Expanding Contributions of Monogenic Very Early Onset Inflammatory Bowel Disease

Abstract

Currently over 70 genes known to be causative in very early onset inflammatory bowel disease (VEOIBD) have been identified. In the current issue of Inflammatory Bowel Diseases, 2 articles describing monogenetic forms of VEOIBD are highlighted. One describes a patient with life-threatening VEOIBD and a mutation in ITGA6, illustrating the importance of the epithelial barrier in maintaining mucosal homeostasis. The other describes the presentation and management of 10 patients with VEOIBD secondary to damaging mutations in MVK, resulting in mevalonate kinase deficiency. Though most monogenic causes of VEOIBD remain “private,” understanding the different categories of pathways affected in children with VEOIBD is critical and has already resulted in invaluable insight in the management of patients with VEOIBD and may hold strong implications for the care of IBD overall.

Genetic predisposition is an important contributing factor in development of inflammatory bowel disease (IBD). A major advance was the identification of over 240 risk loci associated with development of IBD through large genome wide association studies (GWAS).^{1, 2} Although these variants shed insight in the polygenic nature of adult onset IBD, most reside outside the coding exome; and so for the most part, their specific contribution to disease remains elusive. However, many patients with very early onset IBD (VEOIBD) have monogenic disease inherited in a mendelian fashion that affords invaluable insight on the genes and pathways directly involved in maintaining mucosal homeostasis. Currently, over 70 genes known to be causative in VEOIBD have been identified.³ Insights revealed that the study of monogenic VEOIBD can be regarded as the building block onto which the functional consequences of the more elusive risk association loci from GWAS can be pieced together.

In the current issue of Inflammatory Bowel Diseases, 2 articles describing monogenetic forms of VEOIBD are highlighted, imparting important lessons to the field of IBD overall.

Vahidnezhad et al report on a 3-year-old female with a blistering skin condition since birth, consistent with epidermolysis bullosa, who also manifested gastrointestinal complications including imperforate anus, pyloric stenosis, necrotizing enterocolitis, and very early onset Crohn’s disease. She was found to have junctional epidermolysis bullosa secondary to damaging mutations in ITGA6, encoding α6 integrin. She passed away at a young age secondary to her disease. The authors propose that ITGA6 is thereby a likely candidate for the growing number of monogenetic causes of VEOIBD. The gene ITGA6 encodes α6 integrin, which is required for the formation of α6β4 integrin responsible for binding intestinal epithelial cells to the underlying stroma. Their work illustrates the importance of an intact epithelial barrier in maintaining intestinal homeostasis. Specifically, without intact α6β4 integrin, epithelial fragility results in life-threatening colitis secondary to junctional epidermolysis bullosa.

The article by Bader-Meunier et al describes the presentation and management of 10 patients with VEOIBD secondary to damaging mutations in MVK, resulting in mevalonate kinase deficiency (MKD). Many of the patients described had severe colitis with ulcerating and fistulizing disease, along with a high rate of acute abdomen (6 of 10), and abdominal adhesions (6 of 10). Moreover, the histologic features described in this cohort are atypical in that there was a predominance of lymphoplasmocytic and neutrophilic inflammatory infiltrate with cryptic abscesses, profound ulcerations occasionally with necrosis and glandular apoptosis, and small intestinal villous atrophy without increased intestinal epithelial lymphocytes. This study underscores the resistance of these patients to conventional management, such as anti-TNF agents. Understanding that patients with MVK have elevated interleukin (IL)-1β enabled efficacious management with a tailored therapeutic approach of using anti-IL1 agents. This emphasizes the value of understanding the functional genomics of rare mutations and utilizing this knowledge to provide personalized efficacious medical approaches.

Although most monogenic causes of VEOIBD remain “private,” with only a handful of cases for each of these mutations reported to date world-wide, there are distinct VEOIBD conditions that every pediatric gastroenterologist should know. Pertinent examples of situations in which this can significantly alter the therapeutic management are described. It has enabled curative stem cell transplantation in otherwise life-threatening severe manifestations of VEOIBD, such as in dysfunctional IL-10 signaling from mutations in IL-10RA and IL-10RB,⁴ immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome from mutations in FOXP3,^{5, 6} and various forms of severe combined immune dysregulation such as those from mutations in RAG2.⁷ Additionally, understanding the genetics of VEOIBD has warranted the use of medications approved for other purposes to be refurbished for use in patients with specific disruption of an identified signaling pathway such as abatacept for patients with IBD from damaging mutations in LRBA or CTLA4⁸ or anti-IL-1 agents for patients with mutations in MVK.⁹ This holds strong therapeutic implications as depicted in both featured articles, as oftentimes such patients do not respond to conventional IBD therapies. Furthermore, this understanding also helps clarify medical options to avoid in particular genetic conditions; for instance, the use of anti-TNF agents among patients with chronic granulomatous disease is avoided, given predisposition of lethal infection in this group.

