Chronic Granulomatous Disease Research Articles

Detoxification of reactive oxygen species by the hyaluronic acid capsule of group A Streptococcus.

The pro-inflammatory cytokine IL-6 regulates antimicrobial responses that are broadly crucial in the defense against infection. Our prior work shows that IL-6 promotes the killing of the M4 serotype group A Streptococcus (GAS) but does not impact the globally disseminated M1T1 serotype associated with invasive infections. Using in vitro and in vivo infection models, we show that IL-6 induces phagocyte reactive oxygen species (ROS) that are responsible for the differential susceptibility of M4 and M1T1 GAS to IL-6-mediated defenses. Clinical isolates naturally deficient in capsule, or M1T1 strains deficient in capsule production, are sensitive to this ROS killing. The GAS capsule is made of hyaluronic acid, an antioxidant that detoxifies ROS and can protect acapsular M4 GAS when added exogenously. During in vitro interactions with macrophages and neutrophils, acapsular GAS can also be rescued with the antioxidant N-acetylcysteine, suggesting this is a major virulence contribution of the capsule. In an intradermal infection model with gp91phox -/- (chronic granulomatous disease [CGD]) mice, phagocyte ROS production had a modest effect on bacterial proliferation and the cytokine response but significantly limited the size of the bacterial lesion in the skin. These data suggest that the capsule broadly provides enhanced resistance to phagocyte ROS but is not essential for invasive infection. Since capsule-deficient strains are observed across several GAS serotypes and are competent for transmission and both mild and invasive infections, additional host or microbe factors may contribute to ROS detoxification during GAS infections.

Successful treatment of disseminated granuloma annulare with adalimumab

Granuloma annulare (GA) is a chronic inflammatory necrobiotic granulomatous skin disease, which is based on a delayed hypersensitivity reaction caused by the production of interferon- (IFN-) by tissue macrophages and th1-limocytes, tumor necrosis factor- (TNF-) and matrix metalloproteinases (MMP), which leads to the degradation of connective tissue.
 The most frequent form of GA if localized which is characterized clinically by grouped papules and plaques of red or pink color on the extremities. although disseminated variants of disease occur in 15% of all cases of ag. in contrast to the practically asymptomatic course of the localized form, typical signs of disseminated form are intensive sense of itching, the presence of at least ten foci of skin lesions, recurrent and resistance to treatment course.
 A 53-year-old female patient with a long-term recurrent course of annular granuloma after a weak clinical response to therapy with pentoxifilin, methotrexate and azathioprine turned to the dermatology department of the university hospital. In light of the lack of satisfactory treatment options anti-cytokine therapy with adalimumab was recommended at a daily dosage of 80 mg, once a week, for 2 weeks, then 1 time every two weeks for 1.5 months. Already on the 5th day after receiving the first injection, the patient reported that the feeling of itching disappeared. By the end of the second week of the induction phase of biotherapy, it became obvious that new rashes did not appear, and the old elements of the skin rash had significantly flattened, turned pale and decreased in volume. After the second week of consolidated therapy, the dermatologist confirmed the convalescence.

Aspergillus fumigatus cytochrome c impacts conidial survival during sterilizing immunity.

Aspergillus fumigatus can cause a life-threatening infection known as invasive pulmonary aspergillosis (IPA), which is marked by fungus-attributable mortality rates of 20%-30%. Individuals at risk for IPA harbor genetic mutations or incur pharmacologic defects that impair myeloid cell numbers and/or function, exemplified by bone marrow transplant recipients, patients that receive corticosteroid therapy, or patients with chronic granulomatous disease (CGD). However, treatments for Aspergillus infections remain limited, and resistance to the few existing drug classes is emerging. Recently, the World Health Organization classified A. fumigatus as a critical priority fungal pathogen. Our cell death research identifies an important aspect of fungal biology that impacts susceptibility to leukocyte killing. Furthering our understanding of mechanisms that mediate the outcome of fungal-leukocyte interactions will increase our understanding of both the underlying fungal biology governing cell death and innate immune evasion strategies utilized during mammalian infection pathogenesis. Consequently, our studies are a critical step toward leveraging these mechanisms for novel therapeutic advances.

