A Pattern-Based Pathology Approach to Very Early-Onset Inflammatory Bowel Disease: Thinking Beyond Crohn Disease and Ulcerative Colitis

Abstract

Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed in children less than 6 years old, is phenotypically and genetically distinct from older onset IBD. Monogenic and digenic causative defects, particularly in primary immunodeficiency and intestinal epithelial barrier genes, have been identified in a subset of patients with VEO-IBD allowing for targeted therapies and improved outcomes. However, these findings are the minority, thus strategies to correctly diagnose patients, including identification of specific histopathologic findings with correlating clinical and laboratory features may provide critical and necessary insight into mechanisms of disease pathogenesis and subsequent therapeutic options. In this article, we review the pathologic findings seen in patients with VEO-IBD and outline a pattern-based approach to diagnosis using examples from primary immunodeficiencies with gastrointestinal manifestations.

Inflammatory bowel diseases (IBD) are a spectrum of diseases, including Crohn disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U), characterized by chronic inflammation of the gastrointestinal tract. IBD is hypothesized to be the result of a dysregulated immune response to pathogenic and commensal microbes in a genetically susceptible host. Differences in these contributing factors among individuals with IBD likely leads to a wider range of disease phenotype and activity than previously recognized.¹ Approximately 25% of patients with IBD are diagnosed before 20 years of age, and the onset of disease during childhood has unique considerations from adult onset IBD, including impact on growth and pubertal development, cognitive and psychosocial development, as well as differences in disease phenotype and therapeutic response. In the United States, pediatric IBD has increased in prevalence over the past few decades from 33/100,000 to 77/100,000, with Crohn disease being more common than ulcerative colitis.² The most rapid rise in incidence has been observed in children diagnosed <6 years of age, known as very early onset IBD (VEO-IBD), with 7.2% increase in incidence from 1999 to 2010 in Canada whereas other age groups did not have an annual percentage change in incidence during this time period.³

VEO-IBD comprises neonatal onset (<1 month of age), infantile onset (<2 years old), and early childhood onset (2-<6 years old). The population in general has a heterogeneous phenotype that ranges from mild to severe disease, similar to older onset IBD. However, children with VEO-IBD can present with unique features and a subset of these patients are refractory to conventional medical therapies used successfully in older onset pediatric IBD. The underlying disease etiology may account for the differences in phenotype and disease activity, specifically the genomic drivers. The genetic predisposition in older children and adults with IBD is largely polygenic, characterized by 240 disease loci identified by genome wide association studies, but these only contribute a small amount to IBD heritability.^4,5 In contrast, causative monogenic variants, especially in primary immunodeficiency genes, have been detected in children with VEO-IBD.⁶ In fact, whole-exome sequencing of 125 VEO-IBD patients showed an average of 4.14 variants/subject in genes associated with primary immunodeficiency, increased over control populations and older onset IBD patients.⁷ Over the last decade, advances in sequencing technology and analyses, including targeted sequencing panels, whole exome and whole genome sequencing, has allowed for the identification of rare disease-causing variants in genes involved in immune response or the epithelial barrier.⁸ Younger age of IBD onset, particularly the neonatal and infantile period, is associated with increased likelihood of an underlying monogenic defect.^6,9 The identification of monogenic disease can be transformative and in some cases can lead to a personalized medical approach, including hematopoietic stem cell transplant or targeted therapy. Still, most patients with VEO-IBD do not have a causal genetic defect identified, and there is a critical need for therapeutic strategies to improve outcomes in these patients.

