Identification of a founder effect involving n.197C>T variant in RMRP gene associated to cartilage-hair hypoplasia syndrome in Brazilian patients.

Cartilage-hair hypoplasia syndrome (CHH) is an autosomal recessive disorder frequently linked to n.72A>G (previously known as n.70A>G and n.71A>G), the most common RMRP variant worldwide. More than 130 pathogenic variants in this gene have already been described associated with CHH, and founder alterations were reported in the Finnish and Japanese populations. Our previous study in Brazilian CHH patients showed a high prevalence of n.197C>T variant (former n.195C>T and n.196C>T) when compared to other populations. The aim of this study was to investigate a possible founder effect of the n.197C>T variant in the RMRP gene in a series of CHH Brazilian patients. We have selected four TAG SNPs within chromosome 9 and genotyped the probands and their parents (23 patients previously described and nine novel). A common haplotype to the n.197C>T variant carriers was identified. Patients were also characterized for 46 autosomal Ancestry Informative Markers (AIMs). European ancestry was the most prevalent (58%), followed by African (24%) and Native American (18%). Our results strengthen the hypothesis of a founder effect for the n.197C>T variant in Brazil and indicate that this variant in the RMRP gene originated from a single event on chromosome 9 with a possible European origin.

Studying the cellular basis of small bowel enteropathy using high-parameter flow cytometry in mouse models of primary antibody deficiency.

Background: Primary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be caused by abnormalities in both the development and activation of B cells, and may result from B-cell-intrinsic defects or defective responses by other cells relevant to humoral immunity. Inflammatory gastrointestinal complications are commonly observed in antibody-deficient patients, but the underlying immune mechanisms driving this are largely undefined. Methods: In this study, several mouse strains reflecting a spectrum of primary antibody deficiency (IgA-/-, Aicda-/-, CD19-/- and JH -/-) were used to generate a functional small-bowel-specific cellular atlas using a novel high-parameter flow cytometry approach that allows for the enumeration of 59 unique cell subsets. Using this cellular atlas, we generated a direct and quantifiable estimate of immune dysregulation. This estimate was then used to identify specific immune factors most predictive of the severity of inflammatory disease of the small bowel (small bowel enteropathy). Results: Results from our experiments indicate that the severity of primary antibody deficiency positively correlates with the degree of immune dysregulation that can be expected to develop in an individual. In the SI of mice, immune dysregulation is primarily explained by defective homeostatic responses in T cell and invariant natural killer-like T (iNKT) cell subsets. These defects are strongly correlated with abnormalities in the balance between protein (MHCII-mediated) versus lipid (CD1d-mediated) antigen presentation by intestinal epithelial cells (IECs) and intestinal stem cells (ISCs), respectively. Conclusions: Multivariate statistical approaches can be used to obtain quantifiable estimates of immune dysregulation based on high-parameter flow cytometry readouts of immune function. Using one such estimate, we reveal a previously unrecognized tradeoff between iNKT cell activation and type 1 immunity that underlies disease in the small bowel. The balance between protein/lipid antigen presentation by ISCs may play a crucial role in regulating this balance and thereby suppressing inflammatory disease in the small bowel.

Exploring the intersection of epigenetics, DNA repair, and immunology from studies of ICF syndrome, an inborn error of immunity.

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a rare autosomal recessive disorder, manifests with hypoglobulinemia and chromosomal instability accompanied by DNA hypomethylation. Pathological variants in the DNMT3B, ZBTB24, CDCA7, or HELLS genes underlie its etiology. Activated lymphocytes from patients often display distinctive multiradial chromosomes fused via pericentromeric regions. Recent studies have provided deeper insights into how pathological variants in ICF-related proteins cause DNA hypomethylation and chromosome instability. However, the understanding of the molecular pathogenesis underlying immunodeficiency is still in its nascent stages. In the past half-decade, the roles of CDCA7, HELLS, and ZBTB24 in classical non-homologous end joining during double-strand DNA break repair and immunoglobulin class-switch recombination (CSR) have been unveiled. Nevertheless, given the decreased all classes of immunoglobulins in most patients, CSR deficiency alone cannot fully account for the immunodeficiency. The latest finding showing dysregulation of immunoglobulin signaling may provide a clue to understanding the immunodeficiency mechanism. While less common, a subgroup of patients exhibits T-cell abnormalities alongside B-cell anomalies, including reduced regulatory T-cells and increased effector memory T- and follicular helper T-cells. The dysregulation of immunoglobulin signaling in B-cells, the imbalance in T-cell subsets, and/or satellite RNA-mediated activation of innate immune response potentially explain autoimmune manifestations in a subset of patients. These findings emphasize the pivotal roles of ICF-related proteins in both B- and T-cell functions. ICF syndrome studies have illuminated many fundamental mechanisms. Further investigations will certainly continue to unveil additional mechanisms and their interplay.

