Congenital sodium diarrhea is a rare cause of secretory diarrhea caused by defective sodium transport in the small bowel. It is characterized by life-threatening diarrhea, severe hyponatremia, and metabolic acidosis from birth onward. The genetics of this disease have been only partially unraveled (1,2).
Chronic idiopathic intestinal pseudoobstruction is another rare syndrome that is characterized by severe motility disturbances due to a primary disorder of enteric nerve or muscle. It is a heterogeneous syndrome and the cause of the pseudoobstruction is not identified in the majority of patients (3).
We report on a young child who presented with both congenital sodium diarrhea and chronic idiopathic intestinal pseudoobstruction. To our knowledge this combination of 2 rare disorders has not been described before.
The male patient was the third child of healthy unrelated Dutch parents, born at 34 weeks' gestation. There was no family history of congenital gastrointestinal diseases or of miscarriages. Pregnancy was complicated by polyhydramnios, and prenatal ultrasound showed a distended fetal abdomen with dilated intestinal loops.
After birth he had a severely distended abdomen. Radiology showed a markedly dilated small bowel. During the first 5 days of life, oral feeding was not tolerated due to vomiting. He was thought not to be passing stool, and measured urine output was observed to be high. A laparotomy was performed because of the suspicion of an obstructive ileus. During laparotomy the small bowel was found to be hugely dilated until just proximal to the terminal ileum, but no obstruction was found. The colon had a normal diameter. An ileostomy was formed and 500 mL of fluid evacuated from the small bowel. Parenteral nutrition was started because of intolerance to enteral feeding.
Despite total parenteral nutrition and without any oral intake the small bowel remained severely dilated and retention of stomach contents occurred intermittently necessitating frequent gastric drainage by a nasogastric tube. Moreover, the ileostomy had a persistent high output, between 2000 and 3000 mL/day. Biochemically, there was a tendency for hyponatremia and metabolic acidosis. Analysis of the stoma output showed high sodium content (sodium 145 mmol/L, potassium 6 mmol/L, chloride 116 mmol/L, osmolarity 283 mOsm/kg, pH 8). The urine biochemistry was normal. To remain in fluid and electrolyte balance he needed large supplements of fluid (2–3 L/day), sodium (30–40 mmol · kg−1 · day−1), and bicarbonate (8–12 mmol · kg−1 · day−1). Mitochondrial neurogastrointestinal encephalopathy syndrome gene testing was not performed because ophthalmoplegia and polyneuropathy were absent and urine thymidine concentration was normal. Multiple plain abdominal x-rays and a small bowel follow-through examination showed dilated small bowel without anatomical obstruction. On the basis of these findings chronic idiopathic intestinal pseudoobstruction (CIIP) was diagnosed.
Additional investigations into the high output of small-bowel fluid were performed. Infective causes were excluded. Both conventional microscopy and electron microscopy of the small bowel epithelia were normal (Fig. 1). There were no signs of a secretory hormone-producing tumor. Empirically, antibiotics for possible intestinal bacterial overgrowth were given, but without any clinical benefit. Symptomatic treatment with octreotide for cyclic adenosine monophosphate–linked secretory diarrhea did not have any effect at a dosage of 3 μg/kg 2 times per day subcutaneously. Before increasing the dosage, he developed an ileus. Subsequently, octreotide treatment was stopped and not restarted. Clinically and biochemically, the small-bowel output was consistent with congenital sodium diarrhea (CSD). DNA analysis for gene mutations encoding the brush border sodium-proton exchangers 3 and 4 (NHE3-4) and serine peptidase inhibitor 2 (SPINT2) mutations was negative. NHE3-4 immunostaining of small-bowel biopsies showed no abnormalities.
Besides intermittent gastroparesis, the patient remained well on total parenteral nutrition including intravenous supplementation of fluid, sodium, and bicarbonate. At age 2 years recurrent episodes of small bowel ileus with huge small bowel distension occurred and did not resolve with conservative treatment. At each episode, laparotomy showed volvulus of distended small bowel filled with up to 2.5 L of fluid (Fig. 2). Because of these recurrent episodes of volvulus, a small bowel resection was performed from 20 cm after the ligament of Treitz onward. Postoperatively, his jejunostomy produced 1.5 L of fluid each day. Sodium supplementation was reduced to 13 mmol · kg−1 · day−1 and bicarbonate supplementation was stopped. His caregivers reported a greatly improved quality of life after surgery; presently, at age 3 years he continues to thrive and develop normally.
CSD and CIIP both are rare and severe disorders. To our knowledge, the combination of these 2 disorders has never been described. CSD is a clinical diagnosis because there is no diagnostic test for this disorder. The diagnosis is based on the presence of severe congenital diarrhea secretory in nature, severe hyponatremia, and metabolic acidosis resulting from the loss of high quantities of sodium and bicarbonate in stools. Specific epithelial disorders that cause secretory diarrhea should be excluded: congenital tufting enteropathy, caused by mutation in the MYO5B gene on chromosome 18q21 (Online Mendelian Inheritance in Man ID no. 251850), and microvillus inclusion disease, caused by mutation in the TACSTD1 gene on chromosome 2p21 (Online Mendelian Inheritance in Man ID no. 613217). In addition, infectious, metabolic, and autoimmune causes should be excluded (2). In our patient, the high sodium content of the stoma output (145 mmol/L compared with a normal concentration of about 75 mmol/L) and the tendency for acidosis are consistent with CSD.
