Journal of Perinatology (2013) 33, 154–156 r 2013 Nature America, Inc. All rights reserved. 0743-8346/13 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Congenital chloride diarrhea presenting in newborn as a rare cause of meconium ileus

H Shamaly1,2, J Jamalia3, H Omari3, S Shalev2,4 and N Elias1,2 1Pediatric Department and Pediatric Pulmonology Unit, St Vincent Hospital, Nazareth, Israel; 2Department of Pediatrics, Bruce Rappaport School of Medicine, TechnionFInstitute of Technology, Haifa, Israel; 3Neonatal Intensive Care Unit. St Vincent French Hospital, Nazareth, Israel and 4Genetic Department, HaEmek Medical Center, Afula, Israel

polyhydramnios. Parents were not related, reported to be healthy Postpartum abdominal distention and meconium ileus may occur due to and with no family history of gastrointestinal disease. Physical intestinal obstruction, Hirschprung disease or cystic fibrosis. However, other examination revealed distended abdomen with no other significant rare and challenging etiologies such as congenital chloride diarrhea (CCD) findings. should be included in differential diagnosis of such presentation. We present Postnatally the infant did not pass meconium and abdominal a premature baby girl who had distended abdomen and lack of meconium distention increased significantly. Complete blood count, serum immediately after birth. Surgical etiology was excluded and she was electrolyte levels and kidney function tests were initially within mistakenly suspected of having cystic fibrosis due to meconium ileus. CCD normal limits. Abdominal X-ray revealed diffuse dilated intestinal was diagnosed by recognition of watery diarrhea in association with loops without signs of local obstructions (Figure 1). Barium enema hyponatremic, hypochloremic metabolic acidosis. Mutation analysis showed no signs of obstruction and excluded the diagnosis of confirmed the diagnosis. Hirschprung disease. The working clinical diagnosis at this point Journal of Perinatology (2013) 33, 154–156; doi:10.1038/jp.2012.42 was meconium ileus caused by cystic fibrosis. Treatment consisted Keywords: distended abdomen; meconium ileus; congenital chloride of repeated mucomyst (acetylcysteine) enemas along with gastric diarrhea decompression via nasogastric tube. After 5 days meconium passed, abdominal distention resolved and oral feeding was started. A few

Introduction Infants born with distended abdomen and absence of meconium passage require extensive investigation to arrive at an accurate diagnosis. Surgical causes such as small bowel obstructions, malrotation and Hirschprung disease should be excluded early to avoid significant complications and high morbidity.1 Cystic fibrosis is the main non-surgical etiology in newborns.2,3 However, other rare etiologies should be included in the differential diagnosis. We present a case of a premature newborn girl who was born with a distended abdomen and absence of meconium passage that was ultimately diagnosed as congenital chloride diarrhea (CCD).

Case A 36-week gestation female newborn of Arab descent was delivered by spontaneous vaginal delivery. Birth weight was 3015 g and the Apgar score was 9 and10 at 1 and 5 min, respectively. Prenatal ultrasound at 35 weeks gestation noted abdominal distention and

Correspondence: Dr N Elias, Pediatric Department and Pediatric Pulmonology Unit, St Vincent Hospital, PO Box 50294, Nazareth 16102, Israel. E-mail: [email protected] Received 17 January 2012; revised 22 February 2012; accepted 9 March 2012 Figure 1 Distended intestinal loops without signs of local obstruction. CCD a rare cause of meconium ileus in newborn H Shamaly et al 155

Table 1 Normal values at birth. Dehydration, hyponatremia, hypokalemia, hypochloremia at second week of life with normalization after NaCl and KCl solution started

Glucose (mg dl–1) Urea (mg dl–1) Creatinine (mg dl–1) Sodium (mmol l–1) Potassium (mmol l–1) Chloride (mmol l–1)

