Congenital Chloride-Losing Diarrhea in Saudi Children

Transcription

1 Asaad M. A. Abdullah, MRCP(UK), DCH, DTCH; Sujatha M. Katugampola, MRCP(UK), DCH; Mohamed Ahmed Abdullah, FRCP(Edin), DCH, DTCH; Khalifa A. R. Adam, FRCP, DCH; Nuhad Al-Jishi, MD, DCH From the Department of Paediatrics, King Khalid University Hospital, Riyadh. Address reprint requests and correspondence to Dr. Abdullah: P.O. Box 89828, Riyadh 11692, Saudi Arabia. Accepted for publication 9 September Four Saudi patients with congenital chloride-losing diarrhea (CCD) are described. The disease was characterized by polyhydramnios, chronic diarrhea, abdominal distention, growth failure, and delay in diagnosis. In only one patient, the brother of a known case, was the diagnosis made at birth. The first patient had laparotomy at the age of five days for suspected intestinal obstruction, and CCD was not diagnosed until seven weeks of age. The second patient had had chronic diarrhea since birth, but the correct diagnosis was delayed until 11 months of age when he was seen because of chronic diarrhea and severe marasmus. The third patient was a sibling of the second patient, and diagnosis was made on the first day of life. The fourth patient had had symptoms since birth, and was kept in her local hospital for 9 months because of electrolyte abnormalities, but correct diagnosis was not made until she was referred to another hospital. The possibility of CCD should be considered in any infant with persistent watery stools beginning in the first days of life, particularly if there was polyhydramnios during pregnancy. AMA Abdullah, SM Katugampola, MA Abdullah, KAR Adam, N Al-Jishi, Congenital Chloride-Losing Diarrhea in Saudi Children. 1990; 10(4): Congenital chloride-losing diarrhea (CCD) was first reported by Gamble et al 1 and Darrow 2 in It is a genetically transmitted disease with an autosomal recessive pattern of inheritance. 3 We present our experience with the clinical presentation and management of four patients with CCD. Patient 1 Case Reports A one-year-old Saudi male infant was referred to King Khalid University Hospital (KKUH) at the age of 7 weeks because of inadequate weight gain, progressive abdominal distention, diarrhea, and vomiting since birth. He was the product of a 36 weeks' pregnancy that was complicated by polyhydramnios but with normal spontaneous

2 vaginal delivery. His birth weight was 2.5 kg (5th centile); length, 45 cm (< 50th percentile); and head circumference, 35 cm (50th percentile). He was the fifth child born to unrelated parents. Family history was otherwise unremarkable. Soon after birth, the baby was noticed to have abdominal distention, with passing of watery stools noted on rectal examination; otherwise physical findings were normal. Abdominal x-ray study showed distended small bowel loops. A provisional diagnosis of intestinal obstruction was made and a laparotomy on the fifth day showed distended bowel loops. A total of 10 cm of intestine, including terminal ileum and proximal ascending colon, was removed. The child continued to have progressive abdominal distention with watery diarrhea and vomiting and was therefore referred to our hospital. Examination revealed a wasted-appearing infant who was hypotonic. Weight was 2.05 kg (< 5th centile); length, 47 cm (< 5th centile); and head circumference, 36 cm (10th centile). His abdomen was grossly distended with visible multiple bowel loops. He was started on total parenteral nutrition combined with milk formula (hydrolysate formula with medium-chain triglycerides and added amino acids) but did not gain weight adequately. The abdominal distention also persisted. His weight at 4 months was 4 kg. During this time his blood gas values showed persistent metabolic alkalosis (ph, 7.49; HCO 3, 50 mmol/l; base excess [BE], +40) and the serum chloride value was persistently low despite the low urinary chloride concentration. Therefore, the possibility of chloridelosing enteropathy was considered and repeat separate stool collection demonstrated high chloride content (Table 1). He was then started on an electrolyte-replacement solution (sodium, 6 mmol/kg/day; potassium, 6.5 mmol/ kg/day; and chloride, 12.5 mmol/kg/day), and on this regimen he started to gain weight. His serum chloride level improved, though he continued to have chloridorrhea. Apart from development of hydrocephalus, for which a shunt was installed, the child continued gaining weight, but rather slowly. He was discharged home at the age of