Syndromic congenital sodium diarrhea (ORPHA:563708)
A rare, genetic, syndromic intestinal disorder, characterized by congenital onset of severe watery diarrhea containing high concentrations of sodium, hyponatremia and metabolic acidosis, and generally, uni- or bilateral choanal atresia, and corneal erosions. Additional congenital malformations may include intestinal atresia, and hexadactyly.
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. 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 requires 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 reveal characteristic epithelial tufts, small crowding of enterocytes, which are often hard to find. Generally, uni- or bilateral chonal atresia is observed at birth, and most often, episodes of corneal erosions are seen. Additional congenital malformations are observed in some patients, most often intestinal atresia, and hexadactyly. In the case of unrecognized bilateral choanal atresia, aspiration and breathing difficulties can occur postnatally, in addition to the congenital diarrhea; the congenital diarrhea can go unrecognized (as the diarrhea is mistaken for urine), and severe dehydration can occur within the first days of life.
Etiology
The disorder is due to homozygous or compound-heterozygous mutations in serine peptidase inhibitor, Kunitz type 2 (SPINT2; encoded by SPINT2, 19q13.2), resulting in abrogated sodium absorption, enhanced fluid secretion and diarrhea.
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 non-syndromic (classical) form of congenital sodium diarrhea (due to NHE3 or GUCY2C mutations) which is typically distinguished by the absence of congenital malformations or corneal erosions. 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 (AR) for SPINT2 mutations. The risk of disease transmission to offspring for AR disease is 25% where both parents are unaffected carriers.
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%). Choanal atresia and anal intestinal atresia require surgical treatment.
Prognosis
Total parenteral nutrition carries the risk of bacteremia, and the risk of acute liver failure in very young children. Affected individuals may continue to have mild-to-moderate watery diarrhea but otherwise tend to lead a normal life. Reported complications include growth delay and hypoaldosteronism. Some patients episodically develop corneal erosions which are associated with pain and visual disturbances, and are treated with hydrating eye drops.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Dr Andreas JANECKE