Non-Syndromic Congenital Sodium Diarrhoea With a SLC9A3 Gene Variant: A Case Report

Congenital sodium diarrhoea (CSD) is a rare autosomal recessive disease characterised by polyhydramnios, hyponatraemia, metabolic acidosis and diarrhoea with high sodium content, and fewer than 50 cases have been reported in the literature to date [1]. We believe that a high level of suspicion is important for the diagnosis and early treatment of the disease.

The female baby was born to a 26-year-old gravida 1 mother by caesarean section at 33 2/7 weeks of gestation, weighing 2480 g. The newborn was admitted to the neonatal intensive care unit with abdominal distension at first evaluation and suspected obstruction. Prenatal history showed maternal polyhydramnios, distended foetal abdomen and generalised widening of foetal intestinal loops (Figure 1). Family history showed that the mother and father were first-degree cousins. The patient's complete blood count, C-reactive protein (CRP) level, glucose, serum electrolytes, lipid profile, kidney and liver function tests were normal. Blood gas parameters were as follows: pH 7.29, pCO₂ 41.1 mmHg, HCO₃ 19 mmol/L and the base deficit was −6 mmol/L. No gas was observed in the intestinal system on abdominal radiography.

Abdominal ultrasonography revealed no findings other than a gas-filled abdomen. Contrast-enema radiography showed dilated intestinal loops and no contrast material passing beyond the descending colon. The patient underwent exploratory laparotomy on the third day of life. Intraoperative findings included extensive intestinal distension with fluid-filled bowel without any obstruction or atresia. Frozen section pathologic examination of biopsies revealed aganglionic rectum, and the patient underwent a sigmoid colostomy; the procedure was terminated in accordance with surgical procedures.

The patient's complete blood count, CRP level, glucose, serum electrolytes, lipid profile and kidney and liver function tests were repeatedly normal. The baby continued to live with acidosis and high stool output, which required strict treatment adjustments and prolonged the length of stay (Figure 2). Diarrhoea continued even after oral feeding was discontinued. There was no evidence of systemic or local inflammation. On the 74th day of life, the patient's serum sodium was 112 meq/L, pH was 7.28, pCO₂ was 31.3 mmHg, HCO₃ was 18 mmol/L and the base deficit was −7.6 mmol/L. Stool microscopy and stool culture were normal for infectious agents. The stool pH was 8. The stool sodium level was 130 mmol/L (reference: 20–50 mmol/L), the stool chloride level was 78 mmol/L (reference: 5–25 mmol/L) and the stool potassium level was 15 mmol/L (reference: 55–65 mmol/L). Stool osmolarity was measured as 0 mmol/L, resulting in secretory diarrhoea. No fat vacuoles were seen in direct stool examination. Newborn screening was normal. Stool pancreatic elastase levels were in the low range as a result of watery stools. Colonoscopy showed normal macroscopic and histopathologic findings. There was no evidence of structural mucosal defects such as inflammatory bowel disease, microvillus inclusion disease or tufting enteropathy. Absolute urinary sodium excretion was 36 mmol/L (reference: 2–28 mmol/L) and urinary fractional sodium excretion was 1.2% (reference: 0.3%–1.6%). Low serum sodium, metabolic acidosis and diarrhoea with high sodium content were present, suggesting CSD. Based on suspicion, clinical exome sequencing was performed when the patient was 3 months old. Clinical exome sequencing revealed a pathogenic homozygous variant in the SLC9A3 gene (NM_004174.4: c.65_74dup [p. Gly27AlafsTer178]), thus confirming the diagnosis. The patient was hospitalised and followed up with prolonged intravenous fluid and sodium bicarbonate requirement (6 mmol/kg/day) during the neonatal period. At 6 months of age, he was discharged with a weight of 4200 g, age-appropriate food and low sodium oral rehydration solution (ORS). One month later, the patient died of sudden infant death, thought to be caused by aspiration or electrolyte imbalance.

