Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies

Very early onset inflammatory bowel disease (VEO-IBD) reflects IBD presenting before 6 years of age. We provide an approach to diagnosis and management of patients with VEO-IBD, based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org).

Abstract

Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.

INTRODUCTION

Inflammatory bowel disease (IBD) is comprised of a manifold of diverse diseases that are multifactorial in origin and are usually categorized clinically into Crohn’s disease (CD), ulcerative colitis (UC), and IBD-unspecified (IBD-U) based on phenotypic characteristics. These disorders of chronic intestinal inflammation are thought to develop primarily in genetically susceptible subjects in association with a dysregulated immune response, microbial dysbiosis, and environmental triggers. Very early onset IBD (VEO-IBD) is defined as clinical manifestations and/or receiving the diagnosis when younger than 6 years of age.^{1, 2} Although genetics play a role in IBD at any age, monogenic etiologies are more highly represented in patients presenting with VEO-IBD as compared with IBD diagnosed at an older age. Indeed, a growing number of causative monogenic variants have been and are continuing to be identified among patients with VEO-IBD, especially within the infantile-onset IBD (younger than 2 years old).^{1, 3–7} Uhlig et al reported that although the majority of monogenic IBD cases occur under 6 years of age, this is a spectrum with a predominance of cases occurring before the age of 2.¹ A large proportion of monogenic etiologies reflect underlying primary immune deficiencies (PIDs), highlighting the importance of a dysregulated immune system in VEO-IBD.^{1, 8, 9} The monogenic etiologies of VEO-IBD identified to date can be divided into 6 main (and sometimes overlapping) categories: (1) general immune dysregulation, (2) T and B cell defects, (3) phagocytic defects, (4) hyper- and auto-inflammatory conditions, (5) epithelial barrier dysfunction, and (6) other conditions.^{1, 8, 9} It is important to emphasize that although some patients with VEO-IBD have underlying monogenic etiologies, often reflecting PIDs, the majority (>70%–80%) of VEO-IBD patients will not have a specific identified causal genetic etiology.¹⁰http://www.VEOIBD.orgUnlike older-onset IBD, patients with VEO-IBD have a higher rate of inflammatory bowel disease unclassified (IBD-U) (18%–33%) as compared with adult patients (6%).^{11, 12} Additionally, a positive family history is also more likely within this group (19%–41% compared with 5%–10% in adults), supporting an increased genetic contribution.^{13, 14} Finally, some—but not all—studies have suggested that the VEO-IBD group is often resistant to conventional therapy for IBD.^{15, 16} It is hard to categorize VEO-IBD based on standard clinical and histological features of classic polygenic IBD. Multidisciplinary approaches, including a comprehensive immune evaluation, are important in directing the management of VEO-IBD.^{1, 2, 17} In this review, we summarize the background, clinical characteristics, and treatment strategies of VEO-IBD while highlighting the importance of identifying underlying PIDs.

DEFINITION

The age cutoff of VEO-IBD is currently defined as clinical manifestations and/or being diagnosed before 6 years of age. This has its origins in the fact that there is an increase in monogenic etiologies of VEO-IBD before 6 years old as compared with that diagnosed in older ages,^{1, 2, 12, 18–20} though this definition continues to evolve with increasing knowledge. A subcategory of VEO-IBD is infantile-onset IBD, reflecting patients diagnosed younger than 2 years old. Some further subcategorize neonatal-onset IBD as that presenting within the first 27 days of life.^{1, 16}

EPIDEMIOLOGY

Epidemiologic data indicates that the incidence of IBD is rising, especially in the pediatric population.^21–27 Currently, it is estimated that 3 million Americans have IBD,²⁸ and approximately 25% of those patients will develop the disease during childhood or adolescence.²⁹ A retrospective review of the Canadian population identified that the incidence of childhood-onset IBD is 9.68 in 100,000 children, with a prevalence increasing significantly over recent years to 38.25 per 100,000 children.²⁷ Very early onset IBD makes up 3%–15% of all pediatric IBD.¹² Although relatively rare, it seems, at least in Canada, to be the fastest growing subset of all IBD patients. Among children 0–5 years old, the incidence increased most notably (+7.2% per year).²⁷ Ong et al recently published increases in pediatric IBD in Singapore, with roughly 20% of their cohort being under 6 years of age at diagnosis (a higher proportion than referenced in other populations).³⁰ A French study reported that VEO-IBD represented 3% of their pediatric population with no increase in VEO-IBD over time.³¹ Although genetics play an important role in this age group, environmental triggers are likely also contributory.

CLINICAL APPROACH TO PATIENTS WITH VEO-IBD

Multidisciplinary Team Approach

The diagnostic approach and management of infants and young children with VEO-IBD is challenging, especially when manifesting a concurrent underlying PID. However, though there is an increased likelihood of monogenic etiologies and underlying PIDs in patients with VEO-IBD than in those with older-onset disease, most children with VEO-IBD do not have an underlying PID. Given the rarity of IBD in this age group and the challenges in making a diagnosis, pediatric gastroenterologists often feel hesitant to label a young infant/toddler with a chronic inflammatory disease necessitating medical interventions with significant risk profiles. Understandable concerns exist regarding the use of conventional immunosuppressive IBD therapies, especially given potential underlying immune deficiency. There is additional responsibility to assure appropriate vaccination schedule, growth, nutrition, and overall health. Care of a patient with VEO-IBD should be a coordinated effort of a team of specialists, including not only gastroenterologists but also immunologists, geneticists, bone marrow transplant experts, nutritionists, surgeons, and other specialists depending on the extraintestinal manifestations. Referral to centers with expertise in this field is often pursued. The following approach and guidelines are based on expert opinion of the tertiary referral centers among our VEO-IBD Consortium (www.VEOIBD.org).

Distinguishing VEO-IBD from more Common Presentations

Patients with VEO-IBD can present with a wide variety of symptoms, both gastrointestinal and extraintestinal. Gastrointestinal symptoms include bloody and/or mucus-containing diarrhea, frequent emesis, failure to thrive, perianal skin tags, or fistulas. Systemic symptoms and/or extraintestinal symptoms include intermittent fevers, arthritis, arthralgias, folliculitis, uveitis, and dermatologic manifestations. Often, the initial set of diagnoses considered by the practicing pediatrician or general gastroenterologist are not chronic inflammatory bowel diseases because more common etiologies with similar symptoms are usually considered first, including cow’s milk protein intolerance or other food allergies, infections, celiac disease, and inadequate caloric consumption. Although it may initially be challenging to distinguish these more common causes of gastrointestinal symptoms from VEO-IBD, it is important to keep VEO-IBD on the list of differential diagnoses^{21, 32} so as not to delay treatment.

In patients with chronic diarrhea, infection should be ruled out regardless of age. These include Shigella, Salmonella, Yersinia, Escherichia coli, Campylobacter, Cryptosporidium, Giardia, and depending on a patient’s geographic location and risk factors, tuberculosis (TB), and HIV. For patients older than 12 months of age, one should also consider testing for Clostridioides difficile. In patients presenting between 12 months to 6 years of age, stool lactoferrin/calprotectin can be elevated in infection, chronic inflammation, or allergic gastrointestinal disorders. Stool lactoferrin and calprotectin have not been well validated in very young children and can be elevated above the adult range in infants. Intestinal TB is challenging to diagnose, as it can easily be misdiagnosed as Crohn’s disease.³³

For infants under 12 months of age presenting with bloody stools, cow’s milk protein intolerance or allergic colitis and infection are often the initial considerations. Distinguishing features that should raise suspicion for VEO-IBD include failure to thrive, weight loss, frequent infections, arthritis, folliculitis, intermittent fevers, and severe perianal disease (skin tags, abscesses, fistulae). Additionally, a refractory course with persistent symptoms despite an appropriate 2-week trial of an exclusive amino acid–based diet should prompt consideration for further investigation for VEO-IBD. It is important to mention that patients with IBD and those with cow’s milk protein intolerance can both improve significantly within 2 weeks of providing exclusive elemental amino-based formula feeds. This can make the distinction between VEO-IBD and cow’s milk protein intolerance challenging if there is a positive response. If patients are not thriving despite these dietary changes for 2 weeks or have other concerning features for VEO-IBD, more extensive workup for VEO-IBD should be pursued.

Celiac disease is another disease often considered before VEO-IBD in patients presenting with nonbloody diarrhea, malabsorption, anemia, weight loss, and failure to thrive. Serologies for celiac disease can be helpful in distinguishing the two, but there can be concurrent IBD and celiac disease, especially in light of the increased risk of underlying autoimmunity. In addition, certain primary immunodeficiencies can be nearly indistinguishable from celiac disease [eg, Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) deficiency].³⁴ It is important to remember that in young children, particularly those younger than 2 years old, deamidated gliadin peptide IgG may be more helpful than tissue transglutaminase IgA in screening for celiac disease, especially in patients with IgA deficiency.^{35, 36}

Other Noninflammatory Diagnoses

Although the focus of this manuscript is VEO-IBD, it is important to keep in mind that there are numerous additional noninflammatory etiologies for diarrhea. These include a variety of congenital intestinal transport defects such as specific carbohydrate malabsorption (eg, glucose-galactose malabsorption), disorders of amino acid and peptide assimilation (eg, enterokinase synthesis deficiency), disorders of fat assimilation (eg, abetalipoproteinemia), and disorders of mineral and electrolyte absorption and secretion (eg, congenital chloride diarrhea and congenital sodium diarrhea).³⁷ In contrast, VEO-IBD more commonly presents as bloody diarrhea, whereas these disorders usually do not. Additionally, inflammatory markers in the blood and stool can help distinguish VEO-IBD from noninflammatory etiologies.

Appreciation for Underlying PIDs Increases Suspicion for VEO-IBD

Many of the currently identified monogenic etiologies of VEO-IBD are associated with PIDs. It follows that PIDs should be considered in any patient with VEO-IBD and a thorough immune workup be completed in patients with VEO-IBD to identify possible underlying immunodeficiency. Primary immune deficiencies should be strongly considered and evaluated in patients with ≥4 new ear infections per year; ≥2 severe sinus infections in a year; ≥2 months of antibiotic treatment with little effect; ≥2 pneumonias per year; insufficient weight gain or growth delay; recurrent deep skin or organ abscesses; persistent thrush in mouth or fungal infection of the skin; need for intravenous antibiotics to clear infections; ≥2 deep seated infections; or a family history of PID.³⁸ History of infection with an unusual microbe (eg, Serratia) should raise suspicion for this, as well. Nevertheless in some cases, IBD is the initial manifestation of a PID, and the infectious problems will develop later. Therefore, a detailed immune workup in patients with VEO-IBD is required, even in the absence of chronic, recurrent, or atypical infections.

CLINICAL ASSESSMENT

A high index of suspicion is needed to guide the history and physical exam in order to diagnose VEO-IBD. Distinguishing which patients with VEO-IBD also have an underlying PID is a challenge, but there are certain manifestations that support the diagnosis of an underlying immune disorder. For instance, thrombocytopenia and eczema are common in patients with Wiskott-Aldrich syndrome. Glycogen storage disease type 1b typically presents with hypoglycemia and hepatomegaly. Recurrent infections are commonly identified in patients with chronic granulomatous disease (CGD), severe combined immunodeficiency (SCID), or common variable immune deficiency (CVID). An extensive list of monogenic etiologies of VEO-IBD and their associated distinguishing clinical and laboratory features are presented in Table 1, which has been expanded from that of Uhlig et al.¹ With this understanding and a systematic approach of a targeted history, physical exam, blood work, and stool studies, it should become apparent which subset of patients merits further investigation.

TABLE 1.

Monogenitc Etiologies of VEO-IBD.

