Manish Butte

Front Immunol. 2025 Feb 12;16:1532645. doi: 10.3389/fimmu.2025.1532645. eCollection 2025.

ABSTRACT

INTRODUCTION: Infections are a major cause of early morbidity and mortality in patients with multiple myeloma (MM) who are characterized by immunodeficiency secondary to disease. However, prospectively collected data on infection risk in this population are scarce. We aimed at identifying parameters in monoclonal gammopathy of undetermined significance (MGUS) and newly diagnosed MM (NDMM) patients with predictive power for early severe infections (SI).

METHODS: We conducted a prospective study with newly diagnosed MGUS and NDMM patients. Besides clinical and laboratory data, immune parameters were collected at initial diagnosis before therapy initiation. Primary endpoint was the occurrence of SI within 12 months after diagnosis.

RESULTS: 45% of patients developed infection, 26% with SI. Four main risk factors for SI were identified: ECOG ≥ 2 (p < 0.001), ISS stage II/III (p = 0.002), therapeutic intervention (p < 0.001), and elevated CD8⁺ TEMRA cells (p = 0.027). A risk score was compiled, enabling the stratification of patients with low or high risk for SI with a sensitivity of 92.9% and a specificity of 80%.

CONCLUSION: We developed a straightforward risk score that considers the relevance of T cell fitness in MGUS and NDMM patients and can help physicians to identify patients at risk of infection, thus enabling the implementation of timely and individualized prevention strategies.

PMID:40013147 | PMC:PMC11862831 | DOI:10.3389/fimmu.2025.1532645

Oncol Lett. 2025 Feb 13;29(4):188. doi: 10.3892/ol.2025.14934. eCollection 2025 Apr.

ABSTRACT

Hepatic marginal zone B-cell lymphoma (MZL) is a rare and challenging entity that is often misinterpreted as hepatocellular carcinoma owing to its non-specific radiological features. The current case report details the clinical presentation, diagnosis and treatment of an older adult female with hepatic MZL involving both lobes, complicated by Sjögren’s syndrome and common variable immunodeficiency. Given the patient’s immunodeficiency and the risks associated with chemotherapy, involved site radiotherapy (ISRT) was administered as the primary treatment. Using a response-adapted approach, an initial radiotherapy dose of 24 Gy over 16 fractions was delivered to the major hepatic lesion, followed by a local boost to both lobes after significant tumor shrinkage. The patient tolerated the treatment well with minimal side effects, and post-treatment imaging showed a complete metabolic response. This case highlights the effectiveness of response-adapted ISRT in managing hepatic MZL in immunocompromised patients and underscores the need for individualized treatment approaches for rare lymphomas.

PMID:40007623 | PMC:PMC11851431 | DOI:10.3892/ol.2025.14934

Int J Mol Sci. 2025 Feb 18;26(4):1744. doi: 10.3390/ijms26041744.

ABSTRACT

Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence variants (PSVs) in the SMARