Endocrinopathy In Primary Immunodeficiency Patients: A Single Center Retrospective Study

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). We retrospectively evaluated IEI patients on IGRT at a tertiary care center. Data on vaccinations and respiratory infections were extracted from medical records. : 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. 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.

ABSTRACTHuman inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially result in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as the single influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with radiosensitivity.

For over 20 years, haematopoietic stem cell (HSC) gene therapy (GT) has been developed for several inborn errors of immunity (IEI) and transformative results have been seen, particularly for severe combined immune deficiency (SCID) disorders. Gene therapy was developed as an alternative to haematopoietic stem cell transplant (HSCT), where outcomes are dependent on a well‐matched donor. The most common approach is gene addition, adding a functional copy of the defective gene into the patient's genome using lentiviral vectors. This autologous approach offers a potentially safer treatment than HSCT by reducing risks of alloreactivity, using less preparative chemotherapy and no requirement for immune suppression after transplant. Clinical trials have been undertaken and preclinical studies performed for an expanding range of IEIs including Wiskott‐Aldrich syndrome (WAS) and Leukocyte adhesion deficiency type I (LAD‐I). More recently, gene editing platforms such as CRISPR/Cas9‐based strategies are being explored but are yet to enter the clinic. Key Concepts Inborn errors of immunity are rare genetic disorders caused by gene mutations leading to abnormal development or function of the immune system or immune dysregulation. The first clinical trial to address an IEI, X‐SCID, used a gammaretroviral vector (ɣRV) which led to the development of leukaemia in several patients, termed insertional mutagenesis. Viral long terminal repeat (LTR) regions within γRVs were responsible for these adverse events and so self‐inactivating vectors were developed, which resulted in a safer and still effective approach. Self‐inactivating lentivirus vectors have proven to be a safer option for gene addition, reducing the risk of oncogenesis and being employed in numerous clinical trials for not only IEIs but also metabolic, haematological and oncological indications. More recently gene editing platforms have been applied to several IEIs to deliver precise gene correction in situ and likely we will see these therapies entering clinic in the coming years.

Inborn errors of immunity (IEI) are a group of disorders that are mostly caused by genetic mutations affecting immune host defense and immune regulation. Although IEI present with a wide spectrum of clinical features, in about one third of them various degrees of gastrointestinal (GI) involvement have been described and for some IEI the GI manifestations represent the main and peculiar clinical feature. The microbiome plays critical roles in the education and function of the host’s innate and adaptive immune system, and imbalances in microbiota-immunity interactions can contribute to intestinal pathogenesis. Microbial dysbiosis combined to the impairment of immunosurveillance and immune dysfunction in IEI, may favor mucosal permeability and lead to inflammation. Here we review how immune homeostasis between commensals and the host is established in the gut, and how these mechanisms can be disrupted in the context of primary immunodeficiencies. Additionally, we highlight key aspects of the first studies on gut microbiome in patients affected by IEI and discuss how gut microbiome could be harnessed as a therapeutic approach in these diseases.

Gene therapy for inborn errors of immunity: Current clinical progress.

Subclinical infection and dosing in primary immunodeficiencies.

Immunoactinopathies caused by mutations in actin-related proteins are a growing group of inborn errors of immunity (IEI). Immunoactinopathies are caused by a dysregulated actin cytoskeleton and affect hematopoietic cells especially because of their unique capacity to survey the body for invading pathogens and altered self, such as cancer cells. These cell motility and cell-to-cell interaction properties depend on the dynamic nature of the actin cytoskeleton. Wiskott-Aldrich syndrome (WAS) is the archetypical immunoactinopathy and the first described. WAS is caused by loss-of-function and gain-of-function mutations in the actin regulator WASp, uniquely expressed in hematopoietic cells. Mutations in WAS cause a profound disturbance of actin cytoskeleton regulation of hematopoietic cells. Studies during the last 10 years have shed light on the specific effects on different hematopoietic cells, revealing that they are not affected equally by mutations in the WAS gene. Moreover, the mechanistic understanding of how WASp controls nuclear and cytoplasmatic activities may help to find therapeutic alternatives according to the site of the mutation and clinical phenotypes. In this review, we summarize recent findings that have added to the complexity and increased our understanding of WAS-related diseases and immunoactinopathies.

