Ulcerative Lesion of the Ileocecal Region in a Patient With Immunodeficiency

Abstract

A male patient had atopic dermatitis at 1 month of age, and at 1 year of age, he contracted infectious mononucleosis and varicella. Since 2 years of age, the patient repeatedly had pneumococcal pneumonia and bacteremia, and each time, he was hospitalized and treated with antibiotics. At 2 years of age, hypodontia with conical teeth, sparse hair, and anhidrosis were noted, and a skin biopsy revealed the absence of eccrine sweat glands. A G524C (A175P) missense mutation in his IKBKG gene was confirmed and diagnosed as X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID). Since 4 years of age, he has been receiving gamma globulin every 8 weeks as prophylaxis against infections.

At 21 years of age, the patient presented with right lower abdominal pain and diarrhea. Blood test results were as follows: leukocyte count, 11 800/μL (neutrophils, 59%; lymphocytes, 30.5%; and lymphocyte fraction: monocytes, 8.5% and eosinophils, 2.0%); HGB level, 12.0 g/dL; PLT count, 652 000/μL; Alb level, 3.1 g/dL; CRP level, 7.1 mg/dL; IgA, 1518 mg/dL; IgG, 1081 mg/dL; and IgM, 17 mg/dL. Tests for cytomegalovirus (CMV), C7-HRP, T-SPOT, antinuclear antibody, P-ANCA, C-ANCA, and HLA-B51 were negative; moreover, stool cultures showed no bacterial growth.

Colonoscopy revealed a large, deep ulcer extending from the terminal ileum to the ileocecal region with a deformed lumen (Figure 1a–d). Additionally, erythema, erosion, and shallow mucosal ulceration were observed in the terminal ileum (Figure 1e) and transverse colon (Figure 1f); however, the intervening mucosa was normal. Histopathological examination of the intestinal mucosa revealed edema and neutrophilic infiltration in the mucosal lamina propria (Figure 2a,b).

What is the most likely diagnosis?

The patient was diagnosed with nuclear factor-κB (NF-κB) essential modulator (NEMO) colitis.

Based on the endoscopic findings, CMV colitis and intestinal tuberculosis were considered differential diagnoses; however, the tests for C7HRP and T-SPOT were negative. Furthermore, no symptoms characteristic of Behçet's disease (recurrent oral ulceration, recurrent genital ulceration, eye lesions, or skin lesions) were observed. Histopathological examination showed only nonspecific inflammation and no crypt distortion or granuloma, which are characteristic of Crohn's disease or intestinal tuberculosis. Because tests for all these diseases were negative, NEMO colitis associated with XL-EDA-ID was diagnosed.

When infliximab, antitumor necrosis factor (TNF)α antibody, was administered for NEMO colitis, abdominal pain, diarrhea, and inflammatory response quickly resolved. In addition to the previously regular administration of intravenous immunoglobulin, infliximab was continued every 8 weeks. Five months after initiating infliximab administration, colonoscopy showed that all ulcerative lesions were scarred and mucosal healing had occurred. After more than 5 years, the patient has remained free of intestinal inflammation recurrence and has not developed any serious infections that had previously recurred during infancy.

EDA-ID, a primary immunodeficiency syndrome, is a rare disease characterized by various symptoms such as ectodermal dysplasia (sparse hair, hypodontia with conical teeth, anhidrosis, or hypohidrosis owing to the absence of sweat glands) and immunodeficiency. Susceptibility to infection because of immunodeficiency makes children susceptible to bacterial and viral infections from birth, and children are prone to repeated episodes of pneumonia, sepsis, and otitis media. Two disease-related genes have been identified in EDA-ID: X-linked recessive EDA-ID (XL-EDA-ID) caused by abnormalities in the NEMO gene and IκBα gene [1]. Both genes regulate NF-κB activation, and various symptoms appear when NF-κB signaling decreases because of genetic abnormalities. Approximately 23% of patients with XL-EDA-ID are reported to have gastrointestinal lesions that resemble the inflammatory bowel disease known as NEMO colitis [2].

Most cases of NEMO colitis develop in infancy and cause intractable diarrhea, bloody stools, and abdominal pain. Colonoscopy often reveals relatively deep digging, small ulcers mainly in the ileocecal region. Histologically, only nonspecific inflammatory findings such as edema, superficial cryptitis, ulceration, and infiltration of neutrophils into the intrinsic layer were observed. There is no established treatment for NEMO colitis; however, mesalazine, steroids, and anti-TNFα antibodies are used in refractory cases. In this case, owing to the presence of a deep and extensive ulcer in the ileocecal region and high disease activity, anti-TNFα antibody was administered from the outset, considering the risk of steroid-refractory disease. There have been reports of improvements in bone marrow stem cell transplantation; however, transplantation-related complications may occur, and the efficacy and safety of bone marrow stem cell transplantation have not been completely investigated.

Nenci et al. reported that intestinal inflammation is spontaneously induced in mice with intestinal epithelial cell–specific suppression of NEMO [3]. They also found that intestinal epithelial cells exhibit an increased susceptibility to TNFα-induced apoptosis, leading to the disruption of the epithelial barrier. Furthermore, the lack of TNF receptor-1 in the mice inhibited intestinal inflammation. These findings are consistent with the fact that anti-TNFα antibody ameliorated NEMO colitis in our patient.

The authors declare no conflicts of interest.