ResultsTreatment of congenital chloride diarrhoea involves (i) life-long salt substitution; (ii) management of acute dehydration and hypokalaemia during gastroenteritis or other infections; and (iii) recognition and treatment of other manifestations of the disease, such as intestinal inflammation, renal impairment and male subfertility. ConclusionsThis review summarizes data on congenital chloride diarrhoea and provides guidelines for treatment. After being a mostly paediatric problem, adult patients constitute a rare challenge for gastroenterologists worldwide.

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl À /HCO 3 À transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n 5 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n 5 21; 38%), major deletions (n 5 3; 5%), and a major insertion (n 5 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl

Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients.

Congenital chloride diarrhea is due to mutations in the intestinal Cl(-)/HCO(3)(-) exchange (SLC26A3) which results in sodium chloride and fluid depletion leading to hypochloremic and hypokalemic metabolic alkalosis. Although treatment with sodium and potassium chloride offers protection from renal involvement in childhood, the long-term renal outcome remains unclear. Here we describe two cases of congenital chloride diarrhea-associated end-stage renal disease with transplantation. Further, we show that there is a high incidence of mild chronic kidney disease in 35 other patients with congenital chloride diarrhea. The main feature of the renal injury was nephrocalcinosis, without hypercalciuria or nephrolithiasis with small sized kidneys and commensurately reduced glomerular filtration rates. This suggests that diarrhea-related sodium chloride and volume depletion, the first signs of non-optimal salt substitution, promote urine supersaturation and crystal precipitation. The poor compliance with salt substitution along with long-lasting hypochloremic and hypokalemic metabolic alkalosis is likely to induce progressive calcification and renal failure. Both our patients developed nephrocalcinosis in the transplanted kidneys suggesting that this complication is a consequence of intestinal SLC26A3 deficiency. Interestingly, the transporter is expressed in the distal nephron but the recurrence of nephrocalcinosis in the transplanted kidney suggests that it does not play a significant renal role in this syndrome.

Formation of apatite crystals during enamel development generates protons. To sustain mineral accretion, maturation ameloblasts need to buffer these protons. The presence of cytosolic carbonic anhydrases, the basolateral Na(+) bicarbonate cotransporter Nbce1, and the basolateral anion exchanger Ae2a,b in maturation ameloblasts suggests that these cells secrete bicarbonates into the forming enamel, but it is unknown by which mechanism. Solute carrier (Slc) family 26A encodes different anion exchangers that exchange Cl(-)/HCO3 (-), including Slc26a3/Dra, Slc26a6/Pat-1, and Slc26a4/pendrin. Previously, we showed that pendrin is expressed in ameloblasts but is not critical for enamel formation. In this study, we tested the hypothesis that maturation ameloblasts express Dra and Slc26a6 to secrete bicarbonate into the enamel space in exchange for Cl(-). Real-time polymerase chain reaction detected mRNA transcripts for Dra and Slc26a6 in mouse incisor enamel organs, and Western blotting confirmed their translation into protein. Both isoforms were immunolocalized in ameloblasts, principally at maturation stage. Mice with null mutation of either Dra or Slc26a6 had a normal dental or skeletal phenotype without changes in mineral density, as measured by micro-computed tomography. In enamel organs of Slc26a6-null mice, Dra and pendrin protein levels were both elevated by 52% and 55%, respectively. The amount of Slc26a6 protein was unchanged in enamel organs of Ae2a,b- and Cftr-null mice but reduced in Dra-null mice by 36%. Our data show that ameloblasts express Dra, pendrin, or Slc26a6 but each of these separately is not critical for formation of dental enamel. The data suggest that in ameloblasts, Slc26a isoforms can functionally compensate for one another.