Group	Syndrome/Disorder	Gene	Inheritance	IBD Phenotype	Key Laboratory Findings	Other Major Clinical Findings	Histology	Reference
IL-10 Signaling Defects	IL-10R	IL-10RA	AR	Crohn’s disease	Defective STAT3 phosphorylation in response to IL-10	Perianal fistula; Arthritis; Eczema; Folliculitis; Pyoderma; B cell lymphoma	Inflammatory infiltrate; Deep ulceration of mucosa; Crypt abscess formation	3, 71, 88–93
	IL-10R	IL-10RB	AR	Crohn’s disease	Defective STAT3 phosphorylation in response to IL-10	Perianal fistula; Arthritis; Eczema; Autoimmune hemolytic anemia; B cell lymphoma	Inflammatory infiltrate; Deep ulceration of mucosa; Crypt abscess formation; +/- Granuloma
	IL-10	IL-10	AR	Crohn’s disease	Decreased functional IL-10	Perianal fistula	Inflammatory infiltrate; Deep ulceration of mucosa; Crypt abscess formation
Immuno-regulation	IPEX	FOXP3	XL	Enterocolitis	Elevated serum IgE; Decrease in Treg number; Decreased Foxp3 expression	Atopic dermatitis; Arthritis; Multiple food allergies; Type 1 diabetes mellitus; Nephropathy, Hepatitis; Autoimmune hemolytic anemia; Hashimoto thyroiditis; Neoplasia	Extensive villous atrophy; Widespread leukocytic and eosinophilic infiltrate	6, 42
	IPEX-like	IL-2RA/CD25	AR	Enterocolitis	Absent CD25 expression	Autoimmune endocrinopathy; Eczema’ Short stature; Interstitial pneumonitis; Alopecia universalis; Bullous pemphigoid; CMV/EBV	Villous atrophy; Chronic inflammatory infiltrate; Propensity to CMV colitis with inclusion bodies	94
	IPEX-like	STAT1 GOF	AD	Enterocolitis	Normal Treg cell number and FOXP3 expression; STAT1 phosphorylation studies abnormal (increased and prolonged)	Autoimmune endocrinopathy; Chronic mucocutaneous candidiasis; Eczema, Recurrent sinopulmonary infections (RSV bronchiolitis common); Bronchiectasis	Villous blunting; Lymphocytic and eosinophilic infiltrate	95
	MALT1 deficiency (IPEX-like)	MALT1	AR	Enterocolitis	High IgE; Low IgM; Normal IgG/IgA; Eosinophilia; Elevated T cell number with decreased FOXP3 expression	Facial dysmorphism; Eczema-like dermatitis; Severe bacterial/viral/fungal infections	Subtotal villous atrophy; Massive duodenal T cell lymphocytic infiltrate	96
	STAT3	STAT3 GOF	AD	Enterocolitis	Hypogammaglob-ulinemia; Decreased class switched memory B cells; Eosinophilia; Decreased NK and Tregs with increased CD4-CD8- T cells	Multisystem autoimmunity; Variable short stature; Lymphoproliferation; Delayed onset mycobacterial disease	Villous blunting; Lymphocytic and eosinophilic infiltrate	97
	JAK1	JAK1 GOF	AD	Enterocolitis	Increased CD56high/CD16; Low NK cells; Heightened STAT1/STAT3 phosphorylation	Membranous nephropathy; Chronic dermatitis; Short stature	Marked eosinophilic infiltrate.	98
T and B cell defects	LRBA deficiency	LRBA	AR	Crohn’s like enterocolitis	Hypogammaglob-ulinemia; Decreased class switched memory B cells; Constrained Treg population; Impaired vesicular trafficking of CTLA4; Lower CD25 levels on Tregs; Exaggerated T follicular helper cell response	Erythema Nodosum; Autoimmune Hemolytic Anemia; Type 1 diabetes mellitus; Burkitt’s lymphoma; Exocrine pancreatic insufficiency; Interstitial lung disease; Splenomegaly; Hepatitis; IgA deficiency; Uveitis	Villous atrophy; Crypt hyperplasia; Chronic/active enterocolitis	40, 64, 99–103
	CTLA4 deficiency	CTLA4	AD with incomplete penetrance	Crohn’s disease	Hypogammaglob-ulinemia; Decreased class switched memory B cells	Type 1 diabetes mellitus; Autoimmune hypothyroidism; Demyelinating encephalopathy; Fibrosing interstitial lung disease; Chronic sinusitis; PSC; Hypogammaglobulinemia; Autoimmune cytopenias; Gastric adenocarcinoma	Severe chronic inflammation; Intestinal metaplasia; intraepithelial lymphocytosis; Villous atrophy; Intraepithelial lymphocytosis	34, 41
	IL-21 deficiency (CVID-like)	IL-21	AR	CD-like enterocolitis	Decreased class switched B cells; Elevated IgE; Decreased IgG	Recurrent Cryptosporidial infections; Recurrent sinopulmonary infections; Chronic cholangitis; Aphthous stomatitis	Eosinophilic and neutrophilic infiltrate; Focal cryptitis; Granulomas	104–106
	Wiskott Aldrich Syndrome	WAS	XL	UC-like colitis	Microthrombocytopenia; Variable lymphopenia; Absent class switched memory B cells; High IgE; Low IgG, IgA, and IgM	Thrombocytopenia; Atopic dermatitis; Autoimmune hemolytic anemia; Arthritis; Bacterial/viral infections; Lymphoreticular malignancy	Cryptitis; Active/chronic colitis	107, 108
	Hyperimmunoglo bulinemia	CD40LG	XL	Mouth and colitis	Elevated/normal IgM; Neutropenia, absent class switched memory B cells	Sinopulmonary infections; Cryptosporidium infections; Sclerosing cholangitis; Autoimmune hemolytic anemia; Aphthous stomatitis associated with neutropenia; Perianal ulcers/fistulae; Neurologic problems	Pronounced lymphoid hyperplasia	109
		AICDA	AR	Crohn’s-like Mouth and enterocolitis	Elevated/Normal IgM; Low IgG and IgA	Sinopulmonary infections; Aphthous stomatitis associated with neutropenia; Perianal ulcers/fistulae; Autoimmune hemolytic anemia; Skin lesions	Pronounced lymphoid hyperplasia	110
	Bruton’s agamm aglobulinemia	BTK	XL	Crohn’s-like colitis	Severe hypogammaglob-ulinemia; Absent B cells; decreased class switched memory B cells	Recurrent infections; Lymphoreticular malignancies; Autoimmune hemolytic anemia	Absent plasma cells	111, 112
	Artemis-deficiency combined immunodeficiency	DCLRE1C/ARTEMIS	AR	Crohn’s-like enterocolitis	Profound lymphopenia; Variable changes to immunoglobulins; Variable specific antibody response	Autoimmune hemolytic anemia; Neutropenia: Thrombocytopenia; Recurrent sinopulmonary infections; Candidiasis; Hepatosplenomegaly	Aphthous lesions over lymphoid aggregates; Rare microgranulomas; Florid cryptitis	113, 114
	PI3K Activation Syndrome	PIK3R1	AR	Colitis	Variable alterations in immunoglobulins; Decreased class switched memory B cells	Recurrent respiratory infections; Lymphoproliferation; Systemic autoimmunity reminiscent of SLE; Erythema nodosum	Not reported	115
	PI3K Activation Syndrome	PIK3CD	AD	Colitis	Variable alterations in immunoglobulins; Decreased class switched memory B cells	Recurrent respiratory infections; Lymphoproliferation; Systemic autoimmunity reminiscent of SLE; Erythema nodosum	Increased intraepithelial lymphocytes; Moderate villous blunting	116
	SCID	ZAP70	AR	Colitis	Absent CD8 cells; Defective CD4 T cells; Some have elevated IgE and eosinophilia.	Profound immunodeficiency with recurrent infections; Other early onset autoimmune diseases: Nephrotic syndrome; Bullous pemphigoid; Rheumatoid arthritis	Not reported	117, 118
	Leaky SCID	RAG2	AR	Colitis	Eosinophilia; T-cell lymphopenia; NK cells present.	Profound immunodeficiency with recurrent infections; Erythroderma; Hepatosplenomegaly; Lymphadenopathy; Autoimmune hemolytic anemia	Marked infiltrate with eosinophils, monocytes, and lymphocytes	119, 120
	SCID/Omenn	IL-2RG	XL	Colitis	Eosinophilia; T-cell lymphopenia; Decreased naive T cells	Profound immunodeficiency with recurrent infections; Candidal infections	Not reported	121
	Leaky SCID	LIG4	AR	Colitis	Variable lymphopenia	Variable presentation—from propensity to leukemia to Omenn syndrome; Aphthous stomatitis	Not reported	122, 123
	SCID	ADA	AR	Colitis	Absent T, B, and NK cells.	Profound immunodeficiency with recurrent infections; Erythroderma; Hepatosplenomegaly; Lymphadenopathy	Not reported	124
	SCID	CD3-Ɣ	AR	Enterocolitis; Perianal disease.	Defective TCR/CD3 expression on CD4/CD8 positive lymphocytes; Variable lymphopenia and hypogammaglob-ulinemia	Profound immunodeficiency with recurrent sinopulmonary infections; Multiple autoimmune diseases: Thyroiditis; AIHA; vitiligo, Nephrotic syndrome;	Mononuclear cellular infiltrate in lamina propria; Crypt abscesses	125
	ICOS deficiency	ICOS	AR	Enterocolitis	Low to absent class-switched memory B cells; Loss of bone marrow plasma cells; Impaired vaccine response	Reurrent sinopulmonary infections; CMV infections; Arthritis; Psoriasis	Chronic, active enteritis.	126–128
	Hoyeraal Hreidarsson Syndrome	DKC1	XL	Enterocolitis with ulcerations and strictures	B and T cell lymphopenia (+/- NK cell reduction)l Low IgA, IgG, IgM; Impaired proliferation to antigens	Skin pigmentation; Nail dystrophy; Hair thin, sparse and discolored; Leukoplakia of tongue and gums; Aplastic anemia; Immunodeficiency; Motor delay; Cerebellar hypoplasia; Growth failure; Microcephaly	Atrophic mucosa; Sparse glands; Increased mononuclear cells in lamina propria; Apoptotic cell death	39, 129, 130
	Hoyeraal Hreidarsson Syndrome	RTEL1	AR	Colitis/enter-opathy	Extremely short telomers	IUGR; Low B, T and NK cells; Hypogammaglobulinemia (IgA, IgM, IgG); Nail dysplasia; Cerebellar hypoplasia; Increased risk of leukemia	Severe colitis with apoptosis	131, 132
	Loeys-Dietz-Syndrome	TGFBR1	AD	Colitis	Anemia; Hypergammaglob-ulinemia	Hypertelorism; Blue sclerae; Bifid uvula; Arachondactyly; Joint hyperplexity; Pes valgus; Dilation of aortic root; Fevers	Chronic colitis; Moderate lymphocytic and plasma cell infilatrate in lamina propria	133, 134
	Loeys-Dietz-Syndrome	TGFBR2	AD	Colitis	Anemia; Hypergammaglob-ulinemia	Hypertelorism; Proprtosis; Blue sclerae; Joint hyperlaxity; Mild dilation of ascending aorta	Moderate lymphoplas macellul-ar infiltrate in lamina propria; Chronic colitis with Paneth cell metaplasia	133
	Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome	ZBTB24	AR	Colitis	Hypogammaglob-ulinemia; Decreased B cells and NK cells; Poor response to vaccines; Centromere instability; Facial anomalies	Hypertelorism; Epicanthal folds; Low-set ears; Developmental delay; Perianal fistula	Colonic ulcerations with chronic colitis and architectural distortion	135
