Manish Butte

Orphanet J Rare Dis. 2025 Mar 24;20(1):142. doi: 10.1186/s13023-025-03661-z.

ABSTRACT

BACKGROUND: Hereditary bronchiectasis refers to a subset of bronchiectasis related to genetic mutations, presenting with common clinical features. Historically, diagnosing this condition has been difficult due to the inaccessibility of diagnostic services coupled with a lack of awareness of the syndrome. We hypothesize that whole exome sequencing (WES) in patients with supporting clinical features, combined with non-genetic testing methods, will enhance the diagnosis of hereditary bronchiectasis.

RESULTS: In total, 87 patients with clinical features suggestive of hereditary bronchiectasis, such as diffuse bronchiectasis (≥ 2 lobes) combined with early onset symptoms, recurrent otitis media, rhinosinusitis, infertility, organ laterality defects or a family history of bronchiectasis, were included in this study. Among them, 49.4% (43/87) were diagnosed with hereditary bronchiectasis, including 15 patients with cystic fibrosis, 27 patients with primary ciliary dyskinesia, and 1 patient with immunodeficiency-21. The combined use of WES and non-genetic testing methods significantly improved the diagnostic rate of hereditary bronchiectasis compared to non-genetic testing alone (47.1% vs. 25.3%, P = 0.005). Re-analysis of negative commercial genetic tests led to two additional diagnoses, though this increase was not statistically significant (47.1% vs. 49.4%, P = 0.879).

CONCLUSIONS: We have described the supporting clinical features of patients with hereditary bronchiectasis. Clinicians should recommend WES for patients exhibiting these characteristics, in combination with accessible non-genetic testing methods, to maximize diagnostic accuracy. For patients with negative initial genetic test results, re-analysis of WES data may facilitate obtaining a new diagnosis.

PMID:40128832 | DOI:10.1186/s13023-025-03661-z

Skin Health Dis. 2025 Jan 20;5(1):45-49. doi: 10.1093/skinhd/vzae003. eCollection 2025 Feb.

ABSTRACT

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that typically manifests as painful ulcers, usually on the lower limbs, and is usually secondary to other conditions, for example inflammatory bowel disease and rheumatoid arthritis. Epidermodysplasia verruciformis (EDV) is an inherited or acquired primary immunodeficiency disorder linked to human papillomavirus susceptibility and an increased risk of squamous cell carcinoma. Occurrence of these conditions together has not been reported before. A 10-year-old boy presented with an extraordinary combination of clinical features consistent with PG and EDV. This unique presentation showcased recurrent nonhealing painful ulcers on the legs and body along with cribriform scarring for the last 8 years, which worsened over the last 1 year. Punch biopsy corroborated the diagnosis of PG. There were no signs and symptoms of other systemic diseases. Hypo- and hyperpigmented papules were spread all over the body with pityriasis versicolor-like macules on the forehead, neck and dorsa of the hands along with a positive family history in his younger brother, confirming the diagnosis of inherited EDV. The patient also had hepatosplenomegaly, for which paediatric workup was suggested. Treatment involved infection control, corticosteroid therapy and wound care, which led to a rapid healing response in the ulcers. This exceptional case sparks the suspicion of a novel syndrome due to its combination of EDV and PG, enhancing existing knowledge of the disease presentation.

PMID:40125015 | PMC:PMC11924357 | DOI:10.1093/skinhd/vzae003

Skin Health Dis. 2025 Jan 22;5(1):41-44. doi: 10.1093/skinhd/vzae002. eCollection 2025 Feb.

ABSTRACT

WHIM syndrome is a rare primary immunodeficiency typically caused by autosomal dominant activating mutations in the CXCR4 gene. WHIM refers to warts, hypogammaglobulinaemia, infections and myelokathexis, which are the primary phenotypes of the syndrome. Here we describe a case of tinea capitis in a patient with WHIM syndrome that was unresponsive to multiple systemic antifungal treatments for over 10 years. The patient’s recalcitrant tinea infection was ultimately cured after treatment with posaconazole. These findings suggest that the CXCR4 defects in WHIM syndrome may confer susceptibility to dermatophyte infections.

PMID:40124996 | PMC:PMC11924356 | DOI:10.1093/skinhd/vzae002

Front Pediatr. 2025 Mar 7;13:1550643. doi: 10.3389/fped.2025.1550643. eCollection 2025.