SAT560 A Case of Medullary Thyroid Carcinoma with Increasing Carcinoembryonic Antigen and Stable Calcitonin Levels

Abstract Disclosure: K.N. Youssef: None. L. Salej: None. A. Gavrila-Filip: None. Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from the parafollicular or C cells of the thyroid gland that secretes different tumor markers, including calcitonin (CT) and carcinoembryonic antigen (CEA). CT is only produced by parafollicular cells, while CEA is a non-specific marker produced in various normal tissues, such as epithelial cells of the gastrointestinal tract, lung, breast, and prostate. Different benign and malignant conditions are associated with elevated serum CEA levels. Clinical case: A 69 years-old active smoker male with a history of nasal squamous cell carcinoma (SCC) status post resection in the remote past and bilateral pulmonary nodules underwent total thyroidectomy for a thyroid nodule with FNA positive for medullary carcinoma. Surgical pathology revealed a unifocal 1.5 cm medullary carcinoma with clean surgical margins and no lymphadenopathy. Pre-operative studies included an elevated serum CT of 388 pg/mL (normal ≤ 10 pg/mL), normal serum calcium and PTH levels and a normal 24-hour urinary test for pheochromocytoma. Family history was irrelevant, and the RET proto-oncogene test was negative. Initial post-operative serum CT levels were undetectable and CEA levels were normal (0-4 ng/mL). CT levels increased slowly over the next five years and then they remained stable in the range of 32 to 45 pg/mL. Serum CEA started to rise progressively 7 years after the thyroid surgery up to 6.5 pg/mL. Follow-up neck ultrasounds showed no local recurrence or lymphadenopathy. An extensive evaluation was performed to search for possible MTC metastases and other etiologies for the elevated CEA levels. Bone scan was negative. Chest CT scans revealed enlarging small bilateral pulmonary nodules; stable calcified mediastinal lymph nodes were noted, consistent with chronic granulomatous disease. PET-CT scan showed pulmonary nodules, too small to characterize. The patient underwent a left lower pulmonary lobe robotic-assisted wedge resection. Surgical pathology revealed keratinizing SCC, though to represent primary lung SCC versus metastases from his prior nasal SCC. Upper endoscopy and colonoscopy with biopsy were negative for malignancy. On further workup, the patient was diagnosed with prostate adenocarcinoma and underwent surgery followed by external beam radiation with hormonal therapy. Serum CEA levels normalized one year after the prostate cancer treatment. Serum CT levels remained stable. Conclusion: In patients with MTC who show increasing serum CEA and stable CT levels during follow-up after the initial treatment, it is important to exclude other etiologies before concluding that this change is related to a progression of the medullary cancer. Reference: Carcinoembryonic Antigen. Kankanala VL, Mukkamalla SKR.2022 Jan 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Presentation Date: Saturday, June 17, 2023

Phenotypic Variability in PRKCD: a Review of the Literature.

Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome-related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency. Literature review was performed using MEDLINE. Twenty cases have been described in the literature with significant heterogeneity. The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.

NOX2 deficiency enhances priming and activation of the NLRP3 inflammasome

Nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2) deficiency, or chronic granulomatous disease (CGD), is an inborn error of immunity associated with increased susceptibility to infection and inflammatory manifestations. The pathophysiologic mechanism leading to the increased inflammatory response in CGD remains elusive. We investigated the pathophysiologic mechanisms leading to NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in NOX2 deficiency. We used NOX2-deficient human primary and CRISPR-engineered macrophages to show that NOX2 deficiency enhances the inflammatory response mainly by modulating the 2 steps of NLRP3 inflammasome activation: its transcriptional priming and its posttranslational triggering. At the transcriptional level, NOX2-deficient phagocytes display increased priming of the NLRP3 inflammasome, as evidenced by increased transcription of NLRP3 and IL-1β through an IL-1β-dependent stimulation of the nuclear factor kappa-light-chain enhancer of activated B cells (aka NF-κB) pathway. At the posttranslational level, the absence of NOX2 triggers the NLRP3 inflammasome activation by increased K+ efflux and excessive release of mitochondrial DNA due to mitochondrial damage. Furthermore, NLRP3-driven pyroptosis in NOX2-deficient phagocytes further enhances NLRP3 activation by increasing K+ efflux. Our results unveil the role of NOX2 as a repressor of the inflammatory response at both transcriptional and posttranslational levels and pave the way for a more targeted approach to treating CGD patients with inflammatory manifestations.

