This article discusses non-classical forms of inflammatory bowel disease (IBD) mainly occurs in infants and very young children. Defects in every aspect of the immune system, such as neutrophils, T-cell and B-cell lymphocytes, and macrophages are associated with IBD in infants. Also, non lympho-hematopoietic defects with primary defects in enterocytes can also lead to IBD-like manifestations. Clinical vignettes are presented and the genetic origins and possible management strategies are outlined. Early evaluation of these patients is important because identification of underlying immune defects would facilitate the use of better-targeted therapy for the specific genetic defect.
Key points
- •
IBD in infant and children is rare. However, its incidence in this age group is increasing.
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Etiology of IBD in this age group is very diverse, a significant proportion of these patients have underlying primary immune defect. Many VEO-IBD have non-classical gut pathology, may not be categorized as Crohn’s disease or ulcerative colitis.
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Earnest attempt need to be made to identify underlying genetic defect in a patient with VEO-IBD. Identification of genetic defects could facilitate the use of targeted therapy in this disease that could otherwise be resistant to usual first line therapy for IBD.
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In many VEO-IBD patients with underlying primary immune defect hematopoietic stem cell transplantation could result in definitive cure.
Introduction
From conception of an embryo in the womb to end of life, the human gastrointestinal (GI) tract interfaces dynamically with the microbial environment and the host immune system. The GI system, which is the largest lymphoid and immune organ in infants and young children, is relatively sterile at birth and encounters a huge onslaught of antigens in the forms of diet and microbes during first few years of life. Robust GI tract barrier function, maturing immune function, and controlled immune tolerance are needed to maintain a healthy interface. This healthy GI mucosa is required to maintain a low-grade physiologic inflammation characterized by normal balance of immune cells, lymphocytes, and plasma cells. Therefore, defects in either mucosal barrier or immune tolerance networks results in abnormal and inappropriate innate and adaptive responses, perhaps directed against intestinal microbes or diet, resulting in mucosal injury and GI inflammation. The human GI system has limited ways to respond to insults and injury. The common form of mucosal injury is infiltration of the GI mucosa with immune cells, neutrophils, and epithelial or crypt architectural damage, which clinicians and pathologists classify under the umbrella term of inflammatory bowel disease (IBD).
The common form of IBD occurs in older children and young adults and comprises Crohn disease (CD) and ulcerative colitis, 2 distinct entities with characteristic clinical, endoscopic, and pathologic features. A subgroup of IBD occurs very early in life and is thus called very early onset IBD (VEO-IBD). Historically, the incidence of VEO-IBD in infants and children has been very low. However, due to still not well-understood reasons, the occurrence of IBD and other autoimmune disease such as type 1 diabetes mellitus has been increasing in alarming rates over the last couple of decades. The incidence of IBD in children younger than 5 years of age has grown by more than 50% over the last 10 years, hypothesized to be due to changing environmental or diet interaction with microbes and genes. Though VEO-IBD contribute to a small percentage to the overall prevalence of IBD, for proper evaluation and management it is important to recognize the salient difference between VEO-IBD and IBD presenting at the older age group. Some of these cardinal features are listed in Table 1 .
| Features | References |
|---|---|
| Chronic intestinal inflammation often tend to involve colon | |
| In a significant percentage of these patients, IBD is the presenting manifestation of underlying primary immune deficiency | |
| The pathologic features might be unclassifiable, patients have IBD-like inflammation without classic CD or ulcerative colitis pathologic features | |
| Severe course with poor response to multiple immunosuppressive medications |
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a disorder of T-cell immune tolerance, a well recognized entity in this group was first reported decades ago. It presents with multiple autoimmune manifestations, with VEO-IBD being among the most prominent clinical presentation, leading to significant diarrhea and failure to thrive. Over the last decade, multiple other defects, most importantly interleukin (IL)-10 receptor (10R) and IL-10 defects, and other monogenetic disorders and variants in the immune pathway and intestinal barrier function have been associated with VEO-IBD.
Early evaluation of these patients is important because identification of underlying immune defects would facilitate the use of better-targeted therapy for the specific genetic defect. Moreover, in a subset of carefully identified patients presenting with VEO-IBD, hematopoietic stem cell transplant (HSCT) could be curative. With more than 50 monogenetic defects that can present with VEO-IBD, evaluation and management of this condition could be challenging and time-consuming. This article presents IBD in infants and very young children as an unsolved jigsaw puzzle ( Fig. 1 ) and then describes at least 6 broad categories to partially resolve the puzzle, leaving some of the pieces yet to be filled with future discoveries.