ABSTRACT

Leukocyte Adhesion Defects (LADs) are a group of rare autosomal recessive immune disorders characterized by constitutional defects in the process of leukocyte migration. Among these, LAD-III is the rarest, with only a few cases documented in scientific literature. It is caused by mutations in the FERMT3 gene, impairing integrin function in both white blood cells and platelets. Thus, patients exhibit a variable degree of immunodeficiency along with a severe bleeding tendency referred to as “Glanzmann-like”, due to dysfunctional platelet GPIIb/IIIa. The diagnosis of LAD-III is typically made in infancy or early childhood, following medical evaluations for recurrent infections and bleeding episodes. Here we report the case of a female newborn admitted to our NICU at day four of life with a history of petechial rash and gross hematuria. Radiological and endoscopic assessments revealed a hemangioma-like lesion of the bladder wall. Blood exams showed persistent leukocytosis without signs of infection, associated with mild thrombocytopenia and normocytic anemia. Notably, platelet function assays demonstrated defective aggregation with all agonists tested. Next generation sequencing analysis identified a homozygous nonsense mutation in the FERMT3 gene, ensuring early access to hematopoietic stem cell transplantation, which is the only curative treatment. To the best of our knowledge, this is the first reported case of LAD-III diagnosed in the neonatal period and the first to associate this rare disorder with bladder angiomatosis. This case highlights the importance of early genetic evaluations in newborns with unexplained hematological abnormalities and bleeding tendencies.

PMID:40123666 | PMC:PMC11926134 | DOI:10.3389/fped.2025.1550643

Respir Med. 2025 Mar 21:108048. doi: 10.1016/j.rmed.2025.108048. Online ahead of print.

ABSTRACT

BACKGROUND: Primary immunodeficiency (PID), particularly B-cell immunodeficiency (BCID), is associated with recurrent infections and significant pulmonary complications. Early and effective diagnostic tools are critical for improving clinical outcomes in these patients.

OBJECTIVE: This study evaluates the effectiveness of spirometry compared to chest CT scans for diagnosing and monitoring pulmonary complications in BCID patients.

METHODS: A case series of 53 BCID patients, predominantly with Common Variable Immunodeficiency CVID, was conducted at Imam Khomeini Hospital (2022-2023). Spirometry patterns, including FEV1, FVC, FEV1/FVC ratios, and FEF25-75, were analyzed alongside CT findings, including air-trapping scores, bronchiectasis, and small airway disease. Statistical analyses included regression models to correlate spirometry and CT results.

RESULTS: Spirometry identified obstructive (49%), normal (41.5%), restrictive (7.5%), and mixed patterns (2%). CT scans revealed bronchiectasis (32%), small airway disease, and ground-glass opacities. A significant correlation was observed between air-trapping scores and spirometry parameters (FEF25-75 and FEV1/FVC). Longitudinal assessments demonstrated a progressive increase in air-trapping scores, emphasizing the chronic nature of small airway involvement.

CONCLUSION: Spirometry offers a safer, cost-effective alternative to CT scans for early detection and monitoring of pulmonary complications in BCID patients. The strong concordance between spirometry results and CT findings supports its routine clinical use, minimizing radiation exposure and facilitating timely interventions.

PMID:40122406 | DOI:10.1016/j.rmed.2025.108048

Pediatr Int. 2025 Jan-Dec;67(1):e15872. doi: 10.1111/ped.15872.

ABSTRACT

INTRODUCTION: Severe combined immunodeficiency (SCID) due to T-cell deficiency is the most severe form of inborn error of immunity (IEI). It frequently leads to severe and recurrent infections and the first infection or live vaccines can sometimes be fatal. Patients with B-cell deficiency (BCD), such as X-linked agammaglobulinaemia (XLA), also suffer from severe or recurrent infections. Thus, early diagnosis via newborn screening (NBS) is suitable for these types of diseases. We developed a lyophylized TaqMan-based quantitative polymerase chain reaction (qPCR) kit with primers and probes for the simultaneous detection of T-cell receptor excision circles (TREC) and κ-deleting recombination excision circles (KREC). We also developed a fully automated DNA extraction and purification process using Magtration technology from dried blood spots (DBS), enabling high-throughput analysis METHODS: We examined 15,258 stored DBS collected from 2014 to 2015 by this method. Newborn screening samples from children with a known SCID, XLA or ataxia-telangiectasia (AT) were also examined as positive controls.

RESULTS: RPPH1 (internal control), TREC, and KREC all had near-normal distributions. One specimen was below the cut-off for TREC (0.00657%) after exclusion of 36 specimens due to the failure of DNA extraction (0.23%). The TREC levels in the patients with AT and SCID, and KREC levels in the patients with AT and XLA were all below cut-off or absent.

CONCLUSIONS: This assay would allow the establishment of qPCR-based NBS in unfamiliar laboratories leading to the early diagnosis of SCID and BCD.

PMID:40121561 | DOI:10.1111/ped.15872

Front Immunol. 2025 Mar 6;16:1538453. doi: 10.3389/fimmu.2025.1538453. eCollection 2025.

