Juan Carlos Bustamante-Ogando

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose‐6‐phosphatase (G6PC3). Patients with mutations in G6PC3 suffer from congenital neutropenia and additional complex developmental abnormalities. Previous reports have found that SCN4 has recognizable dysmorphic facial features. Several features have been described in patients with SCN4, including triangular or round face, full cheeks, midface hypoplasia, malar flattening, frontal bossing, broad forehead, deep‐seated eyes, depressed nasal bridge, high‐arched palate, tented mouth, prominent lips, prognathism, or retrognathia. We report the facial features of nine patients diagnosed with SNC4. Consistent findings among our patients included high hairline, depressed nose, midfacial hypoplasia, high‐arched palate, and full lips. Discrete palpebral edema is present in all our patients. Interestingly, three of our patients presented with ptosis. Our findings align with previous reports, concluding that patients with G6PC3 deficiency exhibit characteristic facial dysmorphisms.

Inborn errors of immunity (IEI) encompass over 600 disorders with diverse and overlapping presentations. Clinicians rely on pattern recognition—clinical pearls—to navigate this complexity, yet this experiential knowledge is rarely systematically compiled. Through a structured expert elicitation, we aimed to capture and organize clinical pearls, pitfalls, and caveats for the differential diagnosis of IEI as a practical educational reference for trainees and non‐specialist physicians. In a structured expert survey with narrative (thematic) synthesis—not a formal consensus process—twenty clinical immunologists were invited and twelve contributed (60% response). Each provided diagnostic pearls across six categories: red flags prompting IEI evaluation, signs suggestive of IEI categories, highly specific (near‐pathognomonic) findings, highly sensitive findings, expected phenotype (including exclusionary findings), and practical clinical wisdom. Responses were translated (Spanish to English where necessary), coded and synthesized by theme by two investigators with disagreements resolved by consensus, reviewed for contradictions, and supplemented with established pearls from the literature, with the origin of each pearl tracked. Contributors provided over 150 diagnostic pearls. High‐consensus red flags included disseminated BCG/mycobacterial disease, very early‐onset inflammatory bowel disease (<6 years), and infant lymphopenia. Highly specific findings included microthrombocytopenia for Wiskott‐Aldrich syndrome, catalase‐positive organism infections for chronic granulomatous disease, and ataxia with telangiectasias for ataxia‐telangiectasia. Important caveats emerged: normal mean platelet volume does not exclude Wiskott‐Aldrich syndrome; normal IgG in older ataxia‐telangiectasia patients may mask antibody deficiency due to oligoclonal production; and absence of fever during serious bacterial infection suggests IRAK4/MyD88 deficiency rather than arguing against it. Contributors emphasized that clinical phenotypes evolve over time and that patients may not fit established patterns at initial evaluation. This structured expert survey provides a practical, organized reference for IEI differential diagnosis. The compilation of pearls, pitfalls, and caveats, presented in eight tables, offers educational and hypothesis‐generating guidance for clinicians and trainees navigating these rare disorders. In an exploratory, qualitative comparison, several types of experiential clinical wisdom—bedside decision rules, laboratory caveats, environmental guidance, and anticipatory management—were underrepresented in the outputs of general‐purpose large language models informally queried on the same task, suggesting that expert‐derived knowledge of this kind may help inform future educational and diagnostic‐support efforts. image

CAR-T cell therapy has shown promising results in treating malignant hematologic diseases. The principle of this therapy is based on the use of genetically modified T lymphocytes to express a Chimeric Antigen Receptor (CAR) on their membrane that specifically recognizes an antigen predominantly expressed on target cells. The molecular design of the CAR, along with advancements in molecular techniques and the development of “omics”, has opened the possibility of discovering new therapeutic targets and thereby expanding the range of diseases treated with CAR-T cells beyond the use of anti-CD19 and anti-BCMA for hematologic cancer. This review summarizes the novel therapeutic targets that are currently used in clinical trials with CAR-T cell therapy on autoimmune diseases and other challenging conditions, such as cardiac fibrosis, and different infections. Additionally, challenges and novel opportunities are discussed for expanding clinical access to this innovative therapy.