	RIPK1 deficiency	RIPK1	AR	Pancolitis, Ulcers; Oral lesions; Perianal disease	Defective differentiation of T and B cells; Lymphopenia; Increased inflammasome activity; Impaired response to TNFR1-mediated cell death	Hepatosplenomegaly; Maculopapular rash; Recurrent fevers; Neonatal infections	Increased apoptotic bodies; Granulomas; Depletion of lamina propria plasma cells	136
	Caspase-8 deficiency	CASP8	AR	Crohn’s like pancolitis; Strictures; Fistulas; Perianal disease	Altered distribution of T cells; Reduced T cell proliferation and activation; Impaired B cell maturation; Elevated IL-1B with altered inflammasome activity	Susceptibility to viral and bacterial infections	Increased epithelial regeneration	137
Phagocyte defects	CGD	CYBB	XL	Crohn’s-like colitis	Decreased neutrophil oxidative burst study; Elevated IgG	Recurrent Infections for catalase positive organisms; Perianal fistula; Gastric outlet obstruction; Eczema; Chorioretinitis	Chronic/active colitis/enteritis; granulomas in 50% on noninflamed background; pigment-laden macrophages	52, 138–141
		CYBA	AR
		NCF1	AR
		NCF2	AR
		NCF4	AR
	Glycogen Storage Disease Type 1 b	SLC37A4	AR	Crohn’s-like colitis with ulcerations; Strictures; Perianal fistula	Neutropenia and/or neutrophil dysfunction with predisposition to infections; Hypoglycemia; Hyperuricemia; Hyperlipidemia	Hepatosplenomegaly; Nephrocalcinosis; Folliculitis	Nonspecific chronic inflammation	142–144
	Congenital neutropenia	G6PC3	AR	Crohn’s like with strictures; Oral and genital aphthous ulcerations	Severe neutropenia; T cell lymphopenia; Elevated IgG	Cutaneous vascular malformation; Cardiac defects; Urogenital developmental defects; Bleeding tendency	Inflammatory infiltrate; Crypt and villi distortion; Paneth cell metaplasia	145–149
	Leukocyte adhesion deficiency 1	ITGB2	AR	Crohn’s like with stenosis/stricturing phenotype; Lip ulcers	Leukocytosis, Absent CD11/CD18 complex expression	Neutrophilia; Recurrent bacterial infections; Delayed separation of umbilical cord; Poor wound healing; Folliculitis; Ulcers of skin; Peridontitis; Gingivitis	Transmural inflammation and ulceration with plasma cell infiltrate; Absent neutrophils.	150, 151
	Niemann-Pick type C disease	NPC1	AR	Crohn’s	Abnormal bacterial handling	Hepatosplenomegaly; Cholestasis; Portal hypertension; Motor or cognitive delay; Seizures; White matter abnormalities; Perianal skin tags; Anal fissures; Arthritis	Inflammatory infiltrate; Granulomas, foam cell macrophages (from abnormal lipid storage)	152–154
Hyperinfl-ammatory and auto-inflammatory	X-linked lymphoproliferative syndrome 2 (XLP2)	XIAP	XL	Crohn’s like granulomatous colitis	Elevated IL-18; Decreased XIAP protein expression by flow; Little expression of IL-8 and MCP-1 in response to MDP stimulation	Perianal fistula; HLH; Splenomegaly; Cholangitis; Skin abscesses; Arthritis, EBV and CMV infections; Hypogammaglobinemia	Chronic colitis; Transmural inflammation; Ulceration; Granulomas	155–160
	Herman-sky-Pudlak syndrome	HPS1	AR	Crohn’s like enterocolitis; Perianal fistula/abscess	Decreased CD107a degranulation	Partial albinism; Bleeding tendency; Recurrent infections; Nystagmus; Pulmonary fibrosis; Bowel perforation	Granulomatous colitis	161–166
		HPS4	AR	Crohn’s like enterocolitis; Perianal fistula/abscess	Decreased CD107a degranulation; Absent platelet dense bodies	Partial albinism; Bleeding tendency; Recurrent infection; Pulmonary fibrosis; Variable hair and skin pigmentation	Granulomatous colitis	161, 163, 165
		HPS6	AR	Enterocolitis	Elevated IgD; Elevated urine mevalonate	Partial albinism; Bleeding tendency; Recurrent infection	Granulomatous enterocolitis	167
	Mevalonate kinase deficiency	MVK	AR	Severe neonatal onset ulcerative colitis; enterocolitis; Strictures; Adhesions; Perforations; Deep ulcers	Majority of cases with hyperimmunoglo-bulinemia D; Neutrophil-predominant leukocytosis during attacks with elevated ESR/CRP; Serum amyloid A when adult	Recurrent fevers; Rash; Macrophage activation syndrome; Recurrent febrile attacks; Polyarthritis; Edema; Urticaial rash; Hepatomegaly	Ulcerated colonic mucosa; Diffuse mixed cellular infiltration; Apoptosis; Crypt distortion	67, 168–171
	Phospholipase Cy2 defects	PLCG2	AD	Infantile-onset ulcerative colitis and early onset enterolocitis		Early onset recurrent blistering skin condition; Interstitial pneumonitis with respiratory bronchiolitis; Arthralgia, Eye inflammation; Cellulitis; Recurrent sinopulmonary infections	Not well characterized	172
	Familial Mediterranean fever	MEFV	AR	Infantile or toddler-onset patchy colitis with white exudate; Nodularity; Anal fissures	Marked elevated ferritin and sIL-2R; Decreased CD107a degranulation	Recurrent fevers; Erythematous rash; Arthralgia; Pericardial effusion; Peritonitis	Chronic active inflammation with leukocytes, eosinophils, cryptitis,	173–175
	Familial hemoph-agoytic lymphohistiocytosis type 5	STXBP2	AR	Enterocolitis	Elevated IL-18	HLH; Hypogammaglobulinemia; Sensorineural hearing loss	Nonspecific inflammation; Slight loss of villi or crypts	176, 177
	TRIM22 defect	TRIM22	AR	Granulomatous Crohn’s colitis; Severe perianal disease		Oral ulcerations, Fevers; Profound anemia; H hypoalbuminemia	Noncaseating granulomas; Chronic inflammatory cell infiltrate	178
	Prostaglandin Transporter Deficiency	SLCO2A1		Chronic nonspecific multiple ulcers of the small intestine (CNSU)	Mild to severe T-cell immune deficiency; Hypogammaglob-ulinemia	CNSU are distinct as multiple shallow, circular or oblique lesions, with sharp demarcation from surrounding normal mucosa; Can lead to primary heterotrophic osteoarthropathy	Nonspecific	179
Epithelial barrier	TTC-7A Deficiency	TTC7A	AR	Severe apoptotic enterocolitis from birth,	Hypogammaglob-ulinemia; Decreased class switched memory B cells; Reduced NK cell cytotoxic activity	Multiple intestinal atresia; Exfoliating and sloughing intestinal mucosa; Hypoplastic thymus; Severe combined immunodeficiency	Extensive apoptosis; Sparse microvilli; Gland dropout; Exploding crypts	180, 181
	NF-κB essential modulator (NEMO) deficiency	IKBKG	XL	enterocolitis	No immune findings	Ectodermal dysplasia; Immunodeficiency	Severe colitis with exudate and friability; Marked acute neutrophilic inflammation with edema; Superficial cryptitis; Ulcerations	43, 182, 183
	Dystrophic epiderm-olysis bullosa	COL7A1	AR	enterocolitis, gastrointestinal strictures	Eosinophilia	Blistering disorder mainly of extremities—knees, elbows, feet and hands	increased inflammatory infiltrate in lamina propria with eosinophilic predominance and focal neutrophilic inflammation; Karyorrhectic cellular debris in colon; Brown pigment containing macrophages	184
	Kindler syndrome	FERMT1 (AKA Kindlin-1)	AR	UC	Moderately elevated IgE; Normal B and T cell subsets; T cell infiltration in skin in absence of acute inflammatory response	Blistering skin; Photosensitivity; Progressive poikiloderma; Diffuse cutaneous atrophy	Chronic inflammation; Mucosal atrophy; Focal detachment of colonic epithelium	184, 185
	ADAM-17 deficiency	ADAM17	AR	enterocolitis since infancy	Hyponatremia; Hypokalemia; Hypomagnesema; Hypoacalcemia; Nutrient deficiencies	Neonatal onset inflammatory skin disease (facial scaling, pustules and erythema); Short and broken hair; Swollen distal phalanges; Abnormal nails with paronychia	Gastritis; Plasma cell duodenitis; Eosinophilia; Mononuclear cell infiltrate; Villous blunting; Lengthened crypts	186
	Familial diarrhea	GUCY2C	AD	Enterocolitis(can also present as congenital sodium diarrhea with intra-uterine onset diarrhea)	High fecal sodium; Low urinary sodium	Strictures; Esophagitis	Variable: normal to ischemic ulcers; Gastroduodenitis; Focal inflammation	187, 188
	Congenital Diarrhea	SLC9A3	AR	Congenital sodium diarrhea (osmotic or secretory), with later development of IBD in ~25%; May develop recurrent small intestinal obstructions; Bloody diarrhea	Elevated liver enzymes and cholestasis		Variable: Chronic inflammation; Villous blunting, +/- granulomas; Increased eosinophils; Ileal and colonic ulcerations	189
Other	Trichohepatoenteric syndrome	SKIV2L	AR	Enterocoliti swithin weeks of life	Low IgG levels or hypogammaglob-ulinemia; Decreased antigen-stimulated lymphocyte proliferation	Intrauterine growth restriction; Wooly, dry, easily removable hair that is poorly pigmented; Large forehead; Skin abnormalities; Mild mental retardation; Bronchiectasis; Cardiac abnormalities	Variable: villous atrophy, small intestinal and pancolonic chronic inflammation; Apoptotic activity; Epilethlial cell irregularity	133, 173, 190, 191
	Trichoh-epatoen-teric syndrome	TTC37	AR	Infantile-onset diarrhea	Elevated liver enzymes; Low IgG, Poor vaccine response; Decreased antigen-stimulated lymphocyte proliferation.	Facial dysmorphism, Hair anomalies; Low birth weight; Cardiac anomalies; Liver cirrhosis	Colitis; Crypt abscess; Shortened villi; Elongated crypts with inflammatory infiltrates	190, 192
		ARPC1B	AR	Colitis	Microthrombocytopenia; Eosinophilia; Elevated IgA, IgG, TRECs, ANA and ANCA	Chronic infections; Eczema; Vasculitis	Not described	193
	CHAPLE syndrome	CD55	AR	Enterocolitis with ulcers in terminal ileum	Terminal complement activation in arterioles; Increased TNF; Reduced IL-10	Early onset protein losing enteropathy; Primary intestinal obstruction; Edema; Malabsorption; Recurrent infections; Angiopathic thromboemboli; Micronutrient deficiencies	Lymphoid aggregates in intestinal wall; Intestinal lymphangiectasia	194

