Diarrhea 8, Secretory Sodium, Congenital

A number sign (#) is used with this entry because of evidence that congenital secretory sodium diarrhea (DIAR8) is caused by homozygous or compound heterozygous mutation in the NHE3 gene (SLC9A3; 182307) on chromosome 5p15.

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

Clinical Features

Holmberg and Perheentupa (1985) described a 9-year-old Finnish girl with congenital diarrhea that seemed to be caused by a specific defect in intestinal sodium absorption. The pregnancy was complicated by maternal polyhydramnios, and in the delivery room the patient had a distended abdomen and passed a voluminous watery stool, indicative of intrauterine onset of the diarrhea. Stool analysis showed an abnormally high chloride level, but an even higher sodium concentration. Administration of standard solutions used to treat congenital chloride diarrhea (CCD; see 214700) resulted in metabolic acidosis and vomiting, with an electrolyte status clearly different than that seen in infants with CCD. She improved after treatment with an alkalinizing sodium and potassium citrate solution, and had normal growth and development despite persistent watery diarrhea of more than 1 liter per day that did not cease on fasting. X-rays of the stomach and intestines were normal except for slight dilation of the ileal loops.

Janecke et al. (2015) reported 9 patients from 8 families with secretory sodium diarrhea. There was maternal polyhydramnios in all pregnancies, and all patients had watery secretory diarrhea and prominent abdominal distention after birth due to dilated fluid-filled loops of intestine, indicating that secretory diarrhea had begun prenatally. None of the patients exhibited syndromic features. Inflammatory bowel disease developed in 2 patients, with onset at 4 years of age in 1 patient, resulting in ileocecal resection and temporary ileostomy due to recurrent episodes of small bowel obstruction. The second patient presented at age 16 years with bloody diarrhea and ulceration in the rectum and sigmoid; 1 year later he had nodular lymphoid hyperplasia with ileal granulomas and colonic ulcers, and he passed 3 to 4 watery stools per day without bleeding. Intestinal anatomy, histology, and transit functions were normal in the other patients.

Molecular Genetics

In 2 unrelated patients with congenital sodium diarrhea (CSD), 1 of whom was a 37-year-old Finnish woman who had been originally studied by Holmberg and Perheentupa (1985), Janecke et al. (2015) performed whole-exome sequencing and identified compound heterozygosity for mutations in the SLC9A3 gene (see 182307.0001-182307.0004). In a 2.5-year-old Canadian girl with CSD, chromosomal microarray analysis revealed compound heterozygosity for a 1.383-Mb deletion on chromosome 5p15.33 that encompassed the SLC9A3 gene, and a missense mutation in SLC9A3 (R382Q; 182307.0003). The same R382Q missense mutation was identified in an apparently unrelated 1.5-year-old Canadian boy, in compound heterozygosity with a 1-bp deletion (182307.0004). Another 5 mutations were identified in 5 probands, including a homozygous missense mutation (A269T; 182307.0005) in 2 affected sibs. In 1 patient, a rare mechanism of recessive disease was revealed: the patient was homozygous for a frameshift mutation (182307.0006) inherited from her heterozygous mother, and SNP array analysis revealed maternal isodisomy of the entire chromosome 5 in the patient. None of the mutations was found in public databases, and segregation with disease was confirmed in 6 of the families by sequencing of DNA samples from available family members. Janecke et al. (2015) noted that probands from 8 additional CSD families were negative for mutation in the GUCY2C (601330) and SLC9A3 genes, indicating further genetic heterogeneity of congenital sodium diarrhea.