At birth 66 22 0.6 140 4.3 98 10 Days old 70 51 0.5 130 2.4 73 12 Days old 63 53 0.4 117 3.8 63 1 Week after NaCl and KCl treatment 88 23 0.5 138 5.1 92 days later, the baby developed hyponatremia, hypochloremia and patients and 2025–2026insATC in Polish patients. Other rare metabolic alkalosis. DNA genetic testing for mutations for cystic mutations were described as well in several other countries.11 fibrosis was negative. Urine chloride concentration was within In newborns presenting with distended abdomen and delayed normal limits. Watery diarrhea developed and increased fecal passage of meconium, both surgical causes and cystic fibrosis need chloride concentration (>100 mmol l–1; normal <40 mmol l–1) to be excluded. Co-existent metabolic disturbance such as was documented (Table 1). As repeated blood and fecal electrolytes hypochloremic and hypokalemic metabolic alkalosis should raise showed same results, CCD was considered as the presumed etiology. the suspicion of Barter disease as well. But clinicians should be The infant was treated with infusion of sodium chloride and vigilant to look for diarrhea in these newborns and include CCD in potassium solutions resulting ultimately in normal serum sodium differential diagnosis. As seen in our case, the diagnosis was only concentration. made at an age of 2 weeks and only after observing watery DNA sequencing revealed that the baby was homozygous for diarrhea. Obtaining fecal samples and measuring chloride C.559G >T disease-causing mutation in the exon 5 of SLC26A3 concentration is an easy and rapid way to make the diagnosis of gene, confirming the diagnosis of CCD. Both parents were found to CCD without delay. Making the correct diagnosis as soon as be heterozygous carriers of the same mutation. At 1 year of age, the possible is highly important as administration of early child was thriving and developing normally. treatment with NaCl and KCl solution supplements allows the maintenance of normal electrolyte and acid–base balance, normal growth and development, and favorable outcome of the disease.12 Discussion CCD is an autosomal recessive inherited disorder caused by a defect Conflict of interest in ClÀ/HCO exchange, mainly expressed in the apical brush 3 The authors declare no conflict of interest. border of ileal and colonic epithelium, resulting in chloride-rich diarrhea leading eventually to hypokalemia, hyponatremia and metabolic alkalosis.1,4 CCD may also present prenatally as Acknowledgments polyhydramnios due to intrauterine diarrhea leading to premature delivery.4–6 The disease is frequently found in Finland with We gratefully acknowledge the support of the Genetic Department of the University incidence of 1 in 30 0007 and in Arab children of Saudi Arabia and of Helsinki for genetic analysis of the patient and his parents. Kuwait with incidence of 1 in 5500.8,9 In spite of this relatively high incidence, the diagnosis is frequently delayed and confused with other similar diseases.6-8 References Intestinal obstruction of the newborn can be caused by multiple 1 Langer JC, Winthrop AL, Burrows RF, Issenman RM, Caco CC. False diagnosis of conditions.1 Surgical conditions include intestinal atresia, intestinal obstruction in a fetus with congenital chloride diarrhea. J Pediatr Surg 1991; malrotation, pyloric stenosis, annular pancreas, duplication cyst 26(11): 1282–1284. and Hirschprung disease. Common non-surgical etiologies include 2 Caspi B, Elchalal U, Lancet M, Chemke J. Prenatal diagnosis of cystic fibrosis: 6 ultrasonographic appearance of meconium ileus in the fetus. Prenat Diagn 1988; cystic fibrosis and Barter syndrome. The clinical signs and 8(5): 379–382. symptoms frequently overlap, making it difficult to distinguish 3 Efrati O, Nir J, Fraser D, Cohen-Cymberknoh M, Shoseyov D, Vilozni D et al. between them.7,8 Meconium ileus in patients with cystic fibrosis is not a risk factor for clinical Genetic testing for gene mutations causing CCD has become deterioration and survival: The Israeli Multicenter Study. J Pediatr Gastroenterol Nutr available to confirm the diagnosis. Our patient was found to have 2010; 50(2): 173–178. 4 Barss VA, Benacerraf BR, Frigoletto Jr FD. Antenatal sonographic diagnosis of fetal C.559G >T mutation similar to that reported in nine children gastrointestinal malformations. Pediatrics 1985; 76(3): 445–449. 9,10 from Kuwait and Saudi Arabia. Other frequent mutations were 5 Holmberg C. Congenital chloride diarrhoea. Clin Gastroenterol 1986; 15(3): described in the literature such as 951–953delGGT in Finish 583–602.

Journal of Perinatology CCD a rare cause of meconium ileus in newborn H Shamaly et al 156

6 Egritas O, Dalgic B, Wedenoja S. Congenital chloride diarrhea misdiagnosed as bartter 10 Hoglund P, Auranen M, Socha J, Popinska K, Nazer H, Rajaram U et al. Genetic syndrome. Turk J Gastroenterol 2011; 22(3): 321–323. background of congenital chloride diarrhea in high-incidence populations: Finland, 7 Kagalwalla AF. Congenital chloride diarrhea. a study in Arab children. J Clin Poland, and Saudi Arabia and Kuwait. Am J Hum Genet 1998; 63(3): 760–768. Gastroenterol 1994; 19(1): 36–40. 11 Kere J, Lohi H, Hoglund P. Genetic disorders of membrane transport III. Congenital 8 Al-Abbad A, Nazer H, Sanjad SA, Al-Sabban E. Congenital chloride diarrhea: a single chloride diarrhea. Am J Physiol 1999; 276(1 Pt 1): G7–G13. center experience with ten patients. Ann Saudi Med 1995; 15(5): 466–469. 12 Hihnala S, Hoglund P, Lammi L, Kokkonen J, Ormala T, Holmberg C. Long-term 9 Lundkvist K, Anneren G, Esscher T, Ewald U, Hardell LI. Surgical implications of clinical outcome in patients with congenital chloride diarrhea. J Pediatr Gastroenterol congenital chloride diarrhoea. Z Kinderchir 1983; 38(4): 217–219. Nutr 2006; 42(4): 369–375.

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