Carrier State of Chronic Granulomatous Disease Presented at Middle Age: A Case Report

Introduction: Chronic granulomatous disease (CGD) is the most common inherited defect of phagocytes. Although most female carriers of X-linked CGD have been considered to be unaffected, they may have similar problems to those of CGD patients. This study suggests that the CGD carrier state might be more complex than it was previously appreciated. Case Presentation: A sixty-year-old woman visited our hospital in June 2021 due to pneumonia and pleural effusion. Chest computed tomography scan revealed left lower lobe pneumonia and mediastinal lymphadenopathies. In July 2021, her symptoms (high-grade fever, chills, and hemoptysis) were initially attributed to a hydatid cyst. Therefore, she underwent a lobectomy, resulting in purulent drainage on the excision site on the skin, refractory to local and systemic treatments. The refractory and recurrent nature of the lesions led to the immunological evaluation, which was completely normal with a 100% nitroblue tetrazolium (NBT) and a dihydrorhodamine (DHR) of 278 (normal > 100). Further DHR123 flow cytometry investigations with multiple stimulants revealed a carrier state of CGD, which was relevant to her history of chronic complications. Conclusions: Adult patients with unusual manifestations suggestive of neutrophil function defects in adulthood should be evaluated for the CGD carrier state. In these cases, NBT alone may miss the diagnosis of CGD. In such cases, DHR testing with multiple stimulants may establish a robust diagnosis.

Small bowel disease prevalence on video capsule endoscopy in chronic granulomatous disease-associated inflammatory bowel disease.

Patients with chronic granulomatous disease (CGD) may develop inflammatory bowel disease (IBD). Characterization of small bowel disease in this cohort is scarce. Here, we sought to determine the prevalence and characteristics of small bowel disease and evaluate the clinical utility of video capsule endoscopy (VCE) for its diagnosis. A retrospective study was performed on patients with CGD who were evaluated for gastrointestinal disease with VCE as a part of ongoing natural history studies at a single academic center. VCEs were reviewed for inflammatory findings and severity of disease utilizing the Capsule Endoscopy Crohn's Disease Activity Index. Radiographic studies and endoscopies performed within 30days of VCE were compared with small bowel inflammatory findings. Twenty-six VCEs corresponding to 25 patients were found. The majority of patients were male and White; mean age was 28years old. The majority (85%) demonstrated presence of small bowel inflammatory findings on VCE including strictures, ulcers, erosions, and erythema. Duodenal and ileal inflammatory disease on endoscopy did not correlate with disease on VCE. Moderate-severe colonic disease correlated with moderate-severe disease on VCE. Radiography did not correlate with disease on VCE. Prolonged small bowel transit time correlated with moderate-severe small bowel disease. Small bowel IBD was highly prevalent in this cohort of patients with CGD. Limitations included small sample size. Given that radiology and duodenal/ileal disease did not correlate with VCE findings, VCE-driven investigation of small bowel disease should be considered in patients with CGD-associated IBD, particularly those with colonic disease.

Pathogens of first-episode pulmonary infection in 141 children with chronic granulomatous disease.

Pathogens of first-episode pulmonary infection in 141 children with chronic granulomatous disease.

Haematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include Staphylococcus aureus and Burkholderia cepacia complex. Fungal pathogens include Aspergillus species, particularly Aspergillus fumigatus. Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970's. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD.

Spontaneous NETosis and type I IFN signaling activation in resting neutrophils of chronic granulomatous disease patients with CYBB mutations

Spontaneous NETosis and type I IFN signaling activation in resting neutrophils of chronic granulomatous disease patients with CYBB mutations

The Radiological Manifestations of Phagocytic Primary Immunodeficiencies in Children.