An improved recognition of inborn errors of immunity (IEI) is associated with an increase in life expectancy and a higher incidence of complications and related conditions. The aim of the study was to analyze factors enabling the primary prevention: BMI, smoking and selected laboratory tests (morphology with smear, creatinine, eGFR, total protein, albumin, ferritin, folic acid, vitamin B12, vitamin D3) included in the protocols of standard of care for adult patients with primary antibody deficiencies (PADs). The study included 94 participants ≥ 18 years old, diagnosed with PADs. Overweight was found in 17%, obesity in 14% and underweight in 15% of patients; 11.5% of patients smoked. Leukopenia was diagnosed in 16%, neutropenia in 8.5%, lymphopenia in 22.5% and thrombocytopenia in 14% of patients. A decreased concentration of hemoglobin was found in 32%, total protein in 19%, albumin in 17%, vitamin D3 in 52%, vitamin B12 in 6.5%, folic acid in 34% and ferritin in 26% of patients. Creatinine concentrations were elevated in 16% of patients, while in 20%, eGFR was reduced. Only a holistic assessment of comorbidities and complications of deficiency, as well as regular follow-up and lifestyle changes, can yield the best results in the long-term care of patients.

Inborn errors of immunity (IEI) represent a heterogeneous large group of genetic disorders characterized by susceptibility of affected individuals to recurrent infections, autoimmune/inflammatory diseases, allergy, and malignancy. We aimed to report for the first time the Algerian registry for IEI in children. We described the characteristics of IEI in Algerian children from the data collected in the Algerian registry for IEI between 1985 and 2021. Over a period of 37years, we included 887 children (530 male, 59.6%) with a mean age at diagnosis of 3.23years and a mean diagnosis delay of 2years. The prevalence rate was estimated at 1.97/100,000 inhabitants or 5.91/100,000 children. The parental consanguinity was found in 52.6%. The most prevalent category was combined immunodeficiencies (CID) (35.5%), followed by predominantly antibody deficiencies (24.5%) and CID with syndromic features (18.3%). The most predominant diseases were severe CID (134 cases), MHC II deficiency (99 cases), agammaglobulinemia (82 cases), common variable immunodeficiency (78 cases), hyper IgE syndromes (61 patients), ataxia-telangiectasia (46 patients), Wiskott-Aldrich syndrome (40 patients) and chronic granulomatous disease (39 cases). The clinical presentation was dominated by lower respiratory tract infections (69%), failure to thrive (38.3%), and chronic diarrhea (35.2%). Genetic analysis was performed in 156 patients (17.6%). The global mortality rate was 28.4% mainly caused by CID. This is the first report of the Algerian registry for IEI in children. Data is globally similar to that of the Middle East and North African (MENA) registries with high consanguinity, predominance of CID, and significant mortality. This registry highlights the weak points that should be improved in order to provide better patient care.

Primary immunodeficiency (PID) is primarily characterized by susceptibility to infectious diseases. In addition, patients with some type of PID are prone to develop autoimmune, autoinflammatory, or malignant diseases. Therefore, the term, inborn errors of immunity (IEI), has been more used rather than PID. In recent years, the number of diseases which belong to PID has been increasing. There were approximately 110 diseases in the report of International Union of Immunological Societies in 1999. Since then, the number increased to 430 diseases in the latest IUIS report in 2019. We conducted PID nationwide survey in Japan for 3 times in the last 15 years. These studies were focused on incidence and complications of PID, the clinical course of viral infection, and methods to prevent infectious diseases in PID patients. For the awareness of PID, it is essential to know the general and fundamental information of PID patients. Needless to say, we need it to offer appropriate medical services for PID patients. Moreover, chances to provide answers to the questionnaires and seeing the results of the analysis should contribute to the awareness of PID among doctors. In this review, I am going to summarize the results of 3 nationwide survey in Japan, and pick up interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency as an example for creating awareness for its appropriate management.

Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive inborn error of immunity (IEI) first described in 1937. Classic WAS is characterized by the triad of thrombocytopenia with small platelets, recurrent infections due to combined immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) was the only curative option available for five decades, with excellent outcomes reported for matched sibling donors (MSD) and matched unrelated donors (MUD). More recently, alternative donor transplants such as umbilical cord blood (UCB) and haploidentical transplant have emerged as viable options due to improvements in better graft selection, cell dosing, and effective allograft manipulation measures. Gene therapy is another potential curative option with promising results, yet currently is offered only as part of a clinical trial.

Disclosure: N. Bapat: None. G. Dawood: None.Introduction: Hiccups, caused by involuntary diaphragmatic spasms, are typically benign but can occasionally signal underlying pathology. Intractable hiccups as a symptom of adrenal insufficiency are rare, with limited reports in the literature. We present a compelling case of intractable hiccups linked to central adrenal insufficiency, highlighting its diagnostic and therapeutic implications. Case Presentation: A 64-year-old male with a history of a 2 cm non-secretory pituitary macroadenoma underwent surgical resection in 2014. Postoperatively, he developed central adrenal insufficiency and was managed with hydrocortisone replacement until 2015, when a morning cortisol of 8.8 mcg/dL prompted cessation of therapy. He continued on levothyroxine and testosterone for central hypothyroidism and hypogonadotropic hypogonadism. In September 2023, he presented with a two-week history of fatigue, non-bloody diarrhea, and persistent hiccups. Emergency department evaluation revealed hyponatremia (sodium 132 mmol/L) and elevated lactate (3.1 mmol/L), which were attributed to a gastrointestinal illness. He received intravenous fluids and was discharged. While diarrhea resolved, hiccups and systemic symptoms persisted, prompting an endocrinology consultation. Morning cortisol was 1.4 mcg/dL, and ACTH was 7.7 pg/mL, confirming central adrenal insufficiency. Hydrocortisone was restarted at 10 mg in the morning and 5 mg in the evening. Persistent hiccups and labile blood pressure resolved after increasing the dose to 20 mg in the morning and 10 mg in the evening. A review of prior records revealed similar presentations of intractable hiccups during his initial diagnosis of adrenal insufficiency, further supporting their association. During follow-up, reduced hydrocortisone dosing led to a recurrence of hiccups during an acute illness, which he promptly recognized as under replacement, leading to timely dose adjustment. Discussion: Intractable hiccups are associated with diaphragm dysfunction, medullary abnormalities, and gastrointestinal disorders. While rare, their link to adrenal insufficiency may be mediated by cortisol deficiency disrupting autonomic or neuromodulatory pathways, compounded by hyponatremia-related neuromuscular instability. This case highlights the importance of considering adrenal insufficiency in patients with unexplained persistent hiccups, particularly when accompanied by systemic symptoms or hyponatremia. Moreover, hiccups may be a clinical marker of insufficient steroid replacement, underscoring the need for vigilant dose titration during acute illness or physiological stress. Conclusion: This case underscores intractable hiccups as a rare but clinically significant symptom of adrenal insufficiency. Recognizing this association can facilitate timely diagnosis and treatment, improving outcomes for affected patients.Presentation: Monday, July 14, 2025