A qualitative study to explore the burden of disease in activated phosphoinositide 3-kinase delta syndrome (APDS).

BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare primary immunodeficiency, with only 256 cases reported globally. This study aimed to explore the disease burden of APDS from the perspective of individuals with APDS and their caregivers. METHODS: Qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers, to explore the symptoms and health-related quality of life (HRQoL) impact of APDS. Some individuals and caregivers also completed a narrative account exercise. All interviews were audio recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded. RESULTS: Semi-structured qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers. Individuals and caregivers had the option of completing a narrative account exercise. Six HCPs participated in an interview. Seven participants completed the narrative account exercise (N = 5 caregivers and N = 2 individuals with APDS) and 12 took part in an interview (N = 4 caregivers and N = 8 individuals with APDS). Themes identified from HCPs interviews included symptoms, clinical manifestations, HRQoL impacts and treatments/management of APDS. The narrative account exercise identified similar themes, but with the addition to the journey to diagnosis. These themes were explored during the individual/caregiver interviews. Reported clinical manifestations and symptoms of APDS included susceptibility to infections, lymphoproliferation, gastrointestinal (GI) disorders, fatigue, bodily pain, and breathing difficulties. HRQoL impacts of living with APDS included negative impacts to daily activities, including work, education and social and leisure activities, physical functioning, as well as emotional well-being, such as concern for the future, and interpersonal relationships. Impacts to caregiver HRQoL included negative impacts to physical health, work, emotional well-being, interpersonal relationships and family life and holidays. The management of APDS included the use of healthcare services and medications including immunoglobulin replacement therapy (IRT), rapamycin, prophylactic antibiotics, leniolisib, as well as medical procedures due to complications. CONCLUSIONS: APDS has a high disease burden and there is an unmet need for licensed, more targeted treatments which modify disease progression. This study was the first to describe the day-to-day experience and HRQoL impact of APDS from the perspective of individuals living with the condition, caregivers and treating physicians.

[Activated phosphoinositide 3-kinase delta syndrome: report of seven cases]. / PI3Kδ过度活化综合征7例报道.

OBJECTIVES: To summarize the clinical data of 7 children with activated phosphoinositide 3-kinase delta syndrome (APDS) and enhance understanding of the disease. METHODS: A retrospective analysis was conducted on clinical data of 7 APDS children admitted to Hunan Provincial People's Hospital from January 2019 to August 2023. RESULTS: Among the 7 children (4 males, 3 females), the median age of onset was 30 months, and the median age at diagnosis was 101 months. Recurrent respiratory tract infections, hepatosplenomegaly, and multiple lymphadenopathy were observed in all 7 cases. Sepsis was observed in 5 cases, otitis media and multiple caries were observed in 3 cases, and diarrhea and joint pain were observed in 2 cases. Lymphoma and systemic lupus erythematosus were observed in 1 case each. Fiberoptic bronchoscopy was performed in 4 cases, revealing scattered nodular protrusions in the bronchial lumen. The most common respiratory pathogen was Streptococcus pneumoniae (4 cases). Six patients had a p.E1021K missense mutation, and one had a p.434-475del splice site mutation. CONCLUSIONS: p.E1021K is the most common mutation site in APDS children. Children who present with one or more of the following symptoms: recurrent respiratory tract infections, hepatosplenomegaly, multiple lymphadenopathy, otitis media, and caries, and exhibit scattered nodular protrusions on fiberoptic bronchoscopy, should be vigilant for APDS. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(5): 499-505.

Cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders harboring RMRP mutations in two Korean children: A case report.