Crohn’s-like disease refers to disease that has features of Crohn’s including deep ulcerations, discontinuous inflammation, strictures, fistulas. Abbreviations: AD, autosomal dominant; AIHA, autoimmune hemolytic anemia; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibody; AR, autosomal recessive; CMV, cytomegalovirus; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; GOF, gain of function; HLH, hemphagocytic lymphohistiocytosis; Ig, immunoglobulin; IUGR, intrauterin growth restriction; MDP, muramyl dipeptide; NK, natural killer; PSC, primary sclerosing cholangitis; R, receptor; sIL-2R, soluble IL-2 receptor; SLE, systemic lupus erythematosus; TREC, T cell receptor excision circle; Treg, T regulatory cells. Expanded from Uhlig et al.¹²⁰

Comprehensive History

A detailed history should identify the onset of symptoms, with careful attention to stooling pattern, frequency, consistency, evidence of macroscopic or microscopic blood or mucus, the progression over time, and the response to dietary or other interventions. It is imperative to inquire about energy, appetite, tolerance of feeds, vomiting, and irritability. Careful review of the patient’s growth parameters and history of frequent or recurrent fever and infections, especially opportunistic or refractory infections, rashes, arthritis or arthralgias, and perianal disease are instrumental. Family history of consanguinity or relatives with immune deficiency, recurrent infections, IBD, autoimmunity (such as type 1 diabetes, autoimmune thyroiditis, or autoimmune liver disease) and atopy might point to a possible monogenic disease.

Physical Exam

General clinical features that can be seen in IBD at any age include clubbing, rashes (eg, erythema nodosum and pyoderma gangrenosum), and perianal disease (eg, fistulas, skin tags, and perianal abscesses). In Crohn’s disease, the oral exam may be notable for classic features of aphthae and orofacial granulomatosis. Manifestations of nutritional deficiencies might also be noted such as peripheral edema from hypoalbuminemia, angular cheilitis from iron/vitamin deficiencies, and perianal and perioral rash reminiscent of acrodermatitis enteropathica. In VEO-IBD, there are unique physical exam findings that may increase suspicion for a monogenic etiology. These include dysmorphic features, hepatomegaly, splenomegaly, atopic dermatitis, hyperkeratoisis, albinism, and epidermylosis bullosa. To give some specific examples, a constellation of severe perianal disease, folliculitis, and arthritis in young patients presenting within the first few months of life is suggestive of interleukin (IL)-10 signaling defects.³ Oral leukoplakia is suggestive of underlying dyskeratosis congenita.³⁹ Features of common variable immunodeficiency such as lipopolysaccharide responsive and beige-like anchor protein or CTLA4 deficiency include recurrent infections, various autoimmune and endocrine features, and organomegaly.^{40, 41} Similarly, patients with immune dysregulation, polyendocrinopathy enteropathy X-linked (IPEX) syndrome not only manifest enteropathy but commonly have type 1 diabetes mellitus, eczema, food allergies, and a variety of other autoimmune manifestations.^{6, 42} Patients with NEMO mutations often have ectodermal dysplasia as an easily recognizable feature on physical examination.⁴³ Lastly, abnormalities in the hair and/or nails are found in Hoyeraal Hreidarsson syndrome, trichohepatoenteric syndrome, and ADAM17 deficiency. The physical exam remains a useful tool that may help distinguish monogenic causes of VEO-IBD.