Introduction
From conception of an embryo in the womb to end of life, the human gastrointestinal (GI) tract interfaces dynamically with the microbial environment and the host immune system. The GI system, which is the largest lymphoid and immune organ in infants and young children, is relatively sterile at birth and encounters a huge onslaught of antigens in the forms of diet and microbes during first few years of life. Robust GI tract barrier function, maturing immune function, and controlled immune tolerance are needed to maintain a healthy interface. This healthy GI mucosa is required to maintain a low-grade physiologic inflammation characterized by normal balance of immune cells, lymphocytes, and plasma cells. Therefore, defects in either mucosal barrier or immune tolerance networks results in abnormal and inappropriate innate and adaptive responses, perhaps directed against intestinal microbes or diet, resulting in mucosal injury and GI inflammation. The human GI system has limited ways to respond to insults and injury. The common form of mucosal injury is infiltration of the GI mucosa with immune cells, neutrophils, and epithelial or crypt architectural damage, which clinicians and pathologists classify under the umbrella term of inflammatory bowel disease (IBD).
The common form of IBD occurs in older children and young adults and comprises Crohn disease (CD) and ulcerative colitis, 2 distinct entities with characteristic clinical, endoscopic, and pathologic features. A subgroup of IBD occurs very early in life and is thus called very early onset IBD (VEO-IBD). Historically, the incidence of VEO-IBD in infants and children has been very low. However, due to still not well-understood reasons, the occurrence of IBD and other autoimmune disease such as type 1 diabetes mellitus has been increasing in alarming rates over the last couple of decades. The incidence of IBD in children younger than 5 years of age has grown by more than 50% over the last 10 years, hypothesized to be due to changing environmental or diet interaction with microbes and genes. Though VEO-IBD contribute to a small percentage to the overall prevalence of IBD, for proper evaluation and management it is important to recognize the salient difference between VEO-IBD and IBD presenting at the older age group. Some of these cardinal features are listed in Table 1 .
| Features | References |
|---|---|
| Chronic intestinal inflammation often tend to involve colon | |
| In a significant percentage of these patients, IBD is the presenting manifestation of underlying primary immune deficiency | |
| The pathologic features might be unclassifiable, patients have IBD-like inflammation without classic CD or ulcerative colitis pathologic features | |
| Severe course with poor response to multiple immunosuppressive medications |
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a disorder of T-cell immune tolerance, a well recognized entity in this group was first reported decades ago. It presents with multiple autoimmune manifestations, with VEO-IBD being among the most prominent clinical presentation, leading to significant diarrhea and failure to thrive. Over the last decade, multiple other defects, most importantly interleukin (IL)-10 receptor (10R) and IL-10 defects, and other monogenetic disorders and variants in the immune pathway and intestinal barrier function have been associated with VEO-IBD.
Early evaluation of these patients is important because identification of underlying immune defects would facilitate the use of better-targeted therapy for the specific genetic defect. Moreover, in a subset of carefully identified patients presenting with VEO-IBD, hematopoietic stem cell transplant (HSCT) could be curative. With more than 50 monogenetic defects that can present with VEO-IBD, evaluation and management of this condition could be challenging and time-consuming. This article presents IBD in infants and very young children as an unsolved jigsaw puzzle ( Fig. 1 ) and then describes at least 6 broad categories to partially resolve the puzzle, leaving some of the pieces yet to be filled with future discoveries.
Clinical presentation and case discussion based on pathophysiological subtypes
Depending on the extent and severity of inflammation of GI tract, infants with IBD can have varied clinical manifestations. Infantile colitis can have an insidious course, with frequent small volume diarrhea with blood and mucus. Because of this insidious onset with symptoms of mild colitis, these infants invariably undergo initial evaluation for allergic colitis and infectious colitis. Many are treated with antibiotics despite negative infectious workup and undergo multiple formula changes for presumed allergic colitis. Clinical presentation of severe enterocolitis in infants is usually much more dramatic. There is usually explosive large volume watery diarrhea and many of these patients have manifestations similar to severe acute graft-versus-host disease (GVHD) of the gut. This presentation is common in infants with IPEX and IPEX-like disorders. Pathologic findings show villous atrophy and apoptotic enterocolitis. Overlapping presentation of large volume diarrhea with blood and mucus is also common. Transmural inflammation resulting in fistulating intestinal disease can be seen in patients with defects in IL-10 signaling, X-linked inhibitor of apoptosis protein (XIAP), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to chronic granulomatous disease (CGD). Infants with IBD can also present with other clinical manifestations of autoimmunity from broader immune dysregulation. Autoimmune endocrinopathy and autoimmune cytopenia are some of the common autoimmune manifestation seen in patients with IPEX and IPEX-like disorders presenting with VEO-IBD.