one year with a weight of less than 5.2 kg and on normal feeds for age. He was taking an oral electrolyte solution (sodium, 30 mmol/day; potassium, 17 mmol/day; and chloride, 47 mmol/day) but continued to have 8 to 10 small loose bowel movements per day. Patient 2 A 1-year-old Saudi male infant was the product of a 35-week twin pregnancy delivered by cesarean section because of hypertension and polyhydramnios. Apgar score was 6 and 8 at 1 and 5 minutes, respectively. He was kept in the nursery at the referral hospital for 26 days. His twin was normal. When the infant was discharged home, his mother noticed he had a consistently watery stool ten times a day along with occasional vomiting. He was admitted to the referral hospital 11 times but treatment there did not lead to improvement. He was then referred to KKUH at the age of 11 months and regarded at admission as a case of marasmus and chronic diarrhea. He was never breast fed but was kept on artificial milk formula. Table 1. Serum, stool, and urine electrolytes in four patients with congenital chloride-losing diarrhea. Patient no. Age (mo) Serum electrolytes (meq/l) Stool electrolytes (meq/l) Na K Cl Urea Na K Cl Urine electrolytes Na K Cl (mmol/ 24h) (meq/l) (meq/l) Normal values* < < < < 15 *Normal values for serum and urine electrolytes were obtained from: Forfar Jo, Arneil GC, eds. Textbook of Paediatrics, ed 3. Edinburgh, London: Churchill-Livingstone, Volume 2, 1984; Normal values for stool electrolytes were obtained from Holmberg. 5 = not done. Examination revealed a severely malnourished infant. His weight was 4.06 kg (< 5th centile); height, 70 cm (< 5th centile); and head circumference, 35 cm (< 5th centile). His parents were unrelated but had lost a male infant who had been born at 28 weeks' gestation. The infant died at 1 week of age because of abdominal distention. The current infant's abdomen was distended but soft and there was no organomegaly. He was maintained on intravenous fluid therapy for one week. No reducing substance was found in stool specimens. Sweat test was

3 normal. Two weeks after admission, he continued to have loose bowel movements. He was put on a trial lactoseand gluten-free diet for two weeks which failed to control his diarrhea. One month after admission, his weight increased to 5.5 kg (< 5th centile) and he was discharged on multivitamins and a normal diet. Four days later, he was readmitted because of recurrent diarrhea associated with vomiting. His weight was 5 kg (< 5th centile) and he was moderately dehydrated. His serum urea and electrolyte and stool electrolyte values were indicative of CCD (Table 1). He was maintained on intravenous fluid therapy for one week and was given oral sodium chloride and potassium chloride. At the age of 1 year, he was discharged on sodium chloride, 7.5 mmol, and potassium chloride, 30 mmol/day. At discharge his weight was 6 kg (< 5th centile). Patient 3 The patient was a 12-week-old male infant who was brother to Patient 2. During pregnancy, the mother was referred to KKUH because of the ultrasound finding of gross polyhydramnios and dilatation of fetal large and small bowel. The infant was born at 30 weeks' gestation by lower-segment cesarean section. His Apgar score was 5 and 7 at 1 and 5 minutes, respectively. The baby was intubated electively and given oxygen by intermittent positive pressure ventilation for respiratory distress syndrome. His weight was g (> 50th centile); height, 45 cm (> 90th centile); and head circumference, 29 cm (> 50th centile). He had no dysmorphic features. The only striking abnormality was a grossly distended abdomen with a girth of 34 cm. Liver, spleen, and kidneys were not palpable. There were no other masses in the abdomen and there was no ascites. Abdominal x-ray study showed grossly dilated bowel loops with fluid levels. Abdominal ultrasonogram was normal. Serum electrolytes are shown in Table 1, and his arterial blood gas values in 50% FIO 2 were: ph, 7.2; partial pressure of oxygen (PO 2 ), 208 mm Hg; partial pressure of carbon dioxide (PCO 2 ), 48 mm Hg; HCO 3, 21 mmol/l; BE, 5.9; total CO 2, 22; saturation, 99. On the third day of life, jaundice developed which resolved with phototherapy. At the age of 2 weeks, the baby remained well with weight 1,750 g. Treatment consisted of nasogastric milk feeding, parenteral nutrition, and extra sodium chloride and potassium chloride supplements. At the age of 4 weeks (32 weeks' gestation), his weight was 2,200 g; he was on sodium chloride (14 mmol/day) and potassium chloride (4 mmol/day) supplements and oral milk feeding only. At the age of 6 weeks, his weight was 2.6 kg and he was on supplements of sodium chloride (13 mmol/day) and potassium chloride (3 mmol/day). He was discharged home at the age of 8 weeks (38 weeks' gestation age). At discharge his weight was 3.2 kg (< 50th percentile) and he was on supplements of sodium chloride (16 mmol/day) and potassium chloride (6 mmol/day). At follow-up at the age of 12 weeks, he was passing loose stools daily but his weight was 4 kg (< 50th percentile); head circumference, 38.5 cm (> 50th percentile); and height, 51.2 cm (< 50th percentile). Patient 4 A 4-year-old Saudi girl was admitted because of persistent vomiting of four days' duration. She was the product of a full-term pregnancy that had been complicated by polyhydramnios. Delivery was normal and spontaneous through the vaginal route with Apgar score of 7 and 8 at 1 and 5 minutes, respectively. Birth weight was 2.2 kg (< 5th centile). She was kept in a local hospital for nine months because of electrolyte abnormalities, and was then referred to another hospital for further investigations. She was subsequently discharged on potassium supplements. Her parents were unrelated. She has two normal siblings. Her 2-year-old sister was said to have the same problem but is not included in the present report because she was not seen by us. On examination, the patient's weight was found to be 8.2 kg (< 3rd centile) and height, 86 cm (< 3rd centile). She was moderately dehydrated. Systemic findings were normal. Serum urea electrolytes and stool and urine electrolytes on admission are shown in Table 1. Blood gas values measured while the infant was in room air were: ph, 7.6; PO 2, 112 mm Hg; PCO 2, 25.7 mm Hg; HCO 3, 28.1 mmol/l; and BE, The hypochloremia and metabolic alkalosis are consistent with the diagnosis of CCD. She was managed with intravenous hydration for 5 days and discharged home on oral supplements of potassium chloride (50 mmol/day) and sodium chloride (40 mmol/day). Discussion Congenital chloride-losing diarrhea is characterized by abdominal distention, chronic watery diarrhea, and growth failure. 4,5 In 1971, Norio et al 3 showed that CCD is inherited as an autosomal recessive trait, and this mode of inheritance has also been reported by Holmberg et al. 4 All the parents of our four patients were unrelated, but two patients are brothers and a sibling died at the age of one week from diarrhea and abdominal distention. Patient 4 has an affected sister who was not included in our study. The frequency of CCD in Finland 5 is approximately 1 in

4 43,000 newborns. Our small number of cases does not allow for us to calculate the exact frequency in Saudi Arabia. CCD was reported from Kuwait 6 and we reported one other case from Saudi Arabia 7 but came across no report from elsewhere in the Arab world. Pregnancy in the mothers of children with CCD is usually complicated by polyhydramnios, 7 which may be due to intrauterine diarrhea. 5 All four patients in the present report were the product of a pregnancy that was complicated by polyhydramnios. CCD can be detected prenatally by the ultrasound finding of distended loops of fetal bowels. 8,9 This made early diagnosis of CCD possible in Patient 3. Other causes of dilatation of fetal bowel should also be considered: Hirschsprung's disease, meconium ileus, anal atresia, and volvulus. 10,11 One method of diagnosing CCD prenatally is measuring the level of alpha-fetoprotein in amniotic fluid. 12 This was not done in any of our patients but we think this method might be useful. Infants with CCD are often born prematurely as a consequence of the polyhydramnios. 5 Patients 1, 2, and 3 were preterm but Patient 4 was born full term. The main clinical presentation of CCD in the neonate is diarrhea with abdominal distention, 5 but because of the lack of meconium in stool, the watery diarrhea may be mistaken as urine and the abdominal distention often leads to an incorrect diagnosis of intestinal obstruction. Laparotomy was performed in several patients with this disease before CCD was correctly diagnosed, 13,14 as happened in our Patient 1. The latest case of CCD that was initially thought to be intestinal obstruction was reported from Belgium. 15 Jaundice is not unknown in the neonate with CCD; 5 our Patient 3 exhibited neonatal jaundice on the third day of life. The jaundice could be due to prematurity and/or dehydration. 