Primary immunodeficiencies are a diverse group of rare genetic disorders, among which phagocytic dysfunction impairs neutrophil function in a wide range of inherited disorders. Due to the heterogeneity of the disorders a multidisciplinary approach is often required for early diagnosis and initiation of appropriate treatments. The aim of this study was to evaluate the imaging findings in children admitted with phagocytic primary immunodeficiencies. Thirty-five children who fulfilled the inclusion criteria for phagocytic dysfunction were enrolled in this study. The patients were under close observation and monitoring from January 2011 until data locking in December 2017. The diagnosis of phagocytic immunodeficiency was confirmed by the patient's clinical course, presentation features, and laboratory data. Among the 35 patients studied, the most frequent condition was chronic granulomatous disease (CGD) (23 patients), followed by different types of neutropenia (8 patients) and Job's syndrome (4 patients). Mediastinal and hilar lymphadenopathies and consolidation were the most frequent presentations. There was a significant relationship between mediastinal/hilar lymphadenopathies and fungal infections. A meaningful relationship was also found between pulmonary noduleswithout halo signs in patients with concomitant tuberculosis and fungal infections. A significant correlation was found between CGD, pulmonary fibrotic changes, and mediastinal lymphadenopathies. The most frequent radiological manifestations in children included mediastinal and hilar consolidations. Physicians' awareness of the radiological and clinical manifestations of these inherited diseases may be helpful in the early diagnosis and timely initiation of specific prophylaxis measures to prevent infections and also to initiate hematopoietic stem cell transplantation as the curative management modality.

PvgAS: A novel two-component system that controls type III and type VI secretion systems and virulence in the fish pathogen Pseudomonas plecoglossicida

Pseudomonas plecoglossicida is a Gram-negative bacterium that causes chronic granulomatous diseases in fish. However, the molecular mechanisms underlying its pathogenicity are poorly understood. Here, we identified a novel two-component system (TCS) named PvgAS in P. plecoglossicida, which regulates the expression of genes including the type VI secretion system-1 (T6SS-1), a key virulence factor, as well as the type III secretion system (T3SS) gene cluster and several genes associated with metabolic pathways. We showed that PvgAS is essential for bacterial virulence in large yellow croaker (LYC), an important aquaculture species, by controlling T6SS-1 expression, which is crucial for tissue colonization and intracellular survival. In contrast, T3SS was dispensable for P. plecoglossicida virulence in this model. We also confirmed T6SS-1 gene regulation by PvgAS at the transcriptional and translational levels using RNA-seq, RT-qPCR, lacZ reporter, and western blot assays. Our study reveals a regulatory and functional role of PvgAS in P. plecoglossicida pathogenicity and suggests that PvgAS may be a potential target for new therapeutic interventions against this bacterium.

Peripheral T Cell Populations are Differentially Affected in Familial Mediterranean Fever, Chronic Granulomatous Disease, and Gout

Both innate errors of immunity, such as familial Mediterranean fever (FMF) and chronic granulomatous disease (CGD), and the common inflammatory disease gout are characterized by episodes of sterile inflammatory attacks in the absence of an infection. While these disorders encompass distinct pathologies due to differentially affected metabolic pathways and inflammasome activation mechanisms, their common features are the excessive production of interleukin (IL)-1ß and innate immune cell hyperreactivity. On the other hand, the role of T cells and innate-like lymphocytes such as gamma delta (γδ) T cells in these pathologies is ill-defined. In order to widen our understanding of T cell involvement in CGD, FMF and gout pathology, we developed multicolour immunophenotyping panels for flow cytometry to characterize γδ T cells as well as CD4 and CD8 T cell populations in terms of their cytokine production, activation status, memory or naive phenotypes, exhaustion status, homing receptor expression, and cytotoxic activity. Our study is the first deep immunophenotyping analysis of T cell populations in CGD, FMF, and gout patients. We found that CGD affects the frequencies and activation status of T cells, while gout impairs the cytokine production capacity of Vδ2 T cells. FMF was characterized by decreased percentages of regulatory T cells in circulation and attenuated IFN-γ production capacity by Vδ2 T cells. Autoinflammatory syndromes and congenital defects of phagocyte differentially affect T cell compartments. Future studies are warranted to assess whether these phenotypical changes are relevant for disease pathology.

