Congenital sodium diarrhea (ORPHA:103908)
A rare, genetic, non-syndromic intestinal transport defect characterized by congenital onset of severe watery diarrhea containing high concentrations of sodium, hyponatremia and metabolic acidosis.
Epidemiology
Whilst the prevelence is unknown, less than 50 cases of both the syndromic and non-syndromic form have been reported in the literature.
Clinical description
Presentation is typically prenatal with polyhydramnios, prominent abdominal distension due to dilated fluid-filled loops of the intestine. A watery diarrhea is present after birth, independent of oral feeding (breast or formula) or nil by mouth. The diarrhea can be described as 'non-stopping', and can be mistaken for urine. There are increased bowel sounds at examination, and passing of meconium is never reported. The infants become irritable and eventually apathetic, and develop moderate to severe dehydration. Rarely, there is no watery diarrhea noticed either due to severe dehydration or intestinal paralysis. This pseudo-obstruction is caused by dilated fluid-filled loops of intestine, which may result in volvulus, and the affected neonate typically undergoes abdominal surgery. Laboratory findings include high stool sodium levels (importantly, this can be normal when the depletion of body sodium has progressed for some time) and low serum sodium levels, metabolic acidosis and alkaline fecal pH, and low urinary sodium excretion. Histological findings include a structurally intact epithelium and brush border with a normal villus-to-crypt ratio.
Etiology
The classical (non-syndromic) form of the disorder is due to loss of function of the intestinal sodium/hydrogen exchanger 3 (NHE3; encoded by SLC9A3, 5p15.33), resulting in abrogated sodium absorption, enhanced fluid secretion and diarrhea. Causal mutations have been identified in both SCL9A3 and GUCY2C, encoding an intestinal receptor guanylate cyclase C (GC-C) and for which activating mutations inhibit NHE3. In 40% of patients a genetic mutation has not yet been identified.
Diagnostic methods
Diagnosis is suspected on clinical presentation and exclusion of the differential diagnosis. Initial diagnosis might include determination of fecal sodium, chloride and potassium. Separate sampling of watery stool and urine should be performed. Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes the syndromic form of congenital sodium diarrhea (due to SPINT2 mutations) which is typically distinguished by the presence of uni- or bilateral choanal atresia at birth. Other differential diagnoses include anatomical bowel obstruction, congenital chloride diarrhea (distinguished by excessive fecal chloride), glucose-galactose malabsorption (which exhibits a diet-induced dehydrating diarrhea with later onset), microvillus inclusion disease and congenital tufting enteropathy (distinguished by histopathology).
Antenatal diagnosis
Diagnosis may be suspected on presentation of polyhydramnios in the third trimester. Early, targeted genetic prenatal testing is possible after identifying disease-causing variants in an index patient; however, general concerns to sampling fetal material and diagnosing genetic conditions late in pregnancy would apply.
Genetic counseling
The pattern of inheritance is autosomal recessive for SLC9A3 mutations and autosomal dominant for GUCY2C mutations. The risk of disease transmission to offspring for autosmal recessive disease is 25% where both parents are unaffected carriers. GUCY2C mutations are most often of de-novo origin; so far, germline mosaicism in unaffected parents of such patients has not been reported, resulting in a very low recurrence risk for sibs of affected patients. If a parent is affected and carrier of the pathogenic GUCY2C mutation, the risk of transmission is 50%. Of note, a number of individuals with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease.
Management and treatment
After birth, total parenteral nutrition for treatment of dehydration for at least several months is required. Sodium supplementation should be provided for treatment of severe dehydration and to maintain normal body growth by preventing total body sodium depletion. In certain cases, patients may be weaned off total parenteral nutrition. For monitoring adequate sodium supplementation, the fractional excretion of sodium (FENa) should be calculated (normal range reportedly between 0.5%-1.5%).
Prognosis
Affected individuals may continue to have mild watery diarrhea but otherwise tend to lead a normal life. Reported complications include growth delay and hypoaldosteronism.

                            Last update: 
                            October 2020


                            - Expert reviewer(s): 
                            Dr Andreas JANECKE  - Pr Thomas MÜLLER