Congenital Short Bowel Syndrome

A number sign (#) is used with this entry because of evidence that congenital short bowel syndrome (CSBS) is caused by homozygous or compound heterozygous mutation in the CLMP gene (611693) on chromosome 11q24.

A possible form of congenital short bowel syndrome (see 300048) is caused by mutation in the FLNA gene (300017) on chromosome Xq28.

Description

Infants with congenital short bowel syndrome are born with a shortened small intestine, with a mean length of 50 cm compared to the normal length of 190 to 280 cm, and intestinal malrotation. Severe malnutrition develops as a result of the hugely reduced absorptive surface of the small intestine, and infants require parenteral nutrition for survival; however, parenteral nutrition itself causes life-threatening complications such as sepsis and liver failure which are associated with a high rate of mortality early in life (summary by van der Werf et al., 2012).

Clinical Features

Hamilton et al. (1969) described a 7-year-old girl, born to nonconsanguineous French Canadian parents, who presented at 4 months of age with chronic diarrhea and failure to thrive. Barium enema showed the cecum in the left upper quadrant, indicating partial malrotation of the gut. Laparotomy at 7 months of age confirmed that the cecum, with normal appendix, was on the left, and also revealed that the small intestine was only 40 cm in length. There was no obstruction. Her severe diarrhea persisted until 5 years of age, when spontaneous improvement occurred. At 7 years of age, on no medications, she had 2 semiformed stools per day but no clinical features of intestinal malabsorption other than short stature. Analysis of intestinal absorptive function at 20 months and 3.5 years of age showed steatorrhea, with fecal fat excretion at 40% of dietary intake; oral glucose tolerance and D-xylose excretion were initially abnormal as well. These parameters improved spontaneously over the 6 years of follow-up, and her electrolyte balance and hematologic indices were always normal. Hamilton et al. (1969) suggested that the improvement might have been due to an increase in intestinal length, since later intestinal x-rays indicated a length in excess of 40 cm; they also noted that adaptation within the villi, comparable to that occurring after resection of the intestine, might have taken place. The proband had 3 healthy sisters and 1 sister who had died at 1 month of age, who at laparotomy 1 week prior to death was found to have a 30-cm small intestine and cecum with appendix in the left upper quadrant.

Huysman et al. (1991) reported a 4-year-old girl with congenital short bowel and malrotation who presented at 9 weeks of age with failure to thrive. She normally defecated 4 times per day and did not vomit. X-ray evaluation during an episode of watery diarrhea showed distended bowel loops with air fluid levels, suggestive of obstruction. Examination of stools revealed steatorrhea; jejunal biopsy was normal with normal values of disaccharide activity. One week later she vomited and again had signs of obstruction on x-ray. Barium enema showed a malrotation with the cecum in the left upper quadrant; cecoileal reflux showed dilated small bowel loops and decreased bowel length. Laparotomy was performed due to suspected intermittent volvulus of the midgut, but demonstrated malrotation with a short bowel without volvulus; total small bowel length was 54 cm. Peeling skin and loss of hair led to evaluation of trace elements, showing deficiency of zinc and vitamin A that normalized after supplementation. At 4 years of age, her height was at the 50th percentile for age and weight at the 10th percentile for age; psychomotor development was normal and she was attending school regularly.

Huysman et al. (1991) reviewed 16 published reports of congenital short bowel and malrotation syndrome since the initial report by Hamilton et al. (1969), noting that the prognosis was poor, with only 3 patients including theirs surviving. Symptoms related to obstruction, such as bilious vomiting and distended abdomen, presented mostly in the first month of life, with failure to thrive, rejected feedings, and persistent diarrhea developing at 2 months of age. There did not appear to be an explicit relationship between the onset of symptoms and total bowel length.