Serious and opportunistic infections can also be another associated manifestation because many monogenic primary immune deficiency disorders present with IBD. Recognizing the underlying immune defect could help in identifying the cause of infantile-onset IBD (eg, a Serratia marcescens abscess on the scalp of an infant with IBD would lead us to the diagnosis of CGD). There are also nonimmune somatic defects in many of the disorders that present with IBD in infants. Knowing these finding could be of immense help in the diagnosis of the underlying genetic condition. For example, infants with nuclear factor-kappa B (NF-κB) essential modulator (NEMO) deficiency usually have a varying degree of ectodermal dysplasia, sparse and brittle hair, and conical teeth, along with IBD.
Defects in every aspect of the immune system, such as neutrophils, T-cell and B-cell lymphocytes, and macrophages, are associated with IBD in infants. Also, nonlymphohematopoietic defects with primary defects in enterocytes can also lead to IBD-like manifestations. Based on the pathophysiology, VEO-IBD can be categorized as
- 1.
Defects in T-cell immune tolerance (IPEX and IPEX-like disorders)
- 2.
Defects in IL-10 signaling
- 3.
Hyperinflammatory disorders (defect in T-cell cytotoxicity or inflammasome)
- 4.
Defects in neutrophil function
- 5.
Defects in epithelial barrier function
- 6.
Isolated or combined T-cell and B-cell defects.
Defects in T-cell immune tolerance
A 2-week-old breastfed infant presented with acute onset large volume watery diarrhea requiring hospitalization and intravenous fluid resuscitation. Over the next 2 weeks he became significantly malnourished and had multiple bouts of significant dehydration from large-volume diarrhea. At 1 month of age, he was also diagnosed to have type 1 diabetes mellitus. He was also noted to have eczematous dermatitis, elevated immunoglobulin (Ig)-E, and peripheral eosinophilia. Laboratory screen for autoantibodies revealed features of autoimmune thyroiditis with high antithyroglobulin antibodies and elevation of IgG tissue transglutaminase antibodies. His duodenal biopsy showed total villous atrophy with mucosal lymphocytic and eosinophil infiltration with apoptosis of epithelial cells and significant depletion of goblet cells mimicking GVHD-like pathologic findings. Based on these findings, a diagnosis of IPEX was suspected. Further work-up revealed marked decrease in T-regulatory (Treg) cells and mutational analysis revealed known mutations in the FOXP3 gene. He received pulse steroids followed by sirolimus with significant improvement in watery diarrhea. He underwent a reduced-intensity HSCT from an unaffected matched sibling. He is currently doing well with resolution of GI symptoms and no new autoimmune manifestations.
Mutations in FOXP3 result in either absent or decreased Treg cell numbers or a qualitative defect in Treg cells, resulting in reduced Treg cell suppressive activity ( Fig. 2 ). This defect results in broader immune dysregulation, resulting in multisystem autoimmunity with autoimmune endocrinopathy, autoimmune cytopenia, autoimmune hepatitis, and severe eczema. Though classic IPEX presents in infancy, depending on the residual protein function, IPEX can present with varying severity of GI involvement. The varying presentation and variable age of onset resulting in disease heterogeneity and phenotype is attributed to the location of the mutation within the FOXP3 gene. The FOXP3 gene is located in the X chromosome, hence male infants are affected but female infants with 1 copy of the gene also exhibit IPEX-like disorders albeit mild disease phenotype. There are many IPEX-like disorders resulting from mutations directly affecting Treg cell development, such as mutation in CD25 and signal transducer and activator of transcription (STAT)-5b . However, a qualitative defect in Treg cell numbers and function resulting in VEO-IBD have also been reported in other immune dysregulation disorders such as STAT-1 gain-of-function (GOF) mutation, STAT-3 GOF mutation, lipopolysaccharide responsive beige-like anchor protein (LRBA) deficiency, and cytotoxic T-lymphocyte-associated protein (CTLA)-4 haploinsufficiency.