RATIONALE: Cartilage-hair hypoplasia (CHH, OMIM # 250250) is a rare autosomal recessive disorder, which includes cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders. CHH-AD is caused by homozygous or compound heterozygous mutations in the RNA component of the mitochondrial RNA-processing Endoribonuclease (RMRP) gene. PATIENT CONCERNS: Here, we report 2 cases of Korean children with CHH-AD. DIAGNOSES: In the first case, the patient had metaphyseal dysplasia without hypotrichosis, diagnosed by whole exome sequencing (WES), and exhibited only skeletal dysplasia and lacked extraskeletal manifestations, such as hair hypoplasia and immunodeficiency. In the second case, the patient had skeletal dysplasia, hair hypoplasia, and immunodeficiency, which were identified by WES. INTERVENTIONS: The second case is the first CHH reported in Korea. The patients in both cases received regular immune and lung function checkups. OUTCOMES: Our cases suggest that children with extremely short stature from birth, with or without extraskeletal manifestations, should include CHH-AD as a differential diagnosis. LESSONS SUBSECTIONS: Clinical suspicion is the most important and RMRP sequencing should be considered for the diagnosis of CHH-AD.

Activated phosphoinositde 3-kinase (PI3Kδ) syndrome: an Italian point of view on diagnosis and new advances in treatment.

Activated phosphoinositide 3-kinase (PI3Kδ) Syndrome (APDS) is an inborn error of immunity (IEI) with a variable clinical presentation, characterized by infection susceptibility and immune dysregulation that may overlaps with other Primary Immune Regulatory Disorders (PIRDs). The rarity of the disease, its recent discovery, and the multiform /multifaced clinical presentation make it difficult to establish a correct diagnosis, especially at an early stage. As a result, the true prevalence of the pathology remains unknown. There is no treatment protocol for APDS, and drug therapy is primarily focused on treating symptoms. The most common therapies include immunoglobulin replacement therapy, antimicrobial prophylaxis, and immunosuppressive drugs. Hematopoietic stem cell transplantation (HSCT) has been used in some cases, but the risk-benefit balance remains unclear. With the upcoming introduction of specific medications, such as selective inhibitors for PI3Kδ, clinicians are shifting their attention towards target therapy.This review provides a comprehensive overview of APDS with a focus on diagnostic and treatments procedures available. This review may be useful in implementing strategies for a more efficient patients' management and therapeutic interventions.Main Text.

Long-term treatment with selective PI3Kδ inhibitor leniolisib in adults with activated PI3Kδ syndrome.

ABSTRACT: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity that manifests as immune deficiency and dysregulation; symptoms include frequent infections and lymphoproliferation. In our dose-finding and phase 3 placebo-controlled trials, treatment with the selective PI3Kδ inhibitor leniolisib reduced lymphoproliferation and normalized lymphocyte subsets. Here, we present 6 years of follow-up from the 6 adult patients in the original dose-finding trial receiving leniolisib. We used data from the ongoing open-label extension study, which was supplemented at later time points by investigators, including health-related quality of life (HRQoL) assessed through a clinician-reported questionnaire. We observed improvements in HRQoL: 5 of 6 patients experienced an increase in physical capabilities and socialization, and a decrease in prescribed medications. Immune subsets improved in all patients: mean transitional B-cell levels decreased from 38.17% to 2.47% and the CD4:CD8 T-cell ratio normalized to 1.11. Manifestations seen before and within the first year of leniolisib exposure, such as infections and gastrointestinal conditions, attenuated after year 2, with few new conditions emerging out to year 6. Thrombocytopenia or lymphopenia remained present in half of patients at year 6. Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4/5 nor deemed leniolisib related. Collectively, we saw an enhancement in HRQoL as well as durable changes in lymphocyte subsets and clinical manifestations, further supporting the use of leniolisib as a long-term therapeutic option for the treatment of APDS. This trial was registered at www.ClinicalTrials.gov as #NCT02859727.

[Primary antibody deficiencies and respiratory manifestations in adults].

Primary antibody deficiencies (PAD) are a group of congenital disorders caused by genetic defects that affect the development and function of the body's immune defence mechanisms. Patients with PAD may present with recurrent infections, lymphoproliferation, autoimmune diseases, autoinflammation, or malignancies. Respiratory system manifestations may include bronchiectasis, bronchial asthma, and interstitial lung disease, among others. A comprehensive understanding of PADs will help to distinguish these covert cases from more common respiratory diseases.

Vaccination against respiratory tract pathogens in primary immune deficiency patients receiving immunoglobulin replacement therapy.