Purpose Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by pathogenic variants of genes encoding the enzyme complex NADPH oxidase. In countries where tuberculosis (TB) is endemic and the Bacillus Calmette–Guérin (BCG) vaccine is routinely administered, mycobacteria are major disease-causing pathogens in CGD. However, information on the clinical evolution and treatment of mycobacterial diseases in patients with CGD is limited. The present study describes the adverse reactions to BCG and TB in Mexican patients with CGD. Methods Patients with CGD who were evaluated at the Immunodeficiency Laboratory of the National Institute of Pediatrics between 2013 and 2024 were included. Medical records were reviewed to determine the clinical course and treatment of adverse reactions to BCG and TB disease. Results A total of 79 patients with CGD were included in this study. Adverse reactions to BCG were reported in 55 (72%) of 76 patients who received the vaccine. Tuberculosis was diagnosed in 19 (24%) patients. Relapse was documented in three (10%) of 31 patients with BGC-osis and six (32%) of 19 patients with TB, despite antituberculosis treatment. There was no difference in the frequency of BCG and TB disease between patients with pathogenic variants of the X-linked CYBB gene versus recessive variants. Conclusions This report highlights the importance of considering TB in endemic areas and BCG complications in children with CGD to enable appropriate diagnostic and therapeutic approaches to improve prognosis and reduce the risk of relapse.

Purpose: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8‐Def) in a tertiary care center for children.Methods: Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8‐Def. Genetic analysis was performed with targeted‐ or whole‐exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan–Meier method.Results: We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1–54 months). The median follow‐up time was 53.4 months (4.8–118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum‐driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis.Conclusion: DOCK8‐Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI‐associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8‐Def. Therefore, an early diagnosis of DOCK8‐Def is essential to facilitate an adequate treatment such as HSCT.

Leukemias are the most common type of pediatric cancer around the world. Prognosis has improved during the last decades, and many patients are cured with conventional treatment as chemotherapy; however, many patients still present with a refractory disease requiring additional treatments, including hematopoietic stem cell transplantation. Immunotherapy with monoclonal antibodies or cellular therapy is a promising strategy for treating refractory or relapsed hematological malignancies. Particularly, CAR-T cells have shown clinical efficacy in clinical trials, and different products are now commercially approved by regulatory agencies in the USA and Europe. Many challenges still need to be solved to improve and optimize the potential of these therapies worldwide. Global access to cell therapy is a significant concern, and different strategies are being explored in the middle- and low-income countries. In Mexico, leukemias represent around 50% of total cancer diagnosed in pediatric patients, and the rate of relapsed or refractory disease is higher than reported in other countries, a multi-factorial problem. Although significant progress has been made during the last decades in leukemia diagnosis and treatment, making new therapies available to Mexican patients is a priority, and cell and gene therapies are on the horizon. Efforts are ongoing to make CAR-T cell therapy accessible for patients in Mexico. This article summarizes a general landscape of childhood leukemias in Mexico, and we give a perspective about the current strategies, advances, and challenges ahead to make gene and cell therapies for leukemia clinically available.

Los errores innatos de la inmunidad (EII) son un grupo de más de 480 trastornos con origen genético, en su mayoría monogénico, potencialmente graves y que pueden condicionar mayor susceptibilidad a infecciones, inflamación, autoinmunidad, cáncer y/o alergia. Es importante que los médicos de primer contacto, pediatras y sub-especialistas conozcan sobre estas enfermedades, sepan reconocer los datos de alarma y sospecha clínica, inicien un abordaje diagnóstico, y refieran oportunamente con un especialista en inmunología clínica. La referencia temprana de pacientes con sospecha de EII a un centro especializado es fundamental para continuar el abordaje diagnóstico, iniciar un tratamiento adecuado y evitar la aparición de complicaciones graves o mortales.

Inborn errors of immunity may present with autoimmunity and autoinflammation as hallmark clinical manifestations. We aimed to identify the potential monogenic causes of autoimmune disorders in 26 patients from a pediatric reference hospital in Mexico through whole-exome sequencing. We specifically selected patients with a family history of autoimmune diseases, early-onset symptoms, and difficult-to-control autoimmune disorders or autoimmunity associated with infection predisposition. We identified the genetic variants that were compatible with the patients' phenotype in 54% of the patients. Autoimmune diseases are often caused by a combination of genetic factors, but cases that appear at a young age are resistant to treatment or occur in clusters, as well as the presence of autoimmune symptoms alongside infectious diseases should raise suspicion for an underlying inborn error of immunity.