A wide variety of defects have been identified in children with VEO-IBD influencing intestinal homeostasis, including T- or B-cell defects, phagocyte defects, autoinflammatory disorders, disorders of immunoregulation, and epithelial barrier defects. Monogenic infantile IBD with primary immunodeficiency was first described in patients with loss of function mutations in IL10RA or IL10RB, resulting in severe infantile chronic enterocolitis, perianal fistulae, cutaneous folliculitis, and recurrent infections definitively treated with autologous hematopoietic stem cell transplant.¹⁰ This model of mendelian inherited VEO-IBD has served as a framework to search for an underlying etiology, particularly in patients with IBD who are refractory to conventional therapies. Since then >70 monogenic causes for IBD have been identified and their genotype-phenotype associations are outlined extensively in other publications.^6,8,11–13 Recognition of patterns of intestinal and extraintestinal manifestations and associated inflammation in patients with monogenic disorders can inform clinicians on how to approach the patient with non-monogenic VEO-IBD through the use of phenotypic profiling. This strategy has already started to provide the opportunity to develop much needed targeted therapeutic options for children with VEO-IBD.

Clinical Presentation and Diagnosis

While still rare in young children, VEO-IBD should be considered on the differential diagnosis for children with chronic diarrhea, growth failure, abdominal pain, vomiting, perianal lesions and/or hematochezia among other intestinal and extraintestinal symptoms. A comprehensive history and physical exam are necessary to characterize these symptoms and importantly to identify red flags for monogenic disease. Blood in the stool in infants that does not respond to a trial of elemental formula, poor growth, or malnutrition with associated significantly delayed milestones despite age-appropriate caloric intake may point to chronic inflammation. Specific findings that may alert an underlying monogenic defect include neonatal onset, extreme short stature, severe perianal disease, systemic symptoms of fevers, rashes including severe diaper rash and joint involvement including arthritis, failure to bear weight, or abnormalities in gait. Defects in immune response may manifest with recurrent or severe infections and skin lesions, while epithelial defects may present with hair or nail abnormalities, or endocrinopathies among others. Furthermore, a review of the child’s infection history, family history of IBD, autoimmunity, or immunodeficiency, and careful review of the growth chart are necessary. Infectious causes for the child’s symptoms should be ruled out with bacterial, viral, and parasitic stool studies. Laboratory studies including complete blood count with differential, comprehensive metabolic profile, and inflammatory markers including C-reactive protein and erythrocyte sedimentation rate should be performed. Aside from the typical pattern of laboratory abnormalities seen in association with IBD including microcytic anemia, hypoalbuminemia, and elevated inflammatory markers, significant leukocytosis, thrombocytosis, and markedly elevated inflammatory markers should prompt the clinician to consider hyperinflammatory disorders which may be multisystem and can have monogenic causes. In addition, lab abnormalities not classically characteristic of IBD such as thrombocytopenia, leukopenia, neutropenia, and hypoglycemia may also be informative and suggest consideration of alternative monogenic etiologies for VEO-IBD. In addition to the standard laboratory evaluation, all patients being evaluated for VEO-IBD should undergo an immune evaluation, including dihydrorhodamine test or neutrophil oxidative burst test for chronic granulomatous disease (CGD) and selective antibody deficiencies by quantitative immunoglobulins and vaccine titers. Consultation by an expert immunologist for in depth immune deficiency evaluation and testing is also recommended, especially in infants, before initiation of therapy¹².

Ultimately EGD and colonoscopy with biopsies are necessary to make a diagnosis of IBD and rule out other infectious or allergic processes. The macroscopic differences between VEO-IBD and older onset pediatric IBD are largely seen in the distribution and location of disease. The majority of newly diagnosed children with Crohn disease have inflammatory disease behavior, but a proportion develop complicated disease including penetrating or stricturing disease within the first few years after diagnosis.¹⁴ In a retrospective cohort comparing VEO-IBD to older pediatric onset IBD, there were very few cases of penetrating or stricturing disease in the VEO-IBD patients as compared to up to one-third of older onset patients with these phenotypes.¹⁵ Children with VEO-IBD who present with complicated phenotypes are rare and should prompt additional consideration of possible underlying monogenic etiology. Older onset Crohn disease commonly presents as ileocecal or ileocolonic disease, while young children who ultimately have features of CD can present with pan-colonic disease. Indeed, many children with VEO-IBD present with isolated colonic disease but may lack characteristic features specific to UC or CD or have atypical features leading to a diagnosis of IBD-unclassified. Additionally, while higher rates of panenteric distribution of disease has been reported in VEO-IBD compared to older onset IBD at diagnosis, over time this difference is further increased as patients with VEO-IBD often have extension of disease to include the entire GI tract.¹⁵