Introduction: Inborn errors of immunity (IEI) increase morbidity and mortality risks, particularly from respiratory tract infections. Hence, vaccination becomes pivotal for IEI patients. This study aims to examine the vaccination and respiratory tract infection rates in a diverse IEI patient cohort undergoing immunoglobulin replacement therapy (IGRT). Materials and Methods: We retrospectively evaluated IEI patients on IGRT at a tertiary care center. Data on vaccinations and respiratory infections were extracted from medical records. Result: : The study included 33 patients (mean age= 37.7 ± 11.4 years; 17 male). The most common clinical phenotype in our cohort was primary antibody deficiencies (90.9%). Only two patients had a genetic diagnosis, both of whom were brothers diagnosed with Wiskott-Aldrich syndrome (WAS). Almost half (48.5%) of our patients had bronchiectasis and 81.8% were on prophylactic antibiotics. All patients with IEI included in the study were regularly receiving IGRT. The vaccination rate of patients against respiratory tract infections was 42.4%, 57.6%, and 78.8% for influenza, pneumococcus, and COVID-19, respectively. Only one patient (7.1%) who received the influenza vaccine developed an upper respiratory tract infection. However, viral panel analysis could not be performed for this patient as they did not present to the hospital. The COVID-19 vaccination rate was notably higher than that of other vaccines, likely due to increased awareness during the pandemic, aided by public advisories and media influence. Conclusions: We observed higher vaccination rates for the COVID-19 vaccine compared to other vaccines (influenza and pneumococcal vaccines). Although we observed the potential impact of social and governmental influence in increasing vaccination rates, it is crucial to acknowledge that vaccination decisions in IEI patients must be individualized.

Altered oral microbiome, but normal human papilloma virus prevalence in cartilage-hair hypoplasia patients.

BACKGROUND: Cartilage-hair hypoplasia (CHH) is a rare syndromic immunodeficiency with metaphyseal chondrodysplasia and increased risk of malignancy. In this cross-sectional observational study, we examined HPV status and oral microbiome in individuals with CHH. Oral brush samples were collected from 20 individuals with CHH (aged 5-59 years) and 41 controls (1-69 years). Alpha HPVs (43 types) were tested by nested PCR followed by bead-based probe hybridization. Separately, beta-, gamma-, mu- and nu- HPV types were investigated, and a genome-based bacterial microbiome sequencing was performed. RESULTS: We found a similar alpha HPV prevalence in individuals with CHH (45%) and controls (36%). The HPV types of individuals with CHH were HPV-16 (25%), 27, 28, and 78, and of controls HPV-3, 16 (21%), 27, and 61. Beta HPV positivity and combined beta/gamma/mu/nu prevalence was detected in 11% and 11% of individuals with CHH and in 5% and 3% of the controls, respectively. Individuals with CHH differed from the controls in bacterial microbiota diversity, richness, and in microbial composition. Individuals with CHH had lower abundance of species Mitsuokella sp000469545, Parascardovia denticolens, Propionibacterium acidifaciens, UMGS1907 sp004151455, Salinicola halophilus, Haemophilus_A paraphrohaemolyticus, Fusobacterium massiliense, and Veillonella parvula, and higher abundance of Slackia exigua. CONCLUSIONS: Individuals with CHH exhibit similar prevalence of HPV DNA but different bacterial microbiota on their oral mucosa compared to healthy controls. This may partly explain the previously observed high prevalence of oral diseases in CHH, and regular oral examination is warranted.

CARD11 regulates the thymic Treg development in an NF-κB-independent manner.

Introduction: CARD11 is a lymphoid lineage-specific scaffold protein regulating the NF-κB activation downstream of the antigen receptor signal pathway. Defective CARD11 function results in abnormal development and differentiation of lymphocytes, especially thymic regulatory T cells (Treg). Method: In this study, we used patients' samples together with transgenic mouse models carrying pathogenic CARD11 mutations from patients to explore their effects on Treg development. Immunoblotting and a GFP receptor assay were used to evaluate the activation effect of CARD11 mutants on NF-κB signaling. Then the suppressive function of Tregs carrying distinct CARD11 mutations was measured by in vitro suppression assay. Finally, we applied the retroviral transduced bone marrow chimeras to rescue the Treg development in an NF-κB independent manner. Results and discuss: We found CARD11 mutations causing hyper-activated NF-κB signals also gave rise to compromised Treg development in the thymus, similar to the phenotype in Card11 deficient mice. This observation challenges the previous view that CARD11 regulates Treg lineage dependent on the NF-kB activation. Mechanistic investigations reveal that the noncanonical function CARD11, which negatively regulates the AKT/ FOXO1 signal pathway, is responsible for regulating Treg generation. Moreover, primary immunodeficiency patients carrying CARD11 mutation, which autonomously activates NF-κB, also represented the reduced Treg population in their peripheral blood. Our results propose a new regulatory function of CARD11 and illuminate an NF-κB independent pathway for thymic Treg lineage commitment.