The clinical presentation of our patient with antenatal polyhydramnios and profuse diarrhea from birth is typical of congenital secretory diarrhea. As described before, the output of stools after birth was initially interpreted as high urine output (4,5), and surgery was performed because bowel obstruction was suspected (5). Limited reports of the clinical picture after birth exist, but all of them describe a milder picture than that of our patient: lower volumes of stools (35–75 mL · kg−1 · day−1) and smaller quantities of sodium supplementation (3–10 mmol · kg−1 · day−1) (4,6,7). Some cases in the course of the first year can be managed by oral rather than intravenous fluid and electrolyte supplementation (4,6–8). In 1 case, the diarrhea was reported to have diminished during the first year of life (4). Several cases, however, have been reported of children who die within the first year, mostly because of parenteral nutrition–related complications (2,8). Recently, a syndromic form of SCD was described, which was characterized by the presence of choanal atresia, hypertelorism, and/or corneal erosions (2).
CSD is supposedly caused by a defect in sodium/potassium exchangers on the apical side of the enterocyte (9–11). In the CSD cases with CSD studied up until now, no genetic defect in known NHE genes has been identified. Recently, mutations in the gene coding for SPINT2, a serine protease inhibitor, were identified in 16 cases of syndromic patients with CSD. It was not found in 8 cases of nonsyndromic CSD. These mutations cause a loss of function of the serine protease inhibitor, which possibly affects transmembrane sodium-transporting proteins (2). In our patient, no genetic defects were found.
The diagnosis of CIIP is based on the clinical picture suggestive of a mechanical obstruction in the intestines in the absence of any demonstrable evidence of obstruction. In our patient, an anatomical obstruction was excluded by imaging and during surgery. As in most cases of CIIP, abnormalities of intestinal innervation or muscle were not identified (3). The episodes of recurrent volvulus were probably caused by rapid accumulation of large amounts of fluid in the intestine in periods of increased dysmotility, causing the intestine to rotate. However, volvulus has been reported as a complication of CIIP as well (12,13).
Concomitant CIIP and CSD have not been described in the literature. In cases of CSD, dilated bowel in utero and after birth has been described, suggesting dysmotility. In most of these cases, complete oral feeds could be introduced without any problem (4–6); however, a period of pseudoobstruction requiring parenteral nutritional support followed by recurrent episodes of impaired enteral tolerance and distended small bowel loops with fluid have been observed in 1 of these patients during follow-up into adulthood (personal communication, Dr Puntis) (4). In addition, there was a report on 1 child who did not tolerate any enteral feeding during his 18-month-long life, although radiology did not show bowel distention (8). In many cases with CSD, parenteral feeding is started initially because enteral feeds increase diarrhea and not because of distention (8). In NHE3-knockout mice, which have a CSD phenotype, dilated and enlarged bowels have been described. These mice have mild diarrhea and tolerate normal feeding. The bowel enlargement observed in these mice was interpreted as a compensatory increase in the absorptive area in response to increased bowel fluid (14); however, mild dysmotility cannot be excluded.
An explanation for the concomitant presence of these 2 rare disorders could be that the exceptionally large intestinal fluid load in this patient caused bowel dilatation and dysmotility of the small bowel. In their long-term follow-up study of a cohort of 44 patients with CIIP, Heneyke et al (13) describe their clinical experience that gross intestinal dilatation in CIIP reduces effective motor activity of the gut, thus aggravating intestinal dysmotility. As mentioned above, the amount of bowel fluid in our patient was much larger than that in any other case of CSD described in the literature, possibly explaining why severe dysmotility was not observed in other cases of CSD. Dysmotility also can be a cause of increased intestinal fluid output. Intermittent dysmotility can cause increased intestinal fluid retention and subsequent increased excretion when the dysmotility abates (13,15). Moreover, intestinal dysmotility predisposes to intestinal bacterial overgrowth (16). However, these pathophysiological mechanisms seem unlikely in our patient because he had a continuous high intestinal fluid output, which started in utero and did not diminish after antibiotic therapy for bacterial overgrowth. Moreover, output remained high after extensive small bowel resection, which eliminated the dysmotility complaints. Massive sodium excretion, as in this patient, was not described in patients with CIIP during periods of increased fluid excretion due to dysmotility (13,15). Finally, concomitant presence of these 2 disorders could be explained by a common genetic cause, but because the genetics of these 2 disorders have not been well established, this remains a speculation.
We thank Dr M. Donowitz and Dr A. Janecke for their genetic and immunofluorescence studies in the patient and Prof F.J.W. Ten Kate for supplying and commenting on the histology images.
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