CSD is a rare congenital diarrhoea disease and because it is a life-threatening disease in infancy due to severe dehydration and electrolyte imbalance, early diagnosis of this disease is essential. Typical antenatal symptoms of the disease are polyhydramnios and intestinal dilatation, intestinal obstructions (atresia, meconium ileus, Hirschsprung disease) or congenital diarrhoea [2]. Intrauterine focal dilatations strengthen intestinal obstructions, and diffuse dilatations strengthen congenital diarrhoea [3]. In addition, increased peristalsis may indicate intestinal atresia, normal peristalsis congenital diarrhoea and decreased peristalsis obstruction. Again, high sodium levels in the amniotic fluid may suggest CSD, but it has been described in cases with normal amniotic fluid sodium levels [4]. In our case, widespread dilated intestinal loops suggested congenital diarrhoea. However, it should be kept in mind that none of the antenatal methods are specific for CSD and using them together may increase the probability of a correct diagnosis. A high level of suspicion by obstetricians is important in diagnosis.

The disease is divided into two forms. The syndromic form of CSD is associated with choanal or anal atresia, hypertelorism and corneal erosions, and is caused by SPINT2 variants. This form is also called the syndromic form of congenital tufting enteropathy [5]. Non-syndromic CSD is thought to be caused by loss of function in the intestinal apical membrane Na+/H+ exchanger (NHE3) because of SLC9A3 or GUCY2C variants. NHE3 is responsible for sodium reabsorption in exchange for hydrogen, and therefore, dysfunction of NHE3 leads to diarrhoea, hyponatraemia and metabolic acidosis [6]. Due to excessive diarrhoea, newborns with CSD develop severe dehydration, electrolyte abnormalities and metabolic acidosis that require urgent correction with total parenteral nutrition (TPN) to improve morbidity and mortality.

In this study, we present a new case of non-syndromal CSD associated with an SLC9A3 variant. Although the aganglionic segment was considered suspicious for intestinal atresia during surgery, suggesting Hirschsprung disease, the high volume of watery content coming from the colostomy strengthened the possibility that the patient had congenital diarrhoea. To evaluate our patient (Patient 14 in the literature) in more detail, we combined our clinical and genetic findings with the findings of 13 previously reported patients with CSD with SLC9A3 variants [2, 6-9]. Serum sodium levels were normal except for Patient 10; serum pH was acidic except for Patients 6 and 12, and stool sodium concentrations were high except for Patient 4. All except Patient 9 continued their lives with growth and developmental delay and mild watery diarrhoea (Table 1). Our patient's laboratory findings were similar. Physicians should consider CSD in congenital diarrhoea with resistant metabolic acidosis even if serum sodium levels are normal. However, our patient was different with high colostomy outputs and TPN dependency. We believe that this situation may be related to the expressivity of the genetic variant detected in our patient.

Inflammatory bowel disease (IBD) developed in two previous patients (Patients 6–8) during follow-up, suggesting that NHE3 deficiency predisposed to IBD. Studies have shown a strong relationship between ulcerative colitis and the SLC9A3 locus [10]. Therefore, close clinical follow-up of patients throughout life is important.

This rare disease may cause a delay in diagnosis due to its mild clinical course. However, the patient's prenatal and natural history, physical examination and blood and stool examinations will usually be diagnostic, and advanced genetic evaluations can be performed to support the diagnosis. Early diagnosis of the disease will provide early treatment and prevent unnecessary surgical interventions. The reported patient will contribute to the literature with his clinical and genetic aspects.

Congenital diarrhoea should be considered in the differential diagnosis in patients with prematurity, polyhydramnios and large bowel movements. Even if serum electrolytes are normal, CSD should be kept in mind in patients with resistant metabolic acidosis, and stool and urine examination should be performed for diagnosis. Supporting the diagnosis with advanced genetic studies will help develop new treatment options.

Hatice Yilmaz Dagli: concept, writing, literature research. Nurten Özkan Zarif: design, concept, literature research. Kıymet Çelik and Sema Arayici: design, data collection or processing. Hakan Ongun: design, analysis or interpretation. Reha Artan: writing, literature research. İbrahim İnanç Mendilcioğlu: data collection or processing, analysis or interpretation. All authors have read and approved the final manuscript.

Ethics committee approval was received from the local Ethics Committee of our hospital (Decision Number:28.11.2024-KAEK-776).

We had parents' written consent for publishing the article and images.

The authors declare no conflicts of interest.