Defects in interleukin-10 signaling
An 8-week-old female infant presented with the history of bloody diarrhea and failure to thrive. She had 1 hospital admission for documented bacterial sepsis. She had developed perianal enterocutaneous fistula and an abscess needing surgical drainage and antibiotics. Colonoscopy revealed severe discontinuous colitis with deep ulceration. Histology showed nonspecific acute colitis with dense neutrophilic infiltrates. The systemic examination is significant for deep oral aphthous ulcers and folliculitis. The immune evaluation showed normal T, B, and natural killer (NK) cells with normal proliferative response to mitogens. She had elevated IgA and IgG, and normal IgM, and a neutrophil oxidative burst test was normal. Based on the severe fistulating colitis, a STAT3 phosphorylation study was done that showed normal phosphorylation to IL-6 and no STAT3 phosphorylation to IL-10, suggestive of IL-10R defect. Further, genetic testing (mutation testing) confirmed the presence of the mutation in IL-10R-α. She later underwent allogeneic HSCT with complete resolution of colitis and resolution of perianal enterocutaneous fistula.
A few dozen cases are reported in the literature in IL-10 or IL-10R defects resulting in severe infantile colitis mimicking IBD ( Fig. 3 ). In addition to colitis and fistulating perianal disease, additional clinical manifestations include recurrent infections, folliculitis, and arthritis. A high degree of consanguinity is reported because both copies of IL-10 and IL-10R need to be mutated for this autosomal recessive condition to occur. IL-10 is an important immunomodulatory cytokine. Through its effects on the innate and adaptive immune systems, it maintains mucosal immune tolerance in the GI tract. Its immune modulatory effects are, in part, mediated by promoting Treg cell function and by modulating macrophage to a more antiinflammatory phenotype. Hence, deleterious mutations in IL-10 or its receptor results in the breakdown of immune tolerance and skewed proinflammatory macrophage phenotype with excess IL-1β production, leading to inflammation in GI tract. Patients with IL-10, IL-10RA, and IL-10RB have similar disease phenotype. Recently, increased risk of non-Hodgkin lymphoma is also recognized in these patients.
Hyperinflammatory disorders (defect in T-cell cytotoxicity or inflammasome)
A 12-month-old male infant presented with history of diarrhea, weight loss, and perianal abscess. The abscess failed to heal despite surgical drainage and several courses of antibiotics. His clinical history is also significant for several episodes of self-limiting high-grade fever, variable cytopenia, and mild-to-moderate elevation of liver enzymes. His growth was significantly stunted and he was malnourished (all growth parameters were less than third centile). Further evaluation revealed perianal fistulae with additional deep fissures. Endoscopy showed features of active colitis. Colonoscopic or histologic findings from biopsies were similar to CD pathologic findings with skip lesions, deep linear ulcerations, and chronic inflammation with crypt architectural changes but without granulomas. Despite multiple immunosuppressive and biologic medications for 6 months he had no improvement in IBD. He eventually underwent total abdominal colectomy and end ileostomy. He had extensive immune evaluation, which showed normal neutrophil oxidative burst, lymphopenia with inverted CD4/CD8 ratio, normal percentage of naïve T cells, and decreased NK cell cytotoxicity. His ferritin was elevated at 7286 ng/mL (normal <79 ng/mL) and serum IL-18 was elevated. Flow cytometry-based XIAP protein expression was markedly decreased. Follow-up mutation testing showed he has a known mutation in baculovirus inhibitor of apoptosis repeat containing protein 4 (BIRC4) gene-encoding XIAP protein, leading to markedly decreased XIAP protein expression.
Hyperinflammation could either result from a defect in inflammasome pathway or a defect in T-cell and NK-cell cytotoxicity ( Fig. 4 ). Mutation in BIRC4 results in XIAP deficiency. It is increasingly considered as an inflammasome disorder. In the physiologic state, normal XIAP protects from toll-like receptor and tumor necrosis factor (TNF)-driven inflammasome formation and cell death. Defects in XIAP lead to exaggerated IL-1β and IL-18 secretion, and cell death. A significant percentage of these patients present with recurrent fever and enteropathy, progressing to fistulating VEO-IBD. Recently, GOF mutation in an important inflammasome protein NOD-Like Receptor C4 (NLRC4) is reported to be associated with neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. Recurrent fever and colitis can also been seen in other autoinflammatory periodic fever syndromes, such with mevalonate kinase deficiency.