A pattern-based approach to VEO-IBD diagnosis for the surgical pathologist

Histopathologic diagnosis of older onset inflammatory bowel disease is a skill familiar to most surgical pathologists. Clinical, gross and microscopic features of Crohn disease and ulcerative colitis are taught from medical school onward, and evaluation of IBD specimens are an important part of many surgical pathology practices. Despite this familiarity, VEO-IBD diagnosis offers a number of challenges to the practicing pathologist. We hope to highlight a number of these issues in this review.

Many patients with VEO-IBD likely represent CD or UC manifesting at a young age – complex diseases with genetic predisposition and environmental triggers. However, there are clinical and pathologic differences between VEO- and older-onset IBD, including differences in severity, surgical types and rates, and treatment responses. Histologic features at diagnosis have also been shown to be distinct in children with VEO-IBD with increased incidence of crypt apoptosis, severe mucosal architectural changes, mucosal eosinophils, and small bowel villous blunting as compared to older onset pediatric IBD.¹⁶

A smaller group of patients with VEO-IBD are those with an underlying monogenic (or oligogenic) disease, many of which involve primary immunodeficiency genes. Immunodeficiencies comprise a group of >150 disorders; gastrointestinal disease occurs in 5-50% of these patients, and may be the sole manifestation at presentation.¹⁷ While many of these disorders have been characterized, the advent of widespread genetic testing continues to broaden the spectrum of known and novel diseases. Monogenic disorders causing VEO-IBD may be difficult to diagnose for the pathologist, due to the breadth of possible disorders and variety of pathologic findings – many of which are not considered diagnostic of “typical” IBD. Nevertheless, the pathologist’s primary task when assessing a patient specimen for possible VEO-IBD is to identify features that may be consistent with systemic disease, and to alert the clinical team for further diagnostic work-up.¹² Identifying these monogenic VEO-IBD patients is crucial, as they may respond to targeted therapy rather than conventional IBD therapy that may lead to complications, and may require screening for non-GI complications of their disease.

One approach to simplifying the broad array of histologic findings in VEO-IBD is to group them into patterns (analogous to the mechanistic groupings of monogenic etiologies described above), and use those to narrow the differential diagnosis of possible disorders. This approach has some limits, as features of multiple patterns may overlap in a single patient, and some diseases may present with more than one histologic pattern. There is also a relative paucity of detailed genotype-histology correlation for a broad range of VEO-IBD patients (both monogenic and non-monogenic); further investigations in this vein should improve the future utility of this approach.

Histologic patterns and differential diagnosis of VEO-IBD

Chronic active enteritis, the conventional pathologic pattern of IBD

Conventional chronic active enteritis, as described in multiple histopathological indices for IBD, is a commonly encountered histologic pattern in VEO-IBD, likely reflecting that a majority of patients with VEO-IBD have early onset of Crohn disease or ulcerative colitis. Diagnostic features are similar to those in adults, including active inflammation (neutrophilic cryptitis and crypt abscesses) and chronic mucosal changes (crypt branching, crypt dropout, increased lymphoplasmacytic mucosal inflammation causing crypt liftoff) (Figure 1A). Small bowel architectural changes may be more difficult to appreciate, but severe duodenal villous atrophy and cellular metaplasias (Paneth cell in left colon, pyloric in terminal ileum and colon) are reliable features of chronic inflammation. In rare cases, chronic mucosal alterations may be encountered with relatively mild inflammation (Figure 1B-D).