BASIC WORKUP, INITIAL INVESTIGATIONS, AND EARLY INTERVENTIONS

Upon referral from the general pediatrician, it is vital to confirm that more common causes of colitis have been ruled out (eg, infection, Fig. 1). Stool studies and lab tests can be sent to rule out other causes on the differential (Table 2). Of note, serologic markers commonly obtained due to their association with IBD, such as antibodies to microbial antigens (eg, Anti-Saccharomyces cerevisae antibody, anti-Flagellin) and autoantibodies (eg, Perinuclear antineutrophil cytoplasmic antibodies), have been noted to be different within younger age groups, and they likely have a limited role for VEO-IBD.^{44, 45} Patients younger than 12 months of age suspected to have VEO-IBD should receive an exclusive elemental formula for at least 2 weeks unless the severity of the patient’s symptoms prompts an expedited workup.

FIGURE 1.

Algorithm for work-up of VEO-IBD. Abs, antibodies; CBC with diff, complete blood count with differential; CGD, chronic granulomatous disease; CMP, comprehensive metabolic panel; CRP, C reactive protein; EGD, esophogastroduodenoscopy; ESR, erythrocyte sedimentation rate; H&P, history and physical; mo, month; NOBA, neutrophil oxidative burst assay; TB, tuberculosis; SSCYE, Salmonella, Shigella, Campylobacter jejuni, Yersinia enterocolitica, and E coli; C. Diff, C. Difficile; Wk, week.

TABLE 2.

Initial Bloodwork and Stool Studies

	1st Tier Tests	2nd Tier Considerations
Bloodwork	CBC and differential Comprehensive Metabolic Panel (CMP) ESR CRP Consider celiac screen and thyroid function tests depending on presentation	Immunoglobulin classes (IgA, IgG, IgM, IgE) Must use age-specific norms, especially in infants Lymphocyte subsets by flow cytometry Antibody to vaccines—Vaccination history must be obtained to evaluate this Allergen testing for older children DHR testing TREC/TCR repertoire TB testing HIV serology
Stool studies	Occult blood ShigellaSalmonellaYersiniaEnterohemorrhagic and Enteropathogenic E. coliCampylobacterC. difficile (if >12 months) Calprotectin or quantitative lactoferrin	Giardia Cryptococcus

Abbreviations: NOBA, neutrophil oxidative burst assay, also known as DHR- dihydrohodamine 123

If the initial labs, symptoms, or physical exam findings are concerning or refractory to a 2-week trial of an elemental diet in infants younger than 12 months old, it is recommended to proceed with expedited upper endoscopy and ileocolonoscopy. Endoscopy is technically feasible in the youngest patients (younger than 1 month old) but requires the expertise of an experienced pediatric gastroenterologist. Endoscopy will help to determine if the pattern of disease is more consistent with an allergic, inflammatory, or infectious process. A detailed gross assessment with multiple biopsies is critical to aid in diagnosis. Features consistent with VEO-IBD include evidence of chronic inflammation (architectural changes, crypt branching, increase in chronic inflammatory cells in the lamina propria, and noncaseating granulomas in CD). Although we typically find evidence of chronic inflammation, in some rare cases early evolving VEO-IBD without the typical features of VEO-IBD may be captured on initial scope. Therefore, it is important to not definitively rule out VEO-IBD based alone on the lack of chronic features where clinical suspicion for VEO-IBD is high. One feature suggestive of an underlying monogenic etiology of VEO-IBD is the presence of epithelial cell apoptosis. This finding is identified in several monogenic etiologies of epithelial barrier function (such as dystrophic bullosa, Kindler syndrome, X-linked ectodermal immunodeficiency, TTC7A deficiency, and ADAM17 deficiency) and in IPEX syndrome. Abnormalities in the hair and/or nails are found in telomerase disorders (eg, Hoyeraal Hreidarsson syndrome), trichohepatoenteric syndrome, and ADAM17 deficiency. Many monogenic etiologies have a variety of extraintestinal autoimmune features. Some are associated with either hemophagocytic lymphohistiocytosis (HLH) or macrophage activating syndromes, and some have increased predilection for development of neoplasias (such as diffuse large B cell lymphoma in IL-10 signaling defects).

Despite the predominance of colonic inflammation in VEO-IBD, imaging of the small intestine is helpful in determining the extent of intestinal disease. This is more complicated in very small children. A wireless capsule endoscopy (WCE), which has been used in a child as small as 7.9 kg,⁴⁶ requires sedation to place the capsule itself and consideration of preliminary placement of a patency capsule. A magnetic resonance enterography (MRE) requires a significant amount of contrast and expertise of the radiologist. There are also safety concerns regarding sedating patients for lengthy MREs after providing oral contrast. Because of these concerns, feasible options to image the small intestine in this age group are typically a small intestine abdominal ultrasound by a skilled radiologist or, more specifically, a small intestinal contrast ultrasound (SICUS), a minimized-radiation CT scan, if available, or a small bowel follow-through.⁴⁷

Consultation with an expert immunologist for the consideration of an underlying immunodeficiency is warranted in all patients with VEO-IBD. Examples of underlying PIDs can be found in Table 1. The immunologist will typically send a basic immune workup (listed as 2nd tier in Table 2, in addition to potentially additional investigations such as soluble IL-2 receptor, IL-18, Forkhead box P3 (FOXP3), and X-linked inhibitor of apoptosis (XIAP) by fluorescence-activated cell sorting analysis among others). These initial studies will help direct further specialized workup for specific syndromes or diseases. These tests are best performed before therapy is initiated, as many treatments can obscure the results.

GENETIC SEQUENCING: TARGETED GENE PANELS AND NEXT GENERATION SEQUENCING

If there is no clear clinical suspicion for an underlying monogenic etiology or if specialized directed testing is unrevealing, then a more expansive evaluation using either targeted gene panels for VEO-IBD or next generation sequencing (NGS) is warranted. In many instances, this is performed in research settings.⁴⁸ Physicians and patient families must understand that despite such efforts, the underlying etiology of the disease will remain unknown in most cases. Successful identification of known causal variants typically range between 5%–20%. Some studies have reported a higher identification rate, up to 31%, but these were conducted in tertiary care referral medical centers.⁴⁹ Clinical judgment is required to assess the necessity of genetic testing in those with a relatively benign course without any red flag features who do not fall in the infantile IBD cohort, as the incidence of monogenic mutations does decrease successively with age; however, given the ready availability of genetic panels and even NGS, genetic testing should still be considered. Though only a minority will be identified as having a known monogenic etiology, this holds significant clinical and therapeutic implications when variants are identified. For instance, in VEO-IBD patients with IL-10 receptor signaling deficits, identification enables the possibility for a curative bone marrow transplantation.³ As research continues and we understand more about the underlying monogenic etiologies of VEO-IBD, we anticipate an improved detection rate of causative variants over time. It is important to appreciate that the turnaround time for these tests, both Clinical Laboratory Improvement Amendments (CLIA)–approved and research-based, can be very lengthy (ie, weeks to many months).

Available CLIA-certified genetic panels for VEO-IBD exist. They allow the investigation of a large number of genes known to be causative for infantile/VEO-IBD in a CLIA-approved fashion (eg, Invitae). However, these gene panels often contain only a subset of known genetic etiologies of VEO-IBD, often missing critical candidate genes and lacking interpretation of variants of unknown significance. It is important that if performed and unrevealing, this should not reassure the physician or family that a genetic etiology is not at play, as the list of genes tested is incomplete and should reflex to next generation sequencing (whole genome sequencing [WES] or whole exome sequencing [WGS]).

An alternative is to send next generation sequencing (WES or WGS) straight away. If performed as part of a research endeavor, any pertinent findings would need to be CLIA-confirmed before being communicated back to the family. Appropriate patient/parent and physician expectations need to be set as genetic testing can take months. Additionally, a genetic counselor should be made available to discuss any CLIA-confirmed findings.

