A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant.

PURPOSE: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections. METHODS: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis. RESULTS: WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient's cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient's innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients. CONCLUSIONS: Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.

The Role of Familial Mediterranean Fever Gene Mutation in Treatment of Infantile Colitis With Resistant Perianal Fistula.

Symptoms of infantile inflammatory bowel disease (I-IBD) can be life-threatening and associated with poor prognosis. The presence of Mediterranean fever (MEFV) gene mutations play an important role in treatment of I-IBD. In this article, we describe a case of I-IBD with a resistant fistula, in which remission occurred following colchicine therapy. The patient was a six-month-girl with complaints of bloody diarrhea and a perianal abscess of three months duration. Laboratory tests revealed elevated inflammatory parameters, hypoalbuminemia, and anemia. Results of repeated viral, bacterial and parasitic analyses were negative. Endoscopic and histopathological examinations confirmed a diagnosis of I-IBD. Although diarrhea episodes decreased following intensive conventional treatment with immunosuppressive therapy and anti-tumor necrosis factor, the perianal abscess and fistula did not resolve. Molecular genetic analysis to identify causes of infantile disease revealed the MEFV gene mutation. Thus, colchicine was added to the treatment regimen. Following treatment with colchicine, defecation returned to normal, and the fistula resolved. The MEFV gene mutation should be investigated in children with infantile colitis and resistant fistulas, particularly in Mediterranean countries. In patients with infantile colitis who have the MEFV gene mutation, colchicine treatment may be an alternative to intensive immunosuppressive therapy.