4 The diagnosis of CCD may be delayed even though the symptoms start at birth. Holmberg et al 4 reported four patients from Finland whose CCD was diagnosed between 6 months and 5 years of age. Age at diagnosis in three of our patients with CCD (Nos. 1, 2, and 4) ranged between 4 and 12 months, for a mean of 8.3 months. An interesting finding in our first patient is hydrocephalus, a finding that has not been reported previously in patients with this disease. This patient had no evidence of intraventricular hemorrhage; his CSF protein, glucose, and chloride levels were normal, cell count in CSF was normal, and CSF culture showed no growth. We therefore think this finding was coincidental. Patient 4 manifested one of the common complications of the illness, namely gastroenteritis with dehydration. 5 The diagnosis of CCD cannot be sustained without the characteristic electrolyte abnormalities in both serum and feces. These abnormalities are hyponatremia, hypokalemia, metabolic alkalosis, and high chloride concentration in the stool, 5 and all were present in our four patients. Patients with CCD may have semi-formed stool along with low chloride concentration if they are dehydrated for a long time, 16 but this was not seen in any of our patients. Some patients with CCD will die from dehydration and electrolyte imbalance in the early weeks of life if they are not treated adequately, as happened with a sibling of Patients 2 and 3 who died at 1 week of age. 2 Others may survive to be diagnosed later. The treatment of CCD consists of intravenous replacement therapy of sodium chloride and potassium chloride followed by oral electrolyte solution. 17 All our patients followed this regimen. Another agent which has been used in patients with CCD is prostaglandin synthetase inhibitor, 17 but this was not tried in our patients. Adequate replacement therapy will not stop the diarrhea but children can live perfectly normal lives. 5 Pediatricians must consider the possibility of CCD in any child with chronic watery diarrhea present since birth, accompanied by abdominal distention and failure to thrive. Accurate diagnosis could save patients from unnecessary surgical intervention. Acknowledgment We thank Prof. M. B. Abdurrahman and Prof. Brian Wharton for reviewing the manuscript and Ms. Vangie Simbulan-Carrillo for secretarial assistance. References 1. Gamble JL, Fahey KR, Appleton J, Maclachlan E. Congenital alkalosis with diarrhea. J Pediatr 1945;26: Darrow DC. Congenital alkalosis with diarrhea. J Pediatr 1945;26: Norio R, Perheentupa J, Launiala K, Halman NC. Congenital chloride diarrhoea, an autosomal recessive disease: genetic study of 14 Finnish and 12 other families. Clin Genet 1971;2: Holmberg C, Perheentupa J, Launiala K, Hallman N. Congenital chloride diarrhoea: clinical analysis of 21 Finnish patients. Arch Dis Child 1977;52: Holmberg C. Congenital chloride diarrhoea. Clin Gastroenterol 1986;15: Lubani MM, Doudin KI, Sharda DC, et al. Congenital chloride diarrhoea in Kuwaiti children. Eur J Pediatr 1989;148:333-6.

5 7. Abdullah AMA, Shaheed MM, Katugampola SM, Patel PJ. Congenital chloride diarrhoea: case report and review of the literature. Ann Trop Pediatr (in press, 1990). 8. Kirkinen P, Joupplila P. Prenatal ultrasonic finding in congenital chloride diarrhoea. Prenat Diagn 1984;4: Gvoli C, Zucca S, Cessaretti A. Congenital chloride diarrhoea: antenatal ultrasonographic appearance. J Clin Ultrasound 1986;4: Padula D, de Toni A, Cabona MG, et al. Observatione di un caso di cloridorrea congenita: possibilita di diagnosi prenatale. Riv Ital Pediatrica 1984;10: Peters ER, Redwin OF. Ultrasound in the intrauterine diagnosis and treatment of fetal abnormalities. Clin Obstet Gynecol 1982;25: Hartikainen-Sorri AL, Tuimala R, Koivisto M. Congenital chloride diarrhoea: possibility for prenatal diagnosis. Acta Paediatr Scand 1980;69: Pearson AJG, Salden GE, Edmonds CJ, et al. The pathophysiology of congenital chloridorrhea. Q J Med 1973;42: Buts JP, Goenen M, Claus D, et al. Congenital chloride diarrhoea with functional ileus in a premature infant. Hel Paediatr Acta 1975;30: Vermeylen D, Godart S, Moretto M, et al. Long term follow-up of a case of severe congenital chloride diarrhoea. Eur J Paediatr 1988;147: Holmberg C, Perheen Tupa J, Launiala K. Colonic electrolyte transport in health and in congenital chloride diarrhoea. J Clin Invest 1975;56: Minford AB, Bar DD. Prostaglandin synthetase inhibitor in an infant with congenital chloride diarrhoea. Arch Dis Child 1980;55:70-2.