Extensive and deep granulomatous ulcers as an atypical manifestation of cartilage-hair hypoplasia syndrome: A diagnostic and therapeutic challenge.

Cartilage hypoplasia syndrome is a primary immunodeficiency disease characterized by short stature, hypoplastic hair and a variable degree of immunodeficiency. Noninfectious cutaneous granulomas represent an uncommon yet well-recognized manifestation within the spectrum of primary immunodeficiency diseases. However, cutaneous granulomas as a manifestation of cartilage-hair hypoplasia syndrome, are extremely rare. We present a case of a middle-aged man with cartilage hypoplasia syndrome featuring cutaneous granulomas, manifesting as chronic, extensive and deep cutaneous ulcers. The patient was treated with anti-TNF-alpha adalimumab with partial improvement. Our case underscores the broad spectrum of clinical manifestations associated with cartilage hypoplasia syndrome and adds new evidence to the potential therapeutic efficacy of anti-TNF-alpha drugs in its treatment.

CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.

Warts, hypogammaglobulinaemia, infections and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency caused by the gain of function of the CXCR4 chemokine receptor. We present the prevalence of cancer in WHIMS patients based on data from the French Severe Chronic Neutropenia Registry and an exhaustive literature review. The median follow-up of the 14 WHIMS 'patients was 28.5 years. A central review and viral evaluation of pathological samples were organized, and we conducted a thorough literature review to identify all reports of WHIMS cases. Six French patients were diagnosed with cancer at a median age of 37.6 years. The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%). We observed two human papillomavirus (HPV)-induced vulvar carcinomas, three lymphomas (two Epstein-Barr virus [EBV]-related) and one basal cell carcinoma. Among the 155 WHIMS cases from the literature, 22 cancers were reported in 16 patients, with an overall cancer 40-year risk of 23% (95% CI: 13%-39%). Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive genital and anal cancers as in the French cohort. Worldwide, nine cases of malignancy were associated with HPV and four with EBV. Immunocompromised WHIMS patients appear to be particularly susceptible to developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related lymphomas.

Clinical and genomic evaluations of a persistent fatal SARS-CoV-2 infection in a goods syndrome patient: a case report.

The coronavirus disease of 2019 (COVID-19) resulted from an infection by severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) which is the main cause of acute respiratory distress syndrome (ARDS) in global population from 2019 on. It may contribute to higher rate of death among the patients with immunodeficiency based on recent reports. In addition, Good syndrome (GS) as a result of thymoma removal might cause in some long-lasting microbial infections. We described clinical aspects and viral mutations on a case of GS suffering from COVID-19. A 46-year-old man with fever, common respiratory disease symptoms and positive COVID-19 polymerase chain reaction (PCR) test, with the history of thymoma removal surgery was admitted to Masih Daneshvari Hospital, Tehran, Iran. Lung radiographs and oxygen saturation measurement disclosed considerable implication resulted in application of several anti-microbial medication. The delta variant (B.1.617.2 (21 J Clade)) was the strain isolated from the patient by sequencing methods done by the COVID-19 National Reference Laboratory (CNRL), Pasteur Institute of Iran, while the dominant strain circulated mostly among population was Omicron (B.1.1.529) at the time of sampling. Unfortunately, the patient had passed away a month later by sudden respiratory failure progressed in refractory septic shock. Despite the fact that opportunistic infections may lead the GS patients to a major health problematic condition, unusual persistent of infections such as non-dominant variant of SARS-Cov-2 could be observed through the disease timeline. Therefore, a fully screening of thymoma plus intra-host evolution monitoring of SARS-CoV-2 is highly recommended in immunocompromised patients.