Diarrhea 3, Secretory Sodium, Congenital, With Or Without Other Congenital Anomalies

A number sign (#) is used with this entry because of evidence that congenital secretory sodium diarrhea with or without other congenital anomalies (DIAR3) is caused by homozygous or compound heterozygous mutation in the SPINT2 gene (605124) on chromosome 19q13.

For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700).

Clinical Features

Booth et al. (1985) described a form of congenital secretory diarrhea due to defective sodium/hydrogen exchange. The clinical presentation and course closely resembled that of congenital chloride diarrhea (214700) but stool electrolyte and other studies excluded this possibility. Jejunal perfusion studies showed the jejunum to be in a net secretory state with intact hexose transport, but with an anomalous relation between jejunal sodium and hydrogen transport. The stool showed a high bicarbonate content, as did the duodenal juice during fasting. The case of Booth et al. (1985) was born of a pregnancy complicated by hydramnios. Maternal abdominal ultrasound showed the fetal abdomen to be distended by fluid-filled loops of intestine. Abdominal distention was present at birth and profuse watery diarrhea began immediately.

Keller et al. (1990) reported a boy, born of nonconsanguineous parents, who had protracted and ultimately lethal diarrhea from the third day of life. Radiologic findings in the gastrointestinal tract were unremarkable, and jejunal and ileal biopsy specimens showed mild partial villous atrophy but looked normal on electron microscopy. Analysis of jejunal brush border membrane vesicles revealed a gross defect in sodium/proton exchange (6% of mean control value) but normal sodium-stimulated glucose uptake. He was maintained on parenteral nutrition and died of severe intercurrent infection at 18 months of age. Two previous sibs, both girls, had died of severe protracted diarrhea at 2 and 11 months of age; both had very high stool sodium concentrations. The authors noted that in contrast to the patient reported by Booth et al. (1985), who grew and developed normally on appropriate electrolyte supplements, this patient required prolonged parenteral nutrition and had no history of hydramnios; citing the fatal outcome and strong family history, Keller et al. (1990) suggested that this represented a different disease.

Fell et al. (1992) reported a boy, the first child of nonconsanguineous parents, who was born of a pregnancy complicated by polyhydramnios and had a grossly distended abdomen at birth with immediate onset of profuse secretory diarrhea. He subsequently thrived on breast milk and electrolyte supplements. Studies of jejunal brush border membrane vesicles showed evidence of a partial defect in sodium/proton exchange (45% of mean control value); nonequilibrium rectal dialysis showed rectal sodium and potassium transport to be intact. His diarrhea resolved after 9 months and he subsequently required occasional laxatives. The authors suggested that there is a broad spectrum of clinical severity within congenital sodium-losing diarrhea.

Congenital Secretory Sodium Diarrhea with Associated Features

Muller et al. (2000) stated that only 6 cases of congenital sodium diarrhea had been reported. They studied 5 infants with secretory diarrhea from 2 affected CSD families identified in a circumscribed rural area in Austria, making the diagnosis on daily fecal sodium excretion between 98 and 190 mM/L, hyponatremia, metabolic acidosis, and low to normal urinary sodium concentration. Two of the 5 patients were born with choanal atresia. Muller et al. (2000) cited cases of congenital secretory diarrhea combined with choanal atresia observed in Sweden, Germany, and the Netherlands.

Heinz-Erian et al. (2009) reviewed data from 24 patients with congenital sodium diarrhea from 17 families, including the families previously described by Holmberg and Perheentupa (1985) (see 616868), Booth et al. (1985), and Muller et al. (2000), and found that affected individuals from 10 of the families had a syndromic form of CSD, associated with choanal or anal atresia, hypertelorism, and corneal erosions, whereas patients from the remaining 7 families had isolated CSD. Additional features in the syndromic patients included double kidney, cleft palate, and digital anomalies; 2 patients also had anal atresia.

Bird et al. (2007) reported 3 sibs with intractable diarrhea of infancy who also had choanal atresia/stenosis, mild short stature, prominent and broad nasal bridge, micrognathia, single palmar creases, chronic corneal inflammation, recurrent fevers of unknown origin associated with cytopenia, and abnormal hair texture. Additional features in this family included bifid uvula and bilateral preauricular pits, seen in the proband, as well as 2/3 toe syndactyly, reported in an older sister who had died of congenital diarrhea. Multiple enteric and colonic biopsies over the course of the 8-year-old proband's disease showed chronic active inflammation and moderate to severe villus atrophy; a duodenal biopsy at 6 years of age during an episode of vomiting and gastrointestinal bleeding also showed focal disorganization and crowding of surface enterocytes, and a diagnosis of tufting enteropathy was made. An affected younger sister died at age 4 years with end-stage liver disease that was presumed to be a consequence of chronic parenteral alimentation; necropsy revealed severe small intestinal villus blunting with gland dropout and epithelial tufts consistent with tufting enteropathy.

