium ileus in a Lebanese family secondary to mutations in the GUCY2C gene. Eur J Hum Genet. 2015;23(7):990-992. doi:10.1038/ejhg.2014.236 PMID: 25370039. PMC4463511.
87. Prabhu M, Kuller JA, Biggio JR. Society for Maternal-Fetal Medicine Consult Series #57: Evaluation and management of isolated soft ultrasound markers for aneuploidy in the second trimester: (Replaces Consults #10, Single umbilical artery, October 2010; #16, Isolated echogenic bowel diagnosed on second-trimester ultrasound, August 2011; #17, Evaluation and management of isolated renal pelviectasis on second-trimester ultrasound, December 2011; #25, Isolated fetal choroid plexus cysts, April 2013; #27, Isolated echogenic intracardiac focus, August 2013). Am J Obstet Gynecol. 2021;225(4):B2-B15. doi:10.1016/j.ajog.2021.06.079 PMID: 34171388.
88. Wu W, Tian M, Liu M, Man D, Wang F. Chromosomal microarray analysis for the prenatal diagnosis in fetuses with fetal echogenic bowel: a retrospective cohort study. BMC Pregnancy Childbirth. 2026;26(1):216. doi:10.1186/s12884-026-08655-8 PMID: 41629874. PMC12951919.
89. Mellis R, Oprych K, Scotchman E, Hill M, Chitty LS. Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta-analysis. Prenat Diagn. 2022;42(6):662-685. doi:10.1002/pd.6115 PMID: 35170059. PMC9325531.
90. Monaghan KG, Leach NT, Pekarek D, Prasad P, Rose NC. The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(4):675-680. doi:10.1038/s41436-019-0731-7 PMID: 31911674.
91. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 382–384 (Cystic fibrosis).
92. Online Mendelian Inheritance in Man (OMIM). Martinez-Frias syndrome. MIM 601346 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026 Oct 29]. Available from: https://omim.org/entry/601346
93. Ambartsumyan L. Megacystis-microcolon-intestinal hypoperistalsis syndrome overview. 2019 May 9 [updated 2024 Aug 1]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK540960/
94. Orphanet. Umbilical cord ulceration-intestinal atresia syndrome (ORPHA:3405) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/3405
95. Wadhawan R, Oh W, Vohr BR, Saha S, Das A, Bell EF, et al. Spontaneous intestinal perforation in extremely low birth weight infants: association with indometacin therapy and effects on neurodevelopmental outcomes at 18-22 months corrected age. Arch Dis Child Fetal Neonatal Ed. 2013;98(2):F127-32. doi:10.1136/archdischild-2011-300659 PMID: 22684157. PMC3753803.
96. Wadhawan R, Oh W, Hintz SR, Blakely ML, Das A, Bell EF, et al. Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation or surgical necrotizing enterocolitis. J Perinatol. 2014;34(1):64-70. doi:10.1038/jp.2013.128 PMID: 24135709. PMC3877158.
97. Boni A, Vassallo C, Ciciriello F, Cristiani L, Mancini A, Zucaro L, et al. Prenatal Elexacaftor/Tezacaftor/Ivacaftor for Fetal Meconium Ileus: First Italian Case and Narrative Overview of the Emerging Evidence. J Clin Med. 2026;15(7):2625. doi:10.3390/jcm15072625 PMID: 41976926. PMC13072773.
98. U.S. Food and Drug Administration. TRIKAFTA (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor tablets; oral granules) — prescribing information [Internet]. Boston (MA): Vertex Pharmaceuticals; revision effective 2026 Jun 22 [accessed 2026 Oct 29]. NDA212273, NDA217660. Available from: https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22TRIKAFTA%22
99. European Medicines Agency. Kaftrio (ivacaftor/tezacaftor/elexacaftor): EPAR — product information (Summary of Product Characteristics) [Internet]. Amsterdam: EMA; [accessed 2026 Oct 29]. Available from: https://www.ema.europa.eu/en/documents/product-information/kaftrio-epar-product-information_en.pdf
100. Menditto VG, Pomponio G, Caporelli N, Bordicchia M, Boni A, Rocchi MBL, et al. Prenatal CFTR modulator therapy and fetal meconium ileus in cystic fibrosis: a systematic review and individual patient data meta-analysis. J Cyst Fibros. 2026. doi:10.1016/j.jcf.2026.08.005 PMID: 42632793.
101. Passone CGB, Vermillac G, Staels W, Besancon A, Kariyawasam D, Godot C, et al. Mitchell-Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations. Front Endocrinol (Lausanne). 2022;13:802351. doi:10.3389/fendo.2022.802351. PMID: 35813646. PMC9257252.
102. Turck D, Braegger CP, Colombo C, Declercq D, Morton A, Pancheva R, et al. ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin Nutr. 2016;35(3):557-577. doi:10.1016/j.clnu.2016.03.004. PMID: 27068495.
103. Szentpetery S, Foil K, Hendrix S, Gray S, Mingora C, Head B, et al. A case report of CFTR modulator administration via carrier mother to treat meconium ileus in a F508del homozygous fetus. J Cyst Fibros. 2022;21(4):721-724. doi:10.1016/j.jcf.2022.04.005 PMID: 35422395.
104. Metcalf A, Martiniano SL, Sagel SD, Zaretsky MV, Zemanick ET, Hoppe JE. Outcomes of prenatal use of elexacaftor/tezacaftor/ivacaftor in carrier mothers to treat meconium ileus in fetuses with cystic fibrosis. J Cyst Fibros. 2025;24(3):466-468. doi:10.1016/j.jcf.2024.11.011 PMID: 39645477.
105. Montironi R, Giannubilo SR, Cappanera I, Capogrosso G, Mancinelli R, Rinci A, et al. Antenatal CFTR Modulators to Treat a Healthy Pregnant Woman with a Fetus Affected by Cystic Fibrosis Complicated by Meconium Ileus and Intestinal Volvulus: From a Suspicion of the Disease to a Targeted Treatment in Utero: Case Report and Narrative Review. J Clin Med. 2026;15(5):1933. doi:10.3390/jcm15051933 PMID: 41827350. PMC12985462.
106. ClinicalTrials.gov. Search by condition: "intestinal atresia", "meconium ileus", "TTC7A", "jejunal atresia", "duodenal atresia" [Internet]. Bethesda (MD): National Library of Medicine; [accessed 2026 Oct 29]. Available from: https://clinicaltrials.gov/
107. ClinicalTrials.gov. Prospective Study of Pregnancy in Women With Cystic Fibrosis (MAYFLOWERS). NCT04828382 [Internet]. [accessed 2026 Oct 29]. Available from: https://clinicaltrials.gov/study/NCT04828382
108. Castellani C, Simmonds NJ, Barben J, Addy C, Bevan A, Burgel PR, et al. Standards for the care of people with cystic fibrosis (CF): A timely and accurate diagnosis. J Cyst Fibros. 2023;22(6):963-968. doi:10.1016/j.jcf.2023.09.008 PMID: 37775442.
109. Orphanet. Small bowel atresia (ORPHA:1201) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/1201
110. Orphanet. Duodenal atresia (ORPHA:1203) [Internet]. Paris: INSERM; [accessed 2026 Oct 29]. Available from: https://www.orpha.net/en/disease/detail/1203