Patient: Male, 81-year-oldFinal Diagnosis: Central adrenal insufficiencySymptoms: Anorexia • hypoglycemic coma • astheniaClinical Procedure: Endocrinological examinationSpecialty: Endocrinology and MetabolicObjective:Rare coexistence of disease or pathologyBackground:Alcohol abuse inhibits the ability of the liver to release glucose into the bloodstream, primarily by inhibiting gluconeogenesis, so chronic alcohol abusers exhibit hypoglycemia after drinking alcohol without eating; this is called alcohol-induced hypoglycemia. Central adrenal insufficiency (AI) is characterized by cortisol deficiency due to a lack of adrenocorticotropic hormone. It is challenging to diagnose central AI, as it usually presents with nonspecific symptoms, such as asthenia, anorexia, and a tendency toward hypoglycemia. Here, we report a rare case of central AI that presented with AI symptoms shortly after an alcohol-induced hypoglycemic coma.Case Report:An 81-year-old Japanese man who had been a moderate drinker for >40 years developed a hypoglycemic coma after consuming a large amount of sake (alcohol, 80 g) without eating. After the hypoglycemia was treated with a glucose infusion, he rapidly recovered consciousness. After stopping alcohol consumption and following a balanced diet, he had normal plasma glucose levels. However, 1 week later, he developed asthenia and anorexia. The endocrinological investigation results indicated central AI. He was started on oral hydrocortisone (15 mg/day), which relieved his AI symptoms.Conclusions:Cases of central AI associated with alcohol-induced hypoglycemic attacks have been reported. Our patient developed AI symptoms following an alcohol-induced hypoglycemic attack. His alcohol-induced hypoglycemic attack likely occurred in combination with a developing cortisol deficiency. This case highlights the importance of considering central AI in chronic alcohol abusers presenting with nonspecific symptoms, including asthenia and anorexia, especially when patients have previously experienced alcohol-induced hypoglycemic attacks.

BackgroundInborn Errors of Immunity (IEI) are monogenic disorders that predispose patients to infections, autoimmunity, atopy, and malignancies. Severe Th2-driven atopic dermatitis and asthma are common in several IEIs, including DOCK8 deficiency, STAT3 loss-of-function, and Wiskott–Aldrich syndrome, often refractory to conventional therapies. Dupilumab, a monoclonal antibody targeting IL-4Rα, has shown promise in managing recalcitrant atopic dermatitis and asthma, but data in immunocompromised pediatric populations remain limited.MethodsWe conducted a single-center, retrospective observational cohort study with prospective follow-up of ten pediatric patients with genetically confirmed IEI and atopic manifestations. Patients received subcutaneous dupilumab (300 mg every 4 weeks for atopic dermatitis; every 2 weeks for severe asthma). Outcomes were assessed using the Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), Childhood Asthma Control Test (C-ACT), eosinophil counts, and infection frequency across four time points (baseline, 6 months, 12 months, >18 months).ResultsThe cohort included ten patients (6 males, 4 females) with mutations in DOCK8 (n=5), CARD11 (n=2), STAT3 LOF (n=1), ADA (n=1), and PEPD (n=1). Of ten patients, nine received dupilumab for atopic dermatitis. Baseline EASI and DLQI scores were 34.33 and 25.0, respectively. Following dupilumab therapy, mean EASI decreased to 2.67 (p<0.001) and DLQI improved to 2.67 (p<0.001), with sustained response observed over 18 months. Peripheral eosinophil counts declined from 2.0×109/L to 0.45×109/L (p<0.001). One patient with severe asthma achieved C-ACT improvement from 10 to 26 with no subsequent exacerbations. Treatment was well-tolerated, with only mild conjunctivitis or transient hypereosinophilia reported. Notably, skin infections resolved, and no systemic or opportunistic infections were observed.ConclusionDupilumab is a safe and highly effective therapeutic option for pediatric patients with IEI-associated atopic manifestations, improving clinical outcomes, quality of life, and infection profile while preserving immune function. These findings support broader application of dupilumab in patients with IEI and warrant further investigation in larger, multicenter studies.