Cabergoline and Low-Dose Steroid Therapy İn Idiopathic Granulomatous Mastitis

Introduction: Idiopathic granulomatous mastitis(IGM) is a rare, chronic granulomatous inflammatory disease of the breast. It is mostly seen in young women with a history of breastfeeding. It typically presents as a painful lump in the breast, erythema, focal abscess formation, skin ulceration, or fistula. The etiology and pathogenesis of IGM could not yet be well understood. It is thought to be caused by a localized autoimmune response against fat and protein-rich secretions leaking from the lobules due to previous hyperprolactinemia. There is no definite treatment protocol defined for IGM. Pharmacological agents and surgical interventions are used alone or in combination in the treatment. In this study, we aimed to examine the results of patients who were treated with cabergoline and low-dose steroids for IGM in our center.
 Methods: In this study, the files of patients who were treated with cabergoline and steroids for idiopathic granulomatous mastitis in our clinic were reviewed retrospectively. 36 patients were included in the study. The patients were invited to the outpatient clinic for the final examination. Demographic characteristics of the patients, symptoms at presentation, examination findings, laboratory tests, radiological imaging, tru-cut biopsy results, microbiological culture results, treatment doses and durations, remission times, surgery requirements, and recurrence were recorded.
 Results: All 36 patients included in the study were women of childbearing age. The most common presenting complaint was a palpable painful mass. Abscesses were present in 12 patients. Ulcers were observed in 9 patients and fistulas were observed in 4 patients. The most common involvement was in the lower outer quadrant. S.aureus was detected in the culture of 1 patient. Complete recovery was observed in 20 of 36 patients as a result of the treatment. The mean duration of remission was 2.85±2.54 months. The treatment of 29 (74.3%) patients was completed medically. Surgical excision was performed in 7 patients with a residual lump. No recurrence was observed during the follow-up period of 27.88 ± 8.21 months.
 Conclusion: The treatment of IGM is still controversial. The fact that cabergoline and low-dose steroid therapy provides remission in a short time, minimizes the need for surgery, and does not relapse in medium-term follow-up shows that it is a successful option in IGM treatment.

Discoid lupus erythematosus associated with chronic granulomatous disease

To the Editor, Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder in which a reduced activity of nicotinamide dinucleotide phosphate (NAPDH) oxidase leads to defective reactive oxygen intermediates (ROS) and impairs intracellular killing of microorganisms. Patients have recurrent bacterial and fungal infections as well as granuloma formations, and have a higher risk of autoimmune and inflammatory disorders like lupus erythematosus.1 A 20-year-old caucasian male with a diagnosis of autosomal recessive CGD was referred to our hospital because of a pruritic photosensitive rash on the face and hands, present for more than a year. [...]

Myelodysplasia after clonal hematopoiesis with APOBEC3-mediated CYBB inactivation in retroviral gene therapy for X-CGD

Stem cell gene therapy using the MFGS-gp91phox retroviral vector was performed on a 27-year-old patient with X-linked chronic granulomatous disease (X-CGD) in 2014. The patient's refractory infections were resolved, whereas the oxidase-positive neutrophils disappeared within 6months. Thirty-two months after gene therapy, the patient developed myelodysplastic syndrome (MDS), and vector integration into the MECOM locus was identified in blast cells. The vector integration into MECOM was detectable in most myeloid cells at 12months after gene therapy. However, the patient exhibited normal hematopoiesis until the onset of MDS, suggesting that MECOM transactivation contributed to clonal hematopoiesis, and the blast transformation likely arose after the acquisition of additional genetic lesions. In whole-genome sequencing, the biallelic loss of the WT1 tumor suppressor gene, which occurred immediately before tumorigenesis, was identified as a potential candidate genetic alteration. The provirus CYBB cDNA in the blasts contained 108 G-to-A mutations exclusively in the coding strand, suggesting the occurrence of APOBEC3-mediated hypermutations during the transduction of CD34-positive cells. A hypermutation-mediated loss of oxidase activity may have facilitated the survival and proliferation of the clone with MECOM transactivation. Our data provide valuable insights into the complex mechanisms underlying the development of leukemia in X-CGD gene therapy.

