Crohn Disease in an Adolescent With Galactosemia

Despite intensive research efforts, the cause of inflammatory bowel disease (IBD) is unknown (1). The continuous increase in the incidence and prevalence of IBD throughout most of the last half century highlights the importance of environmental factors in its pathogenesis (2). However, many studies have investigated genetic factors in IBD and certain human leukocyte antigen associations have been made, suggesting the relevance of genes to disease predisposition (3). In the pediatric age group, there is an association between certain congenital metabolic disorders and IBD, including glycogen storage disease type Ib and chronic granulomatous disease (4). Significant advances in the genetics of galactosemia have been made, including cloning the human galactose-1-phosphate uridyltransferase (GALT) gene (5,6). However, no immunologic findings in galactosemia suggest a predisposition to IBD, unlike in other congenital defects (4). We report the unusual case of a child with congenital galactosemia in whom Crohn disease developed during adolescence. CASE REPORT The patient had neonatal cholestasis at 12 days of age and was diagnosed with galactosemia. Treatment consisted of a galactose-free diet. Neonatal course was not complicated by hypoglycemia. Early in life, he showed moderate developmental delay. At 9 years of age, he began anticonvulsive therapy for partial complex epilepsy. The patient was not always compliant with a galactose-free diet, as shown by high serum galactose-1-phosphate concentrations. A younger sister had been diagnosed at birth with galactosemia and also had a milder developmental delay. An older sister is healthy. Neurologic workup showed no disorder to account for the familial developmental delay. There was no family history of IBD or of autoimmune or immunodeficiency disorders. The patient had no history of recurrent infections. An Escherichia coli urinary tract infection was diagnosed during the neonatal period. At 15 years of age, chronic abdominal pain and nonbloody diarrhea developed. The patient lost more than 10 kg during a 5-month period. At examination, he looked unwell, with pallor and slight peripheral edema. The remainder of his examination, including the abdominal examination, was unremarkable except for a large perianal tag. He experienced no pubertal delay (Tanner 4). Investigations showed anemia (hemoglobin concentration, 10.4 g/dL; mean cell volume, 90 fL) and normal leukocyte count and differential. Hypoproteinemia (5.4 g/dL) and hypoalbuminemia (2.0 g/dL) were noted, with an increased erythrocyte sedimentation rate (35 mm/h). Colonoscopy showed multiple aphthous and “collar button” ulcers dispersed throughout the terminal ileum and colon. Upper endoscopy showed duodenal involvement, with aphthous lesions. Barium small bowel studies confirmed extensive involvement of the ileum. Based on the disease distribution and the presence of granulomas at histologic examination of colonic biopsy specimens, a diagnosis of Crohn disease was made. Helicobacter pylori gastritis was found incidentally in gastric biopsy specimens. Therapy with a galactose-free oral 5-amino salicylic acid (5-ASA) preparation (Pentasa, Shire US Inc., Florence, KY, 45 mg/kg daily), and corticosteroid (prednisolone, 1 mg/kg daily) was initiated, and the disease went into remission. The patient's Crohn disease was steroid dependent, and growth failure ensued. Therefore, 6-mercaptopurine (6-MP, 1 mg/kg daily) was initiated 19 months after diagnosis. Despite some improvement in the symptoms, ischiorectal abscesses with perianal fistulae developed in the patient. No significant improvement was achieved despite the addition of metronidazole and ciprofloxacin to 6-MP, steroids, and 5-ASA therapy. Surgical drainage of an ischiorectal abscess and a left colostomy were performed 2 years after diagnosis. Despite this patient's surgery and intensive medical therapy, including 6-MP, oral corticosteroids, and 5-ASA, abdominal pain and diarrhea continued as prominent symptoms. Laboratory findings were consistent with active disease (anemia, hypoalbuminemia, increased erythrocyte sedimentation rate). Mucosal vessel density measurements by color Doppler sonographic assessment (7) confirmed active ileitis. Erythrocyte 6-MP metabolite levels were low, and the dosage was adjusted (1.5 mg/kg daily) to achieve therapeutic 6-thioguanine levels (8). The patient's symptoms regressed, and laboratory and radiographic findings normalized 4 months after. Currently, the