Figure 1:

Conventional pattern (chronic active colitis). A, sigmoid colon biopsy from 4 y.o. female with diarrhea. Note the histologic features typical of older-onset IBD, including basal lymphoplasmacytosis with mild crypt architectural disorder, focal crypt dropout, and neutrophilic inflammation including crypt abscess. B-D, left colon biopsies from another 4 y.o. female with diarrhea. Note the marked Paneth cell metaplasia (arrows in D) despite only mild crypt architectural disorder and mildly increased lamina propria cellularity. (A,D=200X; B,C=40X)

Several monogenic disorders that have been identified in children with VEO-IBD can have fairly typical IBD-like pathology. In some defects, the pattern can be more similar to CD due to the location of disease and presence of granulomas, however it is not uncommon for one gene defect to appear differently depending on the specific mutation. Those that can present with CD like features include patients with IL-10 signaling pathway mutations^10,18, CGD, X-linked lymphoproliferative disorder type 2 (XIAP)¹⁹, familial diarrhea (GUCY2C)²⁰, familial Mediterranean fever²¹, Hermansky-Pudlak syndrome (HPS) types 1, 4, 6,²² glycogen storage disease type I ²³ and Wiskott-Aldrich syndrome. ^24–26 Patients with CGD and HPS often have granulomas, however this is not a uniform finding. Common variable immunodeficiency (CVID) may present with variable histopathology, but in some cases shows neutrophilic inflammation and marked crypt architectural distortion^27,28. A relative lack of mucosal plasma cells and increased intraepithelial lymphocytes in such cases may be a diagnostic clue. Marked mucosal architectural distortion may also be seen in TTC7A deficiency which leads to intestinal atresias with combined immunodeficiency, although severe epithelial injury is often the predominant feature (see below)²⁹.

Apoptosis/Epithelial injury pattern

The hallmark of apoptosis/epithelial injury pattern is epithelial injury or apoptosis out of proportion to inflammatory activity. Apoptosis is a rare finding in normal GI mucosa, and a mild increase in either crypt or surface epithelial apoptosis may be seen in response to a variety of stimuli (inflammation, bowel preparation, viral infection, and ischemia among others). However, epithelial injury as the predominant mucosal finding often shows a typical constellation of features, most reminiscent of intestinal graft versus host disease (GvHD) (Figure 2). Overall mucosal architecture may vary from near-normal to markedly abnormal, but often lacks the marked branching and cellular metaplasias typical of the conventional pattern. Rather, injured crypts appear dilated with attenuated epithelial layers, or contain reactive epithelial changes out of proportion to inflammation with loss of specialized cell types (goblet or Paneth cells). Crypt abscesses may contain neutrophils, but often have a significant proportion of sloughed epithelial cells or apoptotic debris. Mild lymphocytic cryptitis, or neutrophilic and lymphoplasmacytic infiltrates may be present, but appear too mild to cause the profound epithelial injury present. Small bowel biopsies may show villous atrophy. Severely affected mucosa may have the appearance of granulation tissue.

Figure 2:

Epithelial injury-apoptosis pattern. Sigmoid colon (A-B), gastric antrum (C), and duodenum (D) biopsies from 2-month-old female with congenital diarrhea. All biopsies show features of apoptosis or epithelial injury, including apoptotic figures within crypt epithelium (arrows), dilated and/or attenuated crypts with mixed neutrophilic and apoptotic crypt abscesses (arrowheads), and luminal epithelial shedding (circle). Despite these features, lamina propria cellularity is only mildly increased with absence of significant crypt architectural distortion, giving an impression of epithelial injury out of proportion to inflammatory activity. (A=40X; B-D=200X)

Significant apoptosis in the mucosal biopsies of patients with VEO-IBD was shown to be twice as common than older onset pediatric IBD in one study¹⁶. Several causes of monogenic VEO-IBD that lead to severe T and B cell deficiency or dysregulation have marked epithelial injury on biopsies– perhaps not surprising, given the histologic link to graft versus host disease (GvHD). Severe combined immunodeficiency and Omenn syndrome, both linked to mutations in multiple genes, may show predominantly epithelial injury; and the lamina propria in SCID is often markedly hypocellular²⁷. IPEX (immunodeficiency, polyendocrinopathy, enteropathy, X-linked), caused by mutations in FOXP3 or STAT1, classically causes autoimmune enteropathy in early infancy. These patients’ biopsies may show severe enteritis with crypt destruction, villous atrophy, and formation of circulating anti-enterocyte antibodies³⁰. Although patients with TTC7A mutation may show profound epithelial injury due to a mucosal barrier defects, these children also have a SCID-like immunodeficiency that likely contributes to their pathology²⁹. Other monogenic disorders characterized by GI epithelial injury include dystrophic epidermolysis bullosa (epithelial defect), mevalonate kinase deficiency (hyperinflammatory phenotype), and disorders of telomere maintenance, but there remains limited understanding into the mechanisms of intestinal epithelial injury caused by these different disease pathways ^31–33.

