X-linked agammaglobulinemia (XLA or Bruton disease) is a genetic disorder mapped to q21.3-q22 on the long arm of the X chromosome and encodes the B-cell-protein tyrosine kinase Btk. Thus far, all males with XLA have low or undetectable Btk mRNA and kinase activity (1). Affected boys have a profound defect in B lymphocyte development resulting in severe hypogammaglobulinemia, absence of circulating B cells, small to absent tonsils, no palpable lymph nodes and abnormal lymph node architecture (2-5). After 6 to 9 months of life, the patients acquire infections with extracellular pyogenic organisms, such as Streptococcus pneumoniae and Haemophilus influenzae (2). The incidence of lymphatic and hematologic malignancies in patients with primary immunodeficiencies, e.g., common variable immunodeficiency, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome and X-linked lymphoproliferative disorder, are 100-300 times the rate in the normal population (1). In contrast, solid tumors, especially gastric adenocarcinomas, may also occur in adults but are extremely rare in children (1,6,7). This finding corresponds to the rate of colonization with Helicobacter pylori and the development of chronic atrophic gastritis and gastric carcinoma in adults versus children, respectively (8). Gastrointestinal malignancies associated with primary immunodeficiencies generally occur in the colon or lymphatic tissue of the stomach (2,3,5). In XLA, to our knowledge, only two patients with gastric adenocarcinoma have been described (9,10); one of these patients was a young adult aged 23 years (10).
We report on the case of a teenager with XLA. Diagnosis was confirmed by typical clinical and laboratory findings (Tables 1 and 2) and by mutation analysis of the Btk gene SSCP analysis. Subsequent sequencing of polymerase chain reaction products revealed the mutation, Arginine 372 to Glycine (Adenine 1246 Guanine) (11). At age 15 years, the boy developed megaloblastic anemia, sensory deficit in both legs and ataxia. Diagnosis of combined iron deficiency and vitamin B12 deficiency was made. Schilling test confirmed a lack of intrinsic factor with reduced intestinal absorption of vitamin B12. Antibodies against parietal cells and intrinsic factor were not detectable. Chronic atrophic gastritis was suspected and gastroduodenoscopy revealed complete intestinal metaplasia with glandular epithelial dysplasia of the antral mucosa consistent with the suspected diagnosis. Helicobacter pylori was not detected in mucosal biopsies. Parenteral administration of vitamin B12 led to complete remission of the boy's complaints within 3 months. A second gastroduodenoscopy 6 months later revealed a polypoid lesion near the pylorus. Complete gastrectomy with gastroplasty using jejunal interposition (Longmire-Gütgemann procedure) was performed. Upper abdominal lymph nodes were resected for investigation. Histologic examination of the polypoid specimens revealed a highly differentiated gastric adenocarcinoma of the intestinal type (Fig. 1). Histologic examination of more than 32 abdominal lymph nodes revealed typical architectural derangements characteristic of XLA (Fig. 2). No metastases were found. After gastrectomy, the boy's condition improved rapidly. No symptoms of blind loop or short bowel syndrome developed. He received regular parenteral vitamin B12, and laboratory values remained normal. His weight gain was good and he remained in good health 10 years after diagnosis of gastric adenocarcinoma. Repeated follow-up investigations revealed no relapse.
This case demonstrates that XLA may be associated with chronic atrophic gastritis and subsequent upper gastrointestinal malignancy, especially gastric adenocarcinoma, as previously described in other primary immunodeficiency syndromes, even without colonization by Helicobacter pylori (1). Patients with chronic atrophic gastritis are especially prone to the development of gastric cancer. Therefore, children with XLA should be regularly screened for symptoms of chronic atrophic gastritis, i.e., vitamin B12 deficiency. In such cases, early gastroduodenoscopies should be performed to allow diagnosis of gastric malignancies before metastasis has occurred.
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11. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinemia is a member of the src
family of protein-tyrosine kinases. Nature