The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

Abstract

Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel diseases (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histologic features of Crohn’s disease, ulcerative colitis or IBD unclassified. Defects in interleukin 10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histologic and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extra-intestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. We provide approaches for identifying patients likely to have these disorders. We discuss classical approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

Inflammatory Bowel Disease in Childhood and Adolescence

“…Intestinal inflammation in infants and young children can be caused by a number of genetic defects that can lead to involvement of the immune system and the intestinal epithelium (this is known as monogenic IBD). Approximately 1% of children and adolescents with IBD are less than 1 year old; around 15% are younger than 6 years (21). Full physical examination must include oral and perianal inspection (rectal examination if necessary) and evaluation of height and weight using age-and sex-specific percentile curves and pubertal development (Tanner stages).…”

“…Diagnostic procedures for celiac disease must be performed in children and adolescents with growth retardation and/or nonbloody diarrhea (22). In children with suspected IBD before the age of 2 years, primary immunodeficiency must also be ruled out (21). Disease onset before the age of 6 years is probably caused by a genetic, possibly monogenic, immunodeficiency with intestinal inflammation typical of IBD.…”

“…Disease onset before the age of 6 years is probably caused by a genetic, possibly monogenic, immunodeficiency with intestinal inflammation typical of IBD. The incidence of very early disease onset is approximately 4.37 per 100 000; its prevalence is 14 per 100 000 (21). The possibility of an underlying food allergy must also be considered (23, e4).…”

Autoimmunity Including Intestinal Behçet Disease Bearing the KRAS Mutation in Lymphocytes: A Case Report

“…Very early onset IBD (VEOIBD) occurs in children with a diagnosis before 6 years of age, as in our case. More than 50 genes have been identified as candidate genes of VEOIBD, 18 and VEOIBD reveals a low response rate to conventional antiinflammatory and immunomodulatory therapies. Therefore, obtaining a genetic diagnosis of VEOIBD is essential for selecting appropriate treatment, including allogeneic hematopoietic stem cell transplantation.…”

O que podemos fazer para evitar as doenças inflamatórias intestinais? A importância da microbiota

“…Essas doenças são diagnosticadas com base na informação clínica e diagnóstico genético preciso.Somente a análise genética completa é necessária para identificar a causa da doença e oferecer ao paciente opções de tratamento adequados, que incluem a terapia clínica, cirurgia ou transplante de células-tronco hematopoiéticas (19).…”