While most young patients with conventional pattern of IBD histology have some form of VEO-IBD, a number of non-IBD disorders may show an apoptosis/epithelial injury pattern and should be excluded by clinical history or lab testing^34–36. As discussed above, GvHD in the setting of bone marrow transplantation is likely the most common cause of this histologic pattern. Antimetabolite immunosuppression in solid organ transplant patients, particularly using mycophenolate mofetil, may cause similar findings, as does acute rejection of an intestinal transplant. Finally, viral infection may cause significant apoptosis and mucosal injury, including cytomegalovirus (CMV) infection.

Eosinophil-rich pattern

Eosinophils are a normal component of the mucosal chronic inflammatory infiltrate in all compartments of the GI tract except the esophagus. However, their normal number and distribution can vary greatly by location, and may be influenced by geography, season, associated medical conditions, infection and medications. Several prior studies have enumerated “normal” mucosal eosinophils; although absolute numbers may vary, studies generally show peak counts near the ileocecal valve, with decreasing quantities both proximal and distal to it.³⁷ In addition to number, “normal” eosinophils should be distributed fairly evenly throughout the lamina propria, with no significant epithelial invasion.

Deviations from these features of normal mucosal eosinophil presence and distribution form the basis for the eosinophil-rich pattern in VEO-IBD. Much like crypt architectural changes and apoptosis, mucosal eosinophils are more frequently increased in VEO-IBD as compared to older-onset pediatric IBD. However, other features of eosinophil-rich VEO-IBD include lamina propria clustering and eosinophilic infiltration of surface and crypt epithelium (Figure 3). These findings may not be diffuse throughout the GI tract but are typically found in multiple biopsy stations. Omenn syndrome is a well-characterized monogenic cause of mucosal eosinophilia in VEO-IBD (often with co-existing epithelial injury and granulomas)³⁸. However, eosinophil-rich features are also seen in non-monogenic VEO-IBD patients, often in combination with more conventional features of chronic active enteritis (Figure 3).

Figure 3:

Eosinophil-rich pattern. Left colon (A-B), right colon (C), and terminal ileum (D) biopsies from 6 year old male with previous diagnosis of VEO-IBD and stroke, now treated with infliximab and methotrexate. Left colon shows features of chronic colitis including architectural distortion and increased mucosal chronic inflammation, including increased lamina propria eosinophils and scattered intraepithelial eosinophils (arrows in B). Right colon shows similar features, including lamina propria clustering of eosinophils (circle) and a focus of eosinophilic cryptitis (arrow in C). Terminal ileum contains normal numbers of total eosinophils for site, but also has a focus of eosinophilic cryptitis (arrow in D). (A=40X; B-D=200X)

Non-IBD etiologies for GI eosinophilia may mimic some clinical features of VEO-IBD, including diarrhea and hematochezia. In general, patients with VEO-IBD with eosinophil-rich histology often have additional features of epithelial or chronic mucosal injury, which may help differentiate them from these other etiologies. Allergic disease, including eosinophilic gastrointestinal diseases, is probably the most-invoked differential diagnosis for patients who are eventually diagnosed with VEO-IBD. In particular, increased eosinophils in rectosigmoid colon biopsies from infants with bloody stools are often attributed to milk-protein allergy (allergic proctocolitis). However, milk-protein allergy patients are often clinically well, and eosinophils in allergic proctocolitis are typically limited to the distal colon and rectum and not associated with significant epithelial injury or crypt architectural distortion. Mucosal damage with eosinophils should raise the possibility of more severe disease. Parasite infection should be excluded in any patient with significant GI eosinophilia; bowel involvement by Langerhans cell histiocytosis is rare but may also cause eosinophilia in involved areas of mucosa.

