Congenital secretory chloride diarrhea is an autosomal recessive form of severe chronic diarrhea characterized by excretion of large amounts of watery stool containing high levels of chloride, resulting in dehydration, hypokalemia, and metabolic alkalosis. The electrolyte disorder resembles ... Congenital secretory chloride diarrhea is an autosomal recessive form of severe chronic diarrhea characterized by excretion of large amounts of watery stool containing high levels of chloride, resulting in dehydration, hypokalemia, and metabolic alkalosis. The electrolyte disorder resembles the renal disorder Bartter syndrome (see 607364), except that chloride diarrhea is not associated with calcium level abnormalities (summary by Choi et al., 2009). - Genetic Heterogeneity of Congenital Diarrhea Other forms of congenital diarrhea include microvillus inclusion disease (DIAR2; 251850), caused by mutation in the MYO5B gene (606540) on chromosome 18q21; a syndromic form of congenital secretory sodium diarrhea (see DIAR3, 270420), caused by mutation in the SPINT2 gene (605124) on chromosome 19q13.1; malabsorptive congenital diarrhea (DIAR4; 610370), caused by mutation in the NEUROG3 gene (604882) on chromosome 10q21.3; congenital tufting enteropathy (DIAR5; 613217), caused by mutation in the EPCAM gene (185535) on chromosome 2p21; and early-onset chronic diarrhea (DIAR6; 614616), caused by mutation in the GUCY2C gene (601330) on chromosome 12p13.1-p12.3.
This disorder was first described by Gamble et al. (1945) and Darrow (1945). Voluminous watery stools containing an excess of chloride are present from a few weeks of age. The children are often premature. Hydramnios, presumably due to ... This disorder was first described by Gamble et al. (1945) and Darrow (1945). Voluminous watery stools containing an excess of chloride are present from a few weeks of age. The children are often premature. Hydramnios, presumably due to intrauterine diarrhea (Holmberg et al., 1975), may complicate pregnancy. Indeed, polyhydramnios is probably an invariant feature. Pasternack and Perheentupa (1966) described vascular changes resembling those of hypertensive angiopathy in 7 children, aged 1 to 42 months at the time of biopsy. All were normotensive. Kidney and muscle were biopsied. Lubani et al. (1989) identified 16 affected Kuwaiti children over a 7-year period. All children had a shortened gestational period, abdominal distention, and chronic diarrhea. The serum electrolytes in all patients before treatment showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis. Diagnosis was confirmed by a stool chloride content that exceeded the sum of fecal sodium and potassium. In chloride diarrhea, juxtaglomerular hyperplasia, hyperreninemia and hyperaldosteronism, leading to hyperkaluria and hypokalemia, simulate the Bartter syndrome (see 241200). As in the latter disorder, inhibitors of prostaglandin synthetase have beneficial effects (Minford and Barr, 1980). In the intestinal brush border there is both an Na+/H+ and a chloride/bicarbonate exchange mechanism. A defect in either can impede NaCl absorption and lead to secretory diarrhea. The latter exchange mechanism is defective in chloride diarrhea; the former is deranged in sodium diarrhea (270420).
Hoglund et al. (2001) stated that a total of 3 founder and 17 private mutations in the SLC26A3 gene (see, e.g., 126650.0001) underlying congenital chloride diarrhea had been described in various ethnic groups. They screened for mutations in ... Hoglund et al. (2001) stated that a total of 3 founder and 17 private mutations in the SLC26A3 gene (see, e.g., 126650.0001) underlying congenital chloride diarrhea had been described in various ethnic groups. They screened for mutations in 7 unrelated families with CLD and found 7 novel mutations as well as 2 previously identified ones. They reported for the first time rearrangement mutations in SLC26A3 (see, e.g., 126650.0004). Molecular features predisposing SLC26A3 for the 2 rearrangements may include repetitive elements and palindromic-like sequences. Makela et al. (2002) noted that the only extraintestinal tissues showing SLC26A3 expression are eccrine sweat glands and seminal vesicles. They presented a summary of published mutations and polymorphisms of the SLC26A3 gene and reported 2 novel mutations of the gene: a 13-bp deletion (126650.0007) and a trp462-to-ter change (W462X; 126650.0008). Choi et al. (2009) used whole-exome capture and massively parallel DNA sequencing to identify a homozygous pathogenic mutation in the SLC26A3 gene in a Turkish infant with congenital chloride diarrhea who was initially thought to have renal Bartter syndrome. Sequencing this gene in 39 additional patients referred with a suspected diagnosis of Bartter syndrome identified recessive SLC26A3 mutations in 5 patients. All except 1 presented in infancy with watery diarrhea associated with hypokalemia, increased serum bicarbonate, and high aldosterone; the last patient presented at age 6 years. High stool chloride was documented in 2 patients studied. Choi et al. (2009) emphasized the utility of this novel approach for the identification of pathogenic mutations.
Holmberg and Perheentupa (1980) estimated that 31 cases of congenital chloride diarrhea in 21 families have been identified in Finland as compared with 30 cases in 24 families elsewhere. Lubani et al. (1989) identified 16 affected Kuwaiti children ... Holmberg and Perheentupa (1980) estimated that 31 cases of congenital chloride diarrhea in 21 families have been identified in Finland as compared with 30 cases in 24 families elsewhere. Lubani et al. (1989) identified 16 affected Kuwaiti children over a 7-year period, giving an estimated incidence of 7.6 per 100,000 live births. Hoglund et al. (1996) demonstrated that the Finnish form of congenital chloride diarrhea is caused by a homozygous mutation in the SLC26A3 gene. Homozygosity for the same mutation, deletion of GGT(val) of codon 317 (126650.0001), was found in all 32 patients studied. The reverse use of the Luria-Delbruck equation resulted in an estimation of the age of the mutation. The calculation gave an average age of 19 generations, with a range of 13 to 25. This estimate was in agreement with the population history and suggested that the spread of the val317-to-del mutation in the expanding subpopulation in eastern Finland started 400 to 450 years ago. Makela et al. (2002) described the geographic and population distributions of 3 founder mutations in the SLC26A3 gene: the Finnish V317del mutation (126650.0001), the Polish I675-676ins mutation (126650.0005), and the Arabic gly187-to-ter mutation (G187X; 126650.0006). They also tabulated genetic disorders with congenital or neonatal diarrhea as a main symptom.