ABSTRACT

OBJECTIVE: Patients with Inborn Errors of Immunity (IEI) are at higher risk of severe SARS-CoV-2 infection. We evaluated humoral and cellular responses to COVID-19 vaccines in Brazilian patients with IEI and healthy controls.

METHODS: Fifty-five patients with IEI (13-61 years) and 60 controls (13-71 years) received inactivated SARS-CoV-2 (CoronaVac), non-replicating virus-vectored (ChAdOx1 nCoV-19, AstraZeneca) or monovalent mRNA (Original strain of BNT162b2, Pfizer-BioNTech) and bivalent mRNA (Original/Omicron BA.1, Pfizer-BioNTech) vaccines and were sampled five times. Diagnoses included common variable immunodeficiency (n=25), specific antibody deficiency (n=9), ataxia-telangiectasia (n=5), X-linked agammaglobulinemia (n=4), PIK3CD-related disorders (n=4), hyper-IgM syndrome (n=4), combined immunodeficiency (n=3), and STAT1 gain-of-function (n=1). Humoral immunity was assessed via multiplex microarray for Spike, Nucleocapsid, RBD-Wuhan, RBD-Delta, RBD-BA.1, RBD-BA.2 and RBD-BA.5 neutralizing antibodies. T-cell responses to Spike and Nucleocapsid were assessed using ELISpot.

RESULTS: Patients with IEI exhibited significantly lower levels of Nucleocapsid and RBD-neutralizing antibodies (p < 0.05). Notable differences in RBD-BA.2 (p = 0.008) and IgG-Nucleocapsid (p = 0.010) levels emerged over time. T-cell responses to Spike were stronger in patients with IEI post-booster (405 vs. 149 spot-forming cells/million PBMC; p = 0.002). Both groups showed enhanced Nucleocapsid-specific cellular responses over time (p = 0.017). COVID-19 hospitalization rates among patients with IEI with SARS-CoV-2 diagnosis dropped from 33.3% to zero after the first booster dose.

CONCLUSIONS: While humoral responses to SARS-CoV-2 vaccines were weaker in patients with IEI, their cellular immunity was similar to controls. Boosters enhanced both humoral and cellular responses. After completion of the vaccination protocol, none of the patients with IEI were hospitalized with COVID-19. Robust T-cell responses may play a critical role in protecting patients with IEI from severe COVID-19 and mortality.

PMID:40114918 | PMC:PMC11922935 | DOI:10.3389/fimmu.2025.1538453

Health Sci Rep. 2025 Mar 19;8(3):e70497. doi: 10.1002/hsr2.70497. eCollection 2025 Mar.

ABSTRACT

BACKGROUND AND AIM: Hyper IgE syndromes (HIES) are rare primary immunodeficiency characterized by susceptibility to specific infections, eczema, and elevated IgE levels. Pathogenic mutations in STAT3, IL6R, IL6ST, ERBB2IP, PGM3, ZNF431, SPINK5, TGFBR1/2, and CARD11 have been identified as genetic factors contributing to phenotypes of HIES lead to hindered differentiation and activity, aberrant signaling cascades and disrupting immune regulation. HIES present a diverse clinical symptoms, challenging diagnosis and management; understanding its pathophysiology, genetics, and immunological abnormalities offer hope for improved outcomes. In this review we aim to provide a comprehensive understanding of the condition and also discuss latest updates on pathological features, clinical spectrum and its variability, immunological abnormalities, inheritance patterns, new candidate genes, challenges, management strategies, epidemiology and future directions of HIES.

METHODS: This review conducted an extensive search of information from multiple databases, including PubMed, Scopus, WHO, and ClinVar to ensure comprehensive coverage. Preference was given to articles published recently to capture the latest research and developments. Endnote was employed as a reference manager. The relevant literature was meticulously reviewed to address the objectives of the study.

RESULTS: Missense, nonsense, and frameshift variants are commonly observed in HIES. Understanding these genetic mutations is key to diagnosing and managing conditions such as Hyper-IgE recurrent infection syndromes (linked to IL6R, STAT3, and ZNF341 mutations), Atopy associated with ERBIN mutations which links STAT3 and TGF-β pathway, Immunodeficiency 23 (caused by PGM3 mutations), Netherton syndrome (resulting from SPINK5 mutations), and Loeys-Dietz syndrome (related to TGFBR mutations). Each year, new genes and variants responsible for this type of immune deficiency are added to the list.

CONCLUSION: Although rare, HIES significantly impacts patients due to its complex medical manifestations and need for lifelong management. Identifying casual variants is essential for effective clinical management of these complex conditions.