Finally, genetic risk scores are gaining popularity within classically polygenic diseases,⁵⁰ having been shown in some chronic diseases, including IBD, to perform as well in disease prediction as monogenic mutations. Before the inception of current-day polygenic risk scores, using a genetic risk score incorporating 163 risk alleles, a trend was shown in CD toward higher genetic risk scores in those with a lower age of diagnosis (P_trend = 0.008).⁵¹ Use of the polygenic risk score has not been studied within the VEO-IBD population, specifically as the focus remains on identifying actionable monogenic variants.

Overall, though there is great promise in these approaches, because of the time lag, often clinical management must often be initiated before receipt of results.

FUNCTIONAL TESTING

Although the list of monogenic disorders linked to IBD has rapidly increased in the last decade, the number of functional tests that can be applied is very limited. Depending on the clinical features, if there is strong suspicion for a particular underlying genetic etiology, specific functional tests can be valuable. Functional testing will often provide results faster than genetic sequencing. However, it is important to note that any positive functional test should be confirmed by targeted genetic sequencing. We present here a few illustrative examples.

Patients presenting with VEO-IBD and either recurrent infections or numerous granulomas warrant assessment of their neutrophil oxidative burst capacity (NOBA). Dihydrohodamine 123 (DHR) testing is a NOBA that can be helpful in 2 regards. In one respect, classic chronic granulomatous disease (CGD) can present as VEO-IBD associated with an abnormal NOBA. In another respect, some patients with VEO-IBD without infections may have low-normal NOBA, which has been associated with mutations in various members of the NADPH-oxidase complex.^{52, 53}

Patients presenting with classic manifestations of IL-10 signaling defects such as severe colitis, perianal disease, arthritis, and folliculitis within the first months of life warrant functional testing of the IL-10 signaling pathway (either for defects in IL-10 or the IL-10 receptor). Functional assays are available in both research-based non-CLIA approved labs (inquiries can be sent to info@VEOIBD.org to learn about the types of functional assays offered by the VEO-IBD Consortium; VEOIBD.org) and CLIA-approved labs.

Patients with XIAP may present with severe Crohn’s-like colitis, perianal fistula, hemophagocytic lymphohistiocytosi (HLH), splenomegaly, cholangitis, skin abscesses, or fulminant infection to Epstein-Barr virus (EBV) and/or hypogammaglobiulinemia. Functional studies have been employed to diagnose XIAP by use of a flow-based assay measuring tumor necrosis factor (TNF) expression in response to muramyl dipeptide (MDP).^{54, 55}

CLINICAL AND TREATMENT PATTERNS

The severity of the clinical course and response to therapy of VEO-IBD patients compared with IBD patients presenting at an older age is inconclusive. Some studies report that there is an increased risk of earlier colectomy and increased risk for earlier biologic use in patients with IBD in infants less than 1 year of age,¹⁶ whereas other data suggest that patients with VEO-IBD have lower rates of hospitalization, emergency department utilization, and surgical resection.^{15, 21} A prospective observational review by Oliva-Hemker et al of VEO-IBD patients diagnosed between 1 and 5 years old showed that most presented with moderate to severe disease activity.¹⁵ Among those with CD, there was no significant difference in terms of exposure to infliximab, enteral nutrition, or hospitalization. However, these patients were more often exposed to steroids and methotrexate as compared with patients of older ages.¹⁵ With respect to patients with UC, there was no significant difference in use of antibiotics, 5-ASAs, steroids, or thiopurines. Conversely, 5 years after diagnosis, a larger proportion of the youngest patients were on mesalamine and thiopurine as compared with older age groups. Once again, exposure to infliximab and hospitalizations were not significantly different between age groups. It is important to keep in mind that this review did not capture patients diagnosed before 1 year of age, so it may not be capturing those with underlying PID or monogenic etiology.

THERAPEUTIC APPROACHES

Though some studies include patients with VEO-IBD, there are no randomized controlled studies focused on this age group to inform on the therapeutics of choice in patients specifically with VEO-IBD, which can largely be attributed to their rarity. Prioritized medication choices reflect data from older children and adult-onset IBD. We discuss various therapeutic approaches for VEO-IBD including medications, surgery, allogeneic hematopoietic stem cell transplantation (HSCT), nutrition, and complementary medicine.

Medical Therapies

Some but not all studies suggest that VEO-IBD patients may be more refractory to standard therapeutic choices, especially in patients less than 1 year of age. These include 5-ASA, immunomodulators (6MP, azathioprine, methotrexate), and anti-TNF antibodies. It is not surprising that there are also no comprehensive studies using vedolizumab, ustekinumab, tofacitinib, tacrolimus, or thalidomide in this age group.^56–60 Antibiotics have been tried in small cohorts of VEO-IBD with UC. Turner et al report some promising results including some very early onset UC patients receiving metronidazole, amoxicillin, doxycycline +/- vancomycin^{61, 62} and results also on use of oral gentamycin and/or vancomycin for treating VEO-IBD.⁶³

When there is a monogenic cause, identifying the underlying genetic etiology can enable more targeted and successful therapeutic interventions and/or help avoid ones that would be especially harmful to a patient. For example, abatacept—a CTLA4-IgG1 fusion drug—and hydroxychloroquine can be given to patients with CTLA4 and LRBA deficiency, as LRBA deficiency also results in a loss of CTLA4.⁶⁴ For patients with CGD, some centers avoid use of anti-TNF therapy for fear of perpetuating disseminated severe infection,⁶⁵ and clinicians rely instead on antibiotic therapies, thalidomide, or off-label vedolizumab/ustekinubmab. One can also consider anakinra, an IL-1 receptor antagonist, in patients with IL-10 signaling defects who are too ill to undergo transplant or while searching for a suitable donor, as this has led to marked clinical, endoscopic, and histologic improvement in some patients.⁶⁶ Blocking IL-1 has also been shown to be effective in patients with mevalonate kinase deficiency (MVK).⁶⁷ As we learn more about these diseases, it is anticipated that our repertoire of therapeutic alternatives will grow.

Surgery

Reports on the need for surgical intervention in patients with VEO-IBD is inconclusive. Benchimol et al reported less need for surgical intervention among a Canadian cohort of VEO-IBD as compared with that of older-onset,²¹ and Al-Hussaini et al reported no significant difference in surgical interventions in a Saudi Arabian VEO-IBD cohort.⁶⁸ In contrast, Kammermeier et al report an increase need for surgical intervention in infantile Crohn’s-like disease diagnosed before 2 years of age at their European center.⁴⁹ A recent single-center studying surgical interventions in patients with monogenic etiologies of IBD from China report that surgical interventions should be performed earlier because of risk of perforations in monogenic IBD.⁶⁹ These discrepant reports may be due to the fact that surgery may hinge more on the underlying immunodeficiency or monogenic etiology than age of onset of disease.