Usually, defects in T-cell and NK-cell cytotoxicity lead to primary hemophagocytic lymphohistiocytosis (HLH). Primary HLH from defects in syntaxin-binding protein 2 (STXBP2) are known to present with significant colitis and diarrhea. In some cases, the onset of diarrhea could precede the development of HLH. In many cases, the control of hyperinflammation usually controls to diarrhea. A similar presentation can also be seen in Hermansky-Pudlak syndrome, which is an extremely rare autosomal recessive disorder resulting in oculocutaneous albinism (decreased pigmentation) and bleeding problems due to a platelet abnormality (platelet storage pool defect).
Defects in neutrophil function
An 8-month-old male infant presented with complaints of blood in stool since 1 week of age and new left inguinal lymphadenopathy for the last 2 weeks. Given his bright red blood in stool and diarrhea, he has had multiple formula changes. Diarrhea slightly improved on soy-based formula. However, he continued to have blood and mucus stools 7 times a day. Stool calprotectin was 1479 μg/gm (normal <100). Immunoglobulin profile showed elevation in IgA and IgG. The left inguinal budging was later diagnosed as cold abscess from Staphylococcus aureus . Because the abscess caused by commensal skin bacteria, along with IBD-like symptoms, CGD as a diagnosis was considered. Dihydrorhodamine (DHR) testing showed absent neutrophil oxidative burst suggestive of X-linked CGD. Genetic testing showed mutations in Cytochrome B(558) Alpha(CYBA) gene consistent with the molecular diagnosis for CGD.
CGD is a result of defective phagocytosis, specifically in the granulocytes responsible for bacterial killing and clearance ( Fig. 5 ). The NADPH oxidase complex that is responsible for killing ingested bacteria through the production of respiratory burst. Mutation involving NADPH complex (CYBA, CYBB, neutrophil cytosolic factor [NCF]-1, NCF2, NCF4) present with CGD and intestinal inflammation similar to VEO-IBD can be seen up to 40%. Recently, even missense variant in the NCF2 gene and NADPH oxidases are associated with VEO-IBD. Patients with CGD often present during infancy with colitis, severe perianal disease, hepatosplenomegaly, abscesses, and fistulas. Histology from intestinal biopsies may show well-formed granulomas but the main clue with CGD that differentiates it from CD is that in CGD the granulomas are not associated with surrounding mucosal inflammation. Early diagnosis showing absence or very low oxidative burst with DHR tests is essential because some of the established IBD therapies, such as anti-TNF, may increase the risk of serious infections in CGD. Colitis resulting from defective neutrophils is also seen in patients with glycogen storage disease type 1b, leukocyte adhesion defect type 1, and other less common defects highlighted in Table 2 .
| Defects | Gene Defect | Extra Intestinal Immune, Hematologic, or Somatic Manifestations | Laboratory Findings and Functional Evaluation |
|---|---|---|---|
| IPEX and IPEX-like disorders | |||
| IPEX | FOXP3 | Autoimmune endocrinopathy, cytopenia, hepatitis and kidney disease, eczema, food allergy, eosinophilia | Decrease in Treg cells number and function Decreased Foxp3 expression |
| CD25 deficiency | CD25 | Autoimmune endocrinopathy, cytopenia, eczema, gingivitis, alopecia universalis, bullous pemphigoid, CMV, EBV disease | Absent CD25 expression |
| STAT5b deficiency | STAT5B | Autoimmune endocrinopathy, eczema, short stature, interstitial pneumonitis, alopecia universalis, bullous pemphigoid, varicella and herpes zoster infections | Variable immune abnormality Normal to low T, B, and NK cells |
| STAT1 GOF mutation | STAT1 | Mucocutaneous candidiasis, short stature, eczema, autoimmune endocrinopathy, sinopulmonary infection, hypertension, aneurysm | Most have normal Treg cell number and Foxp3 expression, abnormal STAT1 phosphorylation studies |
| STAT3 GOF mutation | STAT3 | Multisystem autoimmunity, variable short stature, lymphoproliferation | Hypogammaglobulinemia Decreased class switched memory B cells |