There is much to be learned from patients with monogenic IBD that may be generalized to the management of older-onset IBD. First, it imparts a focused identification of the various critical pathways that contribute to maintaining mucosal homeostasis and protecting oneself from developing IBD. Second, it can uncover various targetable components within a pathway in question that might not otherwise be exposed. Lastly, it provides opportune candidates for therapeutic targeting that may be expanded toward IBD overall.

The pathways of importance identified through study of monogenic causes of VEOIBD can be divided into different categories.^{10, 11}

The category of IL-10 signaling defects includes damaging mutations in either IL-10, IL-10RA or IL-10RB, which can be life-threatening and are almost always associated with severe perianal disease, occasionally arthritis, folliculitis, and a predisposition to B cell lymphoma.⁴ This epitomizes how a detailed understanding of this disease enabled curative stem cell transplant (SCT).⁴

The immune dysregulation category is exemplified by IPEX syndrome from mutations in FOXP3.^{5, 6} It can manifest with a variety of immune dysregulation in addition to enteropathy such as arthritis, food allergies, type 1 diabetes, nephropathy, hepatitis, and hemolytic anemia.

T and B cell defects represent another category. This includes mutations in RAG2 resulting in leaky severe combined immunodeficiency, characterized by profound immunodeficiency often with hepatosplenomegaly.⁷ Another set of examples in this category include deficiencies in LRBA and CTLA4, both depicted by various immune conditions including: autoimmune hemolytic anemia, type I diabetes, and interstitial lung disease.^8,12

The phagocyte defects category includes chronic granulomatous disease from mutations in CYBB, among others, resulting in decreased neutrophil oxidative burst and can present with recurrent infections with catalase positive organisms.¹³

The category of hyperinflammatory and autoinflammatory conditions, such as those from MVK, can result in hyper immunoglobulinemia D and manifest with recurrent fevers, rash, and macrophage activation syndrome, in addition to severe ulcerative colitis, enterocolitis, strictures and adhesions.⁹

Last, epithelial barrier defects include blistering skin disorders such as mutations in COL7A1,¹⁴ resulting in dystrophic epidermolysis bullosa, and in FERMT1,¹⁵ which results in the Kindler syndrome–type of epidermolysis bullosa; now we know that this may also include ITGA6, as we see in Vahidnezhad et al’s report.

Taken together, though stem cell transplantation is curative for IL-10 signaling defects and some categories of immune dysregulation, it can be exacerbated and even be fatal when applied to VEOIBD secondary to epithelial barrier defects. Thereby, a deep understanding of the genetic defect and the degree of dysfunction measured by functional studies have proved priceless among these VEOIBD categories.

In summary, our understanding of the genetics of IBD is heavily enhanced by studying monogenic VEOIBD. These ongoing contributions have already profoundly advanced our understanding and care of patients with VEOIBD. Importantly, they serve as the foundation to better comprehend IBD and help focus direction toward prolific research for IBD overall. Genes and pathways critical in maintaining healthy intestine, identified through the study of VEOIBD, and paired with multiomic data integrative analysis hold strong potential to decipher the specific contributions of the association loci in IBD. Such a rich and comprehensive understanding is at the core of exponential advancements. Collectively, this holds important prospects to improve and expand on available therapeutics, provide personalized medicine, and refine prognostics among older onset IBD. One can foresee extension toward risk screening and identification of meaningful modulable factors to even prevent the development of IBD altogether. Thus, monogenic VEOIBD findings provide novel crucial insights for the advancement of IBD care.

Funding

Research reported in this publication was supported by the National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under award number K08DK122133.

Conflicts of Interest

JO is an independent contractor as “speaker” for Janssen and is a consultant for Skygenic.