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) may be curative for several monogenic causes of VEO-IBD, including CGD, IPEX syndrome, and IL-10 receptor signaling defects.^{3, 70–74} Umbilical cord transplantation may also correct disease associated with IL-10RA.⁷⁵ Consideration for HSCT should be discussed with experienced physicians who have expertise in transplantation for PID. The risks of HSCT include life-threatening infection, failure of engraftment, graft versus host disease, and acute and long-term toxicity from medications used for conditioning, including infertility, and secondary malignancy. Risks and benefits must be carefully weighed. For instance, VEO-IBD is life-threatening in patients with IL-10 signaling defects, and HSCT can be life-saving. However, VEO-IBD in CGD is more indolent, and the decision to perform HSCT is more nuanced. Thus, even though the procedure is potentially curative, the not insignificant risk of mortality and morbidity must be evaluated carefully. In some diseases, such as WAS, genotype-phenotype correlation can predict whether an individual patient is likely to have a severe course without HSCT.⁷⁶ For others, the variability of penetrance and symptoms among family members with the same mutation make the decision of whether to proceed to HSCT much more challenging. Finally, the timing can also be important, such as in IPEX syndrome, where the pretreatment organ involvement score at time of transplant is associated with improved survival.⁷⁷ It is important to remember that some monogenic causes of IBD have both immune and epithelial defects; accordingly, HSCT may not ameliorate all symptomatology. Table 3 reviews some genetic etiologies of IBD and highlights when HSCT for the purpose of correction of IBD should be strongly considered or discouraged or if there is insufficient evidence to provide strong recommendations.

TABLE 3.

Efficacy of Healing Intestinal Disease With Stem Cell Transplantation in Some Cases of VEO-IBD

Condition	HSCT May Be Efficacious for Intestinal Disease	HSCT Not Efficacious for Intestinal Disease
	IL-10RA, IL-10RB, IL-10 deficiency	TTC7A
	IPEX	STXBP2
	WAS	IKBKG (NEMO)
	Many forms of SCID
	CD40L
	XIAP
	CGD
	LRBA
	CTLA4
	DOCK8

Nutritional Approaches

There are no quality studies assessing the use of nutritional approaches in VEO-IBD. Again, we extrapolate our therapeutic approach from older-onset pediatric IBD. For CD, especially that affecting infants with small intestinal disease, the use of exclusive enteral nutrition is a consideration for induction therapy. This can be given orally or via nasogastric or gastric tube. At present, no data support the use of nutritional therapy in UC. The Specific Carbohydrate Diet (SCD), Mediterranean diet, and newer anti-inflammatory diets are being actively investigated for management of patients with IBD. We currently do not have sufficient data to routinely recommend these to VEO-IBD patients as primary modes of therapy.

Complementary Medicine

Many caretakers are fearful of the risks associated with medications available for patients with VEO-IBD. Families often inquire about nutritional, homeopathic, or complementary approaches and seek out naturopaths and homeopaths for guidance. Physicians should encourage families to discuss the use of alternative therapies. It is important to ascertain whether alternative or complementary agents interact with prescribed therapy or cause harm (eg, CYP450 interactions, drug-induce liver injury, etc). Although we currently do not have enough information to routinely support such interventions as primary therapeutic interventions, some have more scientific validity than others. The use of curcumin has been shown to be helpful in adults with mild to moderate ulcerative colitis.⁷⁸ Though no studies have been performed in IBD—let alone VEO-IBD—cinnamon has been recognized as a potent anti-inflammatory agent.⁷⁹ Some studies have looked at the potential positive effects of fish oil in IBD, as well.^{80, 81}

Experimental Fecal Microbiota Transplantation

Although fecal microbiota transplant (FMT) is being actively studied in children with IBD, its efficacy is unclear. Only a few nonrandomized control studies have been performed in older children (youngest child 7 years old with divergent results).⁸² This is continuing to be investigated; although at this time, we do not currently have evidence of consistent benefit in VEO-IBD.⁸³ Furthermore, long-term effects of manipulating the developing microbiome are unknown.

HEALTH MAINTENANCE

Children with VEO-IBD have unique health supervision considerations, similar to all pediatric IBD patients. Several aspects are described in this section, including immunizations, bone health, skin care, and visual health.⁸⁴

Immunizations

Before starting an infant/toddler on immunomodulators or biologics, it is recommended to assure completion of their vaccination status if time permits. While evaluating infants for VEO-IBD who have not yet received their full set of immunizations, offering a trial of an exclusive elemental diet can optimize nutrition, help their inflammatory disease, and provide time to expedite catch-up immunization before initiating immunosuppression. Annual influenza vaccine and confirmation of immunization against hepatitis B are imperative. If the child did not respond to hepatitis B immunization, it is recommended they repeat the full immunization course. Titers for hepatitis B surface antibody should be rechecked within 4 to 8 weeks after the repeat immunization course. Pneumococcal 23 vaccine should be provided to children over 2 years of age as long as they complete the Prevnar 13 series. Once on an immunomodulator or biologic, children should not receive live vaccines.

Bone Health

Ensuring appropriate vitamin D and calcium intake and regular weight-bearing exercise are important for bone health in IBD, especially in patients with poor nutrition and frequent steroid use.⁸⁵ As no norms for DEXA scans exist before 3 years of age, a DEXA scan should be started at 3 years of age to assess and monitor bone density. Minimizing exposure to frequent steroid use is imperative.

Skin Care

Infants 6 months and older should use regular sunblock; we recommend at least SPF 50, especially when concurrently using immunomodulators or biologics given the slightly increased risk of skin cancer.^{86, 87} Barrier protection of skin is recommended for infants under 6 months old.

Visual Health

Children should be assessed yearly by an ophthalmologist for possible ocular manifestations of VEO-IBD, such as uveitis and episcleritis, and possible cataract formation from regular steroid use.

ONGOING RESEARCH

Very early onset IBD presents unique challenges in comparison with later-onset IBD, such as the increased risk of a monogenic disorder, anticipation of a long disease time course, and lack of clinical and scientific research in this young age group. Very early onset IBD is increasing in frequency, paralleled by an increasing awareness of the need to better understand these diseases and their management. At present, there is little data to guide optimal management of VEO-IBD. Large international efforts are in place to better understand the progression of disease over time and to ascertain the ideal therapeutic interventions. Knowledge continues to evolve on the genetics and immunologic status of patients presenting with IBD at such a young age. Very early onset IBD may represent a greater contribution of genetics, epigenetics, and early life events than later-onset IBD, as the time for environmental influences is less. Next generation sequencing has already identified a variety of novel monogenic etiologies underlying these diseases and has shed light on alternate and targeted therapies. Patients, families, and physicians are encouraged to partake in ongoing research studies. Much work is being performed on murine models of colitis, patient-derived intestinal organoids, assessment of patient microbiome, use of various diets, and antibiotics, among other promising avenues of interest. With advances in next generation sequencing, more tailored approaches can be developed to help unravel the functional genomic relevance of new variants identified. With a better understanding of the underlying genetics and pathophysiology of disease in patients with VEO-IBD, one strives to target the underlying defect directly in a personalized fashion. The Very Early Onset IBD Consortium (www.VEOIBD.org) is a helpful resource for patients, parents, and physicians, representing a large international team devoted to advancing this field.

Supported by: SBS is supported by grants from the NIH NIDDK, The Leona M. and Harry B. Helmsley Charitable Trust, the Kenneth Rainin Foundation, the Crohn’s and Colitis Foundation, the Wolpow Family Chair in IBD Treatment and Research, and the Boston Children’s Hospital Translational Investigator Service Award.

Conflicts of interest: SBS participates on the scientific advisory board for Pfizer, Janssen, Celgene, Lilly, IFM therapeutics, and Pandion Inc., he has received grant support from Pfizer, Janssen, and Novartis, and has consulted for Hoffman La Roche and Amgen.

AB has received research support (subinvestigator on protocols) from Prometheus, Janssen, Abbvie, Takeda, and Buhlmann, he has consulted for Shire, Takeda, Best Doctors, Alivio, Eli Lilly, and has received royalties and honoraria from Boston University (honorarium). MD has consulted for Janssen, Abbvie, Takeda, Pfizer, Genentech, Prometheus Lab’s, celgene, and UCB and has received grant support from Janssen, Abbvie, and Pfizer.