patient is receiving 5-ASA and 6-MP (1.3 mg/kg daily). He has not received steroids for 15 months and has been in sustained remission. DISCUSSION Although the cause of chronic IBD is unknown, environmental, genetic and immunologic factors have been implicated (1,2). Nutritional interventions such as early weaning from breast-feeding have been considered risk factors, probably because of alterations in intestinal flora (9). From the pediatric perspective, IBD has been associated with several congenital disorders, most of which involve dysfunction of the phagocytic component of the immune system, including glycogen storage disease type Ib, chronic granulomatous disease, and adhesion molecule deficiency (4). Inflammatory bowel disease has been associated with other genetically determined diseases, such as Hermansky-Pudlak syndrome (10), Turner syndrome, ankylosing spondylitis, and other human leukocyte antigen–associated diseases (11). An association with galactosemia has only once been associated with Crohn disease (12). Herein, we describe a male adolescent with galactosemia who was diagnosed with severe, steroid-dependent Crohn disease complicated by growth impairment, osteopenia, and multiple fistulae. Galactosemia is an autosomal recessive inborn error of metabolism that results in accumulation of galactose metabolites. The most common variant of this disease is caused by deficiency of the GALT enzyme, as with our patient. Until recently, diagnosis of galactosemia was made by quantifying erythrocyte GALT activity. Now however, the diagnosis can be made by mutational analysis of the gene itself (5). Leslie et al. (6) cloned the human GALT gene in 1992. It is located on chromosome 9 and consists of 4 kilobases with 11 exons. In this case report, we report the association of this rare metabolic disorder with Crohn disease, a relatively frequent disorder among French Canadians (11). Although galactosemia is caused by a single gene defect with simple Mendelian inheritance, IBD represents a complex genetic disorder (2,3,9). It reflects the interplay among multiple genetic and environmental factors. Inflammatory bowel disease is not only polygenic, but also genetically heterogeneous, that is, caused by different genes on different chromosomes in different individuals (13). Linkage data derived from genome-wide scans of IBD sibling-pair families have identified 4 loci on chromosomes 3,7,12, and 16 as potential sites for IBD susceptibility genes (14,15). An association with chromosome 9 that could explain a common causal pattern with galactosemia has not been described thus far. The mainstay of treatment for galactosemia is elimination of all forms of galactose intake. Lactose-free soy and protein hydrolysate formulas are substituted for breast milk or lactose-containing formula. Our patient's Crohn disease may have been influenced by his special diet, potentially altering the intestinal flora. The possibility that components of the intestinal flora could trigger, initiate, or somehow contribute to IBD has intrigued investigators for years (2). Patients who have IBD have been reported to lack tolerance to their flora (16). A recent study found a significant decrease in the number of anaerobic bacteria and Lactobacillus species in patients with active, but not inactive, disease (17). Variations in disaccharide ingestion have been implicated in altered colonic microenvironment, potentially predisposing one to colorectal cancer and IBD (18). Lactose ingestion has effects resembling those of ingesting dietary fiber: lowering colonic pH, altering the bacterial flora by reducing clostridia and Bacteroides species while increasing fecal Bifidobacterium, and increasing fecal short-chain fatty acids, important nutrients for colonic epithelial cells (18). Lactose malabsorption is more prevalent in patients with Crohn disease than in ethnically matched individuals (19). Furthermore, lactose avoidance is more prevalent in Crohn disease than is dictated by true malabsorption (20). Although a causal association has not been proven, patients with galactosemia have lactose avoidance as do many patients with Crohn disease. Recent studies support the benefit of probiotics in preventing postoperative recurrence of Crohn disease and in treating pouchitis (21). In retrospect, the use of probiotics or prebiotics may have benefited our patient. Experimental studies using GALT-deficient knockout mice could serve as a model to better understanding this association.

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