Lymphocytic patterns

Lymphocytic patterns include lymphocytosis and nodular lymphoid hyperplasia; lymphocyte or plasma cell depletion may also be considered in this category. These patterns may overlap and are often the most difficult to reconcile with a diagnosis of VEO-IBD, because they generally lack both the active (neutrophilic) inflammation and chronic mucosal changes (architectural distortion and cellular metaplasias) most often associated with conventional IBD. However, in the correct clinical and laboratory setting, this pattern may be consistent with several monogenic VEO-IBD etiologies.

Lymphocytosis is a pattern most associated with idiopathic lymphocytic colitis in adults (Figure 4), although it has a broad differential diagnosis in young children and may extend to more proximal bowel. Mucosal architecture is generally preserved, and mucosal chronic infiltrates appear normocellular at scanning magnification. At higher magnification, there is diffuse crypt and surface intraepithelial infiltration by lymphocytes; surface epithelium often has a damaged appearance, with epithelial attenuation and focal detachment from basement membrane. Several immunodeficiencies may present with lymphocytosis, including common variable immunodeficiency (CVID), IgA deficiency (with lack of IgA-positive mucosal plasma cells), LRBA deficiency resulting in CTLA4 dysregulation, CTLA4 deficiency and other T cell regulatory disorders^{27,28,39–41}. IPEX syndrome may also show significant lymphocytosis, albeit usually with significant epithelial injury³⁰.

Figure 4:

Intraepithelial lymphocytosis pattern. A-C, rectum (A-B) and ascending colon (C) biopsies from 4 year old female with LRBA mutation, diarrhea, infections, and arthritis. Note the presence of surface and crypt intraepithelial lymphocytes, and surface friability/denudation, with normal mucosal architecture and only mildly increased lamina propria cellularity. D, sigmoid colon biopsy from a 5 year old female with explosive diarrhea and mildly elevated fecal calprotectin. Note the markedly increased crypt and mildly increased surface intraepithelial lymphocytes, with only mildly increased lamina propria cellularity. (A-C=variable magnification, images taken from digitally scanned slides; D=200X)

Nodular lymphoid hyperplasia (NLH) is characterized by diffuse mucosal lymphoid aggregates and follicles that appear to distort crypt architecture beyond terminal ileum and right colon, where Peyer’s patches are a normal component of mucosa. CVID and IgA deficiency both may present as NLH; in CVID there is often concomitant plasma cell depletion^27,28,42. X-linked hyper-IgM syndrome (caused by mutation in CD40L) and familial Mediterranean fever may also present with NLH in the setting of diarrhea^43,44.

Lymphocyte or plasma cell depletion is also a feature of multiple immunodeficiencies. As described above, CVID is rather pleiotropic and may present with lymphocytosis, NLH, or a more conventional pattern of injury. Often plasma cell depletion in these settings is an important diagnostic clue. Hypogammaglobulinemia and X-linked lymphoproliferative disorder type 1 may also be characterized by mucosal plasma cell depletion^28,45. SCID is also characterized by profound mucosal depletion of lymphocytes and plasma cells.

In addition to monogenic VEO-IBD, lymphocytic patterns may be challenging to interpret due to an extensive non-IBD differential diagnosis; many of these etiologies overlap with immunodeficiency. Lymphocytosis is the histologic hallmark of celiac disease, where it may occur in colon prior to small bowel manifestations. Other potential causes of lymphocytosis include infection or post-infectious enteritis (increased in immunodeficient patients), medication effect (particularly non-steroidal anti-inflammatory drugs), and bacterial overgrowth. NLH is prominent in diversion colitis, particularly relevant given the incidence of ostomy formation in patients with severe colonic VEO-IBD^15,46. Lymphoid depletion may result from medical therapy (for example, conditioning chemotherapy prior to bone marrow transplant), or artifactually appear due to mucosal edema. Careful consideration of clinical history and laboratory tests is necessary to exclude these entities.