Schalamon et al. (1999) reported a Turkish boy, born of first-cousin parents, who had vomiting and diarrhea starting at 9 days of age. Radiologic study at 4 months of age showed short bowel without disruption of continuity but with malrotation and delayed gastric emptying. Laparotomy revealed normal-appearing small bowel, except for a shortened length of 47 cm. The colon was of normal length but showed an increasing thickness of the muscle layer towards the rectum, similar to that seen in Hirschsprung disease (see 142623); however, rectal mucosal biopsies showed discrete signs of intestinal neuronal dysplasia but no Hirschsprung disease. After surgery, enteral feedings were gradually introduced with parallel reduction in parenteral nutrition. At 13 months of age, he underwent ventral semifundoplication for gastroesophageal reflux. At 19 months of age, he still received 30% of his calories from parenteral nutrition, and had gastrointestinal transit times of 3 hours with 8 to 12 stools per day. His length was at the twentieth percentile and weight at the third, with normal psychomotor development.

Ordonez et al. (2006) studied a female infant who presented at 5 days of life with a history of bilious vomiting. Abdominal radiographs showed barium in the colon with the cecum in the left upper quadrant. Laparotomy revealed a shortened bowel measuring approximately 30 cm, with malrotation but no volvulus. Postoperatively the patient had diarrhea, continued vomiting, and poor weight gain, resulting in the institution of parenteral nutrition as well as enteral feeding via gastrostomy drip; these were discontinued at 22 months and 32 months of age, respectively. Studies of digestive function at 10 and 11 months of age showed an initial coefficient of fat excretion of 33%, which decreased to 24% after treatment with Lactobacillus casei GG. The patient's height and weight remained around the 75th percentile for age since birth; plasma zinc persisted in the low to low normal range. Neurocognitive testing at 7.5 years of age showed a full-scale IQ of 120 (90th percentile), with intact academic and social skills.

Hasosah et al. (2008) reported a 6-week-old boy who presented with chronic watery diarrhea and failure to thrive. Upper gastrointestinal endoscopy showed a straight duodenum, and multiple small bowel biopsies were histologically normal. Upper gastrointestinal series showed malrotation, and at laparotomy, the small bowel was 50 cm in length, confirming the diagnosis of short bowel syndrome (SBS). Parenteral nutrition was initiated, with early introduction and advancement of enteral feeding. At last follow-up at 24 months of age, he was thriving on a regular diet, with normal growth and development. Hasosah et al. (2008) concluded that long-term survival of children with congenital SBS is possible if enteral feeds are introduced early to promote intestinal adaptation, with subsequent weaning off parenteral nutrition.

Hasosah et al. (2008) reviewed the 37 published cases of congenital short bowel syndrome, all but 1 of which were associated with malrotation. Associated congenital anomalies included pyloric stenosis, appendiceal agenesis, acheiria, dextrocardia, hemivertebrae, and patent ductus.

Mapping

Van der Werf et al. (2012) performed homozygosity mapping using DNA from 5 patients from 4 families with congenital short bowel syndrome and identified a 2-Mb homozygous region shared by 4 patients on chromosome 11q24.1.

Molecular Genetics

In a Dutch girl with congenital short bowel syndrome who was originally reported by Huysman et al. (1991), van der Werf et al. (2012) identified homozygosity for a 12,483-bp deletion on chromosome 11q24 that included exonic and flanking intronic sequence of exon 2 of the CLMP gene (611693). Sequencing of the CLMP gene in 4 more probands with CSBS revealed compound heterozygosity for a frameshift and a splice site mutation (611693.0001-611693.0002) in the patient previously described by Ordonez et al. (2006), homozygosity for a nonsense mutation (R222X; 611693.0003) in the patient reported by Hasosah et al. (2008), and homozygosity for a missense mutation (V124D; 611693.0004) in a previously unreported Italian patient. In the Turkish boy with CSBS described by Schalamon et al. (1999) and an affected female family member, van der Werf et al. (2012) identified homozygosity for a deletion in intron 1 of the CLMP gene encompassing SNP rs7115102, but were unable to fine-map the deletion, presumably due to the presence of a small inversion. All of mutations segregated fully with disease in each family and were not found in known SNP databases or in 154 Caucasian control chromosomes.