Infections due to Salmonella sp. in children with chronic granulomatous disease: Our experience from North India

Infections with non-typhoidal Salmonella sp. have been documented in children with chronic granulomatous disease (CGD), but the prevalence of salmonella infection in children with CGD in underdeveloped countries is unknown. We assessed the clinical profiles of CGD patients diagnosed at our tertiary care centre in north India and had Salmonella sp.infections. We found three patients with Salmonella sp. bloodstream infections (2-proven, 1-probable) among the 99 CGD patients. After receiving cotrimoxazole prophylaxis following a CGD diagnosis, we noted that none of our patients experienced non-typhoidal salmonella infection. One patient experienced severe typhoidal bacteremia despite receipt of cotrimoxazole prophylaxis. This patient required numerous hospital admissions and prolonged intravenous antibiotic regimen. We suggest that vaccination with killed typhoidal vaccines should be regularly given to children with CGD in order to avoid typhoidal bacteremia, in addition to cotrimoxazole prophylaxis and a focus on good hand and food hygiene.

Who's your data? Primary immune deficiency differential diagnosis prediction via machine learning and data mining of the USIDNET registry

PurposeThere are currently more than 480 primary immune deficiency (PID) diseases and about 7000 rare diseases that together afflict around 1 in every 17 humans. Computational aids based on data mining and machine learning might facilitate the diagnostic task by extracting rules from large datasets and making predictions when faced with new problem cases. In a proof-of-concept data mining study, we aimed to predict PID diagnoses using a supervised machine learning algorithm based on classification tree boosting. MethodsThrough a data query at the USIDNET registry we obtained a database of 2396 patients with common diagnoses of PID, including their clinical and laboratory features. We kept 286 features and all 12 diagnoses to include in the model. We used the XGBoost package with parallel tree boosting for the supervised classification model, and SHAP for variable importance interpretation, on Python v3.7. The patient database was split into training and testing subsets, and after boosting through gradient descent, the predictive model provides measures of diagnostic prediction accuracy and individual feature importance. After a baseline performance test, we used the Class Weighting Hyperparameter, or scale_pos_weight to correct for imbalanced classification. ResultsThe twelve PID diagnoses were CVID (1098 patients), DiGeorge syndrome, Chronic granulomatous disease, Congenital agammaglobulinemia, PID not otherwise classified, Specific antibody deficiency, Complement deficiency, Hyper-IgM, Leukocyte adhesion deficiency, ectodermal dysplasia with immune deficiency, Severe combined immune deficiency, and Wiskott-Aldrich syndrome. For CVID, the model found an accuracy on the train sample of 0.80, with an area under the ROC curve (AUC) of 0.80, and a Gini coefficient of 0.60. In the test subset, accuracy was 0.76, AUC 0.75, and Gini 0.51. The positive feature value to predict CVID was highest for upper respiratory infections, asthma, autoimmunity and hypogammaglobulinemia. Features with the highest negative predictive value were high IgE, growth delay, abscess, lymphopenia, and congenital heart disease. For the rest of the diagnoses, accuracy stayed between 0.75 and 0.99, AUC 0.46–0.87, Gini 0.07–0.75, and LogLoss 0.09–8.55. DiscussionClinicians should remember to consider the negative predictive features together with the positives. We are calling this a proof-of-concept study to continue with our explorations. A good performance is encouraging, and feature importance might aid feature selection for future endeavors. In the meantime, we can learn from the rules derived by the model and build a user-friendly decision tree to generate differential diagnoses.

A novel mutation in EROS (CYBC1) causes chronic granulomatous disease

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterised by opportunistic infection and sterile granulomatous inflammation. CGD is caused by a failure of reactive oxygen species (ROS) production by the phagocyte NADPH oxidase. Mutations in the genes encoding phagocyte NADPH oxidase subunits cause CGD. We and others have described a novel form of CGD (CGD5) secondary to lack of EROS (CYBC1), a highly selective chaperone for gp91phox. EROS-deficient cells express minimal levels of gp91phox and its binding partner p22phox, but EROS also controls the expression of other proteins such as P2X7. The full nature of CGD5 is currently unknown. We describe a homozygous frameshift mutation in CYBC1 leading to CGD. Individuals who are heterozygous for this mutation are found in South Asian populations (allele frequency = 0.00006545), thus it is not a private mutation. Therefore, it is likely to be the underlying cause of other cases of CGD.