PMID:40114756 | PMC:PMC11922810 | DOI:10.1002/hsr2.70497

Transl Cancer Res. 2025 Feb 28;14(2):827-842. doi: 10.21037/tcr-24-449. Epub 2025 Feb 26.

ABSTRACT

BACKGROUND: Clear cell renal cell carcinoma (ccRCC), is highly metastatic with unfavorable oncologic outcomes. The metastatic dissemination and underlying mechanisms of ccRCC remain insufficiently understood. The expression of fucosyltransferases (FUTs) has been explored in multiple cancer types, which affect survival of tumor cells and oncology progress. However, the role of fucosyltransferase 10 (FUT10), a member of the FUT family, is still unclear in ccRCC. We aimed to investigate the effects of FUT10 on the prognosis and immune infiltration of ccRCC via The Cancer Genome Atlas (TCGA) database.

METHODS: The relationship between FUT10 expression and clinical-pathologic features was evaluated by Welch’s t-test, Wilcoxon signed-rank test, Dunn’s test, and logistic regression based on TCGA datasets. The FUT10 expression level was converted into a categorical variable by receiver operating characteristic (ROC) and the area under the curve (AUC). The factors associated with the prognosis were determined by Kaplan-Meier method. The function of FUT10 was identified by functional enrichment analysis, gene set enrichment analysis (GSEA), gene correlation analysis, and immune infiltration analysis. At last, we verified the FUT10 messenger RNA (mRNA) expression in ccRCC and adjacent kidney tissues by quantitative real-time polymerase chain reaction (qRT-PCR).

RESULTS: Downregulated FUT10 expression in ccRCC was associated with the clinical stage (P<0.001), T stage (P<0.001), M stage (P<0.001), and overall survival (OS) event (P<0.001). The ROC curve suggested that FUT10 had a certain accuracy in the diagnostic ability in ccRCC (AUC =0.787). It was shown that patient survival was prolonged in the FUT10 high-expression group. Meanwhile, multivariate analysis displayed that FUT10 was an independent risk factor for ccRCC patients (P=0.003). Moreover, we uncovered that FUT10 was involved in the phenotype of the immune response, oxidative phosphorylation (OXPHOS), arachidonic acid (AA) metabolism, and primary immunodeficiency (PID) by function enrichment analysis and GSEA. In addition, in the high FUT10 expression group, natural killer (NK) CD56bright cells exhibited lower enrichment scores, and central memory T cells exhibited higher enrichment scores. Especially, ARL8B, a key factor in NK-mediated cytotoxicity, had a certain correlation with FUT10 (r=0.590, P<0.001). Compared to the normal kidney tissues, the FUT10 mRNA expression in the ccRCC was decreased (P=0.004).

CONCLUSIONS: FUT10 might be a promising immune therapy target and prognostic biomarker in ccRCC.

PMID:40104704 | PMC:PMC11912032 | DOI:10.21037/tcr-24-449

J Clin Immunol. 2025 Mar 17;45(1):82. doi: 10.1007/s10875-025-01874-2.

ABSTRACT

Selective anti-polysaccharide antibody deficiency (SPAD) predisposes to encapsulated bacterial infections. The diagnosis is challenging, and literature reports are scarce in adult patients, we therefore aim to describe the demographics, infectious complications, therapeutic strategies, and outcome of adult patients. We conducted a multicenter observational study involving 55 adult patients with SPAD. The median [interquartile range, IQR] age was 45 [36-60] years at diagnosis of SPAD, and 75% of patients were female. Twenty-one patients (38%) had a history of allergic and/or inflammatory disease, mainly asthma (n = 12), and rheumatic diseases (n = 6). Twelve patients (22%) were diagnosed after a single severe infection and 43 (78%) in a context of recurrent benign and/or severe infections. In the latter, the median time from first infections to diagnosis was 74.5 [33-167] months. Diagnostic delay was significantly higher in patients presenting with bronchiectasis than in those without (122 months [33-219.5] vs 24 months [14.5-74.5], p = 0.0042). In 22 patients (40%) receiving immunoglobulin replacement therapy (IgRT), the mean (min-max) frequency of antibiotic courses decreased from 7.9 (2-18) to 0.7 (0-2) courses per year (p < 0.001) with a median follow-up period of 46 [27-73] months. Patients diagnosed after a single severe infection did not have any relapse during a median follow-up of 85 [80.5-104.5] months after diagnosis. Adult patients with SPAD have allergic or inflammatory disorders which could contribute to the diagnostic delay. IgRT is effective in preventing recurrent infections. Further studies are warranted to confirm if SPAD should be considered after a first unexplained severe bacterial infection.

PMID:40097777 | DOI:10.1007/s10875-025-01874-2