Granulomatous pattern

Non-necrotizing granulomas, although considered a cardinal feature of Crohn disease, may be absent or not sampled in a majority of typical CD cases; conversely, they may be encountered in monogenic VEO-IBD. They may have a variety of appearances, from large and confluent sarcoid-like granulomas with multinucleated giant cells (Figure 5A-B), to inconspicuous histiocyte aggregates (Figure 5C-D). They may be the predominant finding in VEO-IBD patients, or a minor feature in otherwise conventional pattern disease.

Figure 5:

Granulomatous pattern. A-B, duodenum (A) and terminal ileum (B) biopsies from 6-year-old male with diarrhea, weight loss, abdominal pain, and history of C. difficile infection. Note the presence of large, focally confluent sarcoid-like mucosal and submucosal granulomas (arrows). Not pictured are similar large granulomas in esophagus, stomach, and left colon. C-D, duodenum (C) and colon (D) biopsies from 23-month-old male with chronic diarrhea and microcytic anemia. In contrast to prior case, only small mucosal granulomas are present (arrowheads). Not pictured is a similar-appearing small antral granuloma. Dihydrorhodamine (DHR) assay was negative in both patients, excluding chronic granulomatous disease. (A-B=100X; C-D=200X)

A variety of monogenic disorders have been associated with granulomas throughout the gastrointestinal tract. Chronic granulomatous disease (CGD) is caused by gene variants that inhibit phagocyte oxidative burst, which can be functionally assessed by the dihydrorhodamine (DHR) lab assay. CGD is characterized by early onset of a Crohn-like enteritis, also associated with perianal disease and stricturing phenotype. Histologically, large and confluent granulomas often appear increased in number in the mucosal biopsies compared to typical CD, with or without conventional pattern changes. Pigmented lamina propria macrophages are also characteristic and thought to represent accumulation of ceroid pigment due to increased cell turnover. Differentiation of CGD from CD is critical, as TNFα inhibitors, a monoclonal antibody therapy for the treatment of pediatric IBD) may lead to life-threatening infections in CGD patients⁴⁷.

IL-10 signaling pathway mutations, including ligand (IL10) and receptors (IL10RA, IL10RB), were the first identified monogenic causes of VEO-IBD. IL-10 is a key anti-inflammatory cytokine; mutations in this pathway lead to unrestrained pro-inflammatory signaling that causes severe infantile colitis with granulomas, perianal disease, folliculitis, and an increased risk of lymphoma.¹⁰ Much like CGD, VEO-IBD due to IL-10 pathway mutations is generally unresponsive to standard IBD therapy but may be cured by hematopoietic stem cell transplant. In addition, HSCT should be performed due to the increased risk of large B cell lymphoma in these patients. Hermansky-Pudlak syndrome (types 1, 4, 6) is an autoinflammatory disorder that may present with granulomatous colitis in the setting of bloody diarrhea, albinism, and platelet dysfunction⁴⁸.

Unlike some other histologic patterns, non-necrotizing granulomas have a fairly limited differential diagnosis in early childhood. Infectious granulomas (mycobacterial or fungal) tend to be necrotizing, and sarcoidosis is exceedingly rare in this age group. More common is the mis-identification of a mucin (“crypt rupture”) granuloma or germinal center as a non-necrotizing granuloma in limited or crushed biopsy material, risk of which may be decreased by examination of multiple tissue sections and maintaining a high threshold for granuloma morphology.

Conclusion

Very early onset inflammatory bowel disease (VEO-IBD) encompasses a broad range of disorders that cause chronic bowel inflammation in infancy and early childhood. As a group, these patients have different phenotypes than older-onset IBD patients, including more severe clinical disease and a wider variety of pathologic findings. It is important for pathologists to be familiar with these differences, particularly to facilitate identification of patients with suspected monogenic VEO-IBD. These patients may be refractory to conventional IBD treatment and benefit from advances in targeted therapy.