| LRBA deficiency | LRBA | Multisystem autoimmunity, cytopenia, arthritis, recurrent sinopulmonary infection, granuloma, hypogammaglobulinemia | Hypogammaglobulinemia Decreased class switched memory B cells |
| CTLA4 haploinsufficiency | CTLA4 | Diarrhea, enteropathy, hypogammaglobulinemia, granulomatous lymphocytic interstitial lung disease, multisystem autoimmunity | Hypogammaglobulinemia Decreased class switched memory B cells |
| Defects in IL-10 signaling | |||
| Defects in IL-10 and IL-10R | IL-10RA IL-10RB IL-10 | Perianal fistula, folliculitis, arthritis, abscess, lymphoma | STAT3 phosphorylation by IL-6 and IL-10 studies a |
| Defects in neutrophil function | |||
| CGD | CYBB CYBA NCF1 NCF2 NCF4 | Perianal fistula, recurrent cold abscess from catalase positive organisms, b gastric outlet obstruction | Decreased neutrophil oxidative burst study Elevated IgG |
| Glycogen storage disease 1b | SLC37A4 | Recurrent bacterial infections, hypoglycemic seizures, hepatomegaly | Neutropenia, hypoglycemia, hyperuricemia, hyperlipidemia |
| Leukocyte adhesion defect | ITGB2 | Neutrophilia, recurrent bacterial infections, delayed separation of umbilical cord, poor wound healing | Leukocytosis Absent CD18 expression |
| Congenital neutropenia | G6PC3 | Cutaneous vascular malformation and cardiac defect | Severe neutropenia |
| Hyperinflammatory disorders | |||
| XIAP | BIRC4 | Perianal fistula, recurrent HLH, EBV, and CMV infections, hypogammaglobinemia | Markedly elevated IL-18 Decreased or absent XIAP protein expression by flow |
| NLRC4 GOF mutation | NLRC4 | Recurrent macrophage activation, rash | Markedly elevated IL-18 |
| Mevalonate kinase deficiency | MVK | Recurrent fever, rash, abdominal pain and emesis | Elevated inflammatory markers Elevated IgD Elevated urine mevalonate |
| Familial Mediterranean fever | MEFV | Recurrent fever, abdominal pain, arthralgia, peritonitis | Elevated inflammatory markers |
| Familial HLH type 5 | STXBP2 | HLH, hypogammaglobinemia, sensorineural hearing loss | Marked elevated ferritin and sIL-2R Decreased CD107a degranulation |
| Hermansky-Pudlak syndrome | HPS1 HPS4 HPS6 | Partial albinism, bleeding tendency, recurrent infection and immunodeficiency | Decreased CD107a degranulation |
| Defects in epithelial barrier function | |||
| TTC7A deficiency | TTC7A | Varying degree of intestinal atresia, T-cell immune defect and recurrent infections | Mild to severe T-cell immune deficiency Hypogammaglobinemia |
| X-linked ectodermal immunodeficiency (NEMO deficiency) | IKBKG | Varying degree of ectodermal dysplasia, conical teeth, space and brittle hair, recurrent bacterial, viral and mycobacterial infections | Hypogammaglobinemia Decreased class switched memory B cells |
| ADAM17 deficiency | ADAM17 | Neonatal inflammatory skin and bowel disease, generalized pustular rash | Normal T-cell and B-cell numbers |
| Dystrophic epidermolysis bullosa | COL7A1 | Blistering disorder primarily affect the hands, feet, knees, and elbows | Unremarkable immune findings |
| Kindler syndrome | FERMT1 | Acral skin blistering, photosensitivity, progressive poikiloderma, and diffuse cutaneous atrophy | Eosinophilia |
| Isolated or combined T-cell and B-cell immune defects | |||
| X-Linked agammaglobulinemia | BTK | Recurrent sinopulmonary infection | Absent B cells in peripheral blood Absent plasma cells in tissue Decreased class switched memory B cells |
| Common variable immune defect (CVID) | Heterogeneous group of defects with sinopulmonary infections, autoimmunity, lymphoproliferation, and variable T cell immune defect | Hypogammaglobinemia Variable T-cell lymphopenia | |
| X-linked hyper IgM (CD40L) | CD40L | Sclerosing cholangitis, cryptosporidium diarrhea and pneumocystis infection | Elevated or normal IgM, neutropenia Absent class switched memory B cells |
| Wiskott-Aldrich syndrome | WAS | Eczema, recurrent infection, autoimmunity, vasculitis | Microthrombocytopenia Variable lymphopenia, low IgM Decreased WAS protein |
| Leaky SCID or Omenn | RAG1, RAG2 IL-7Ra IL-2RG | Generalized erythroderma, hepatosplenomegaly, lymphadenopathy | Eosinophilia T-cell lymphopenia Decreased naïve T cells |
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