Holt-Danborg et al. (2019) reported 3 additional patients with the syndromic form of DIAR3 and reviewed published cases. Among the 34 patients from 26 families, choanal atresia (20/34) and keratitis of infantile onset (26/34) were the most common findings. All patients presented with intractable diarrhea, with onset typically in the first 2 weeks of life. Episodes of intestinal pseudoobstruction sometimes preceded the onset of diarrhea. Characteristic epithelial tufts on intestinal histology were seen in 13 of the 34 patients. The risk of death from complications (e.g., dehydration, line-related infections, liver failure) was high, with death in 14 of the 34 patients.

Mapping

Muller et al. (2000) performed pedigree analysis in 2 Austrian families with congenital sodium diarrhea and demonstrated parental consanguinity and a single common ancestral couple 5 generations earlier. Homozygosity mapping and/or multipoint linkage analysis excluded previously mapped sodium-hydrogen exchanger (NHE) loci except NHE4 (SLC9A4; 600531), for which the results were considered inconclusive because the precise location of the gene on chromosome 2 was unknown.

Heinz-Erian et al. (2009) performed a genomewide linkage scan in 2 affected and 11 unaffected members of a consanguineous Austrian kindred with syndromic congenital sodium diarrhea, previously reported by Muller et al. (2000), and identified a single region of extended homozygosity on chromosome 19q13; recombination events defined a 6.754-Mb critical interval between rs1363364 and rs2317314.

Molecular Genetics

In a male infant who died at age 13 months from congenital sodium diarrhea, from a consanguineous Austrian CSD kindred with the associated features of choanal atresia, hypertelorism, and corneal erosions previously reported by Muller et al. (2000), Heinz-Erian et al. (2009) sequenced 10 candidate genes on chromosome 19q13 and identified homozygosity for a splice site mutation in the SPINT2 gene (605124.0001). The mutation was found in homozygosity in 3 other affected members of that kindred and in an apparently unrelated Austrian CSD patient who also displayed hypertelorism and corneal erosions. The authors sequenced the SPINT2 gene in 18 additional patients from 15 families and identified homozygosity or compound heterozygosity for 4 more mutations in SPINT2 (see 605124.0002-605124.0005, respectively) in all 8 kindreds with syndromic CSD, but did not find any mutations or copy-number changes in the remaining 7 families with isolated CSD.

In a 10-year-old boy with intractable diarrhea of infancy associated with syndromic features including choanal atresia and corneal erosions, who was 1 of 3 affected sibs originally described by Bird et al. (2007), Sivagnanam et al. (2010) identified homozygosity for the Y163C mutation in the SPINT2 gene (605124.0002). An enteric biopsy at 6 years of age had shown histology consistent with congenital tufting enteropathy (see DIAR5, 613217); however, screening of the causative gene in that disorder, EPCAM (185535), revealed no mutations.

Slae et al. (2013) reported a male infant with congenital diarrhea associated with choanal atresia and punctate keratitis, who died at 6 months of age due to refractory gastrointestinal bleeding. Microscopic analysis of patient duodenal biopsies had shown prominent enterocyte tufts, resulting in an initial clinical diagnosis of congenital tufting enteropathy. No mutations were found in the EPCAM gene, but analysis of SPINT2 revealed homozygosity for the Y163C mutation (605124.0002). Slae et al. (2013) suggested that enterocyte tufting should be considered a nonspecific sign of intestinal epithelial dysplasia rather than a finding that defines a discrete entity.

In a study of 57 patients from 46 families who were clinically diagnosed with congenital tufting enteropathy, Salomon et al. (2014) identified EPCAM mutations in 41 patients (73%) (see DIAR5, 613217) and SPINT2 mutations in 12 patients (21%) (see, e.g., 605124.0002 and 605124.0006). All patients with SPINT2 mutations exhibited syndromic features, including superficial punctate keratitis and choanal atresia, as well as other atresias, dermatologic anomalies, and bone malformations, whereas the patients with EPCAM mutations had isolated congenital diarrhea.

In 3 patients with the syndromic form of DIAR3, Holt-Danborg et al. (2019) identified homozygous or compound heterozygous mutations in the SPINT2 gene (see, e.g., Y163C, 605124.0007 and W149X, 605124.0008). In a review of published cases, Holt-Danborg et al. (2019) found that among the 34 patients from 26 families, 13 different variants in SPINT2 were seen, including 3 premature termination codons, 2 start codon removals, and 3 canonical splice site variants, supporting loss of function as the pathogenic mechanism. The most commonly observed variant was Y163C, observed in 40 (59%) of 68 disease alleles. Seven unrelated patients with the Y163C mutation had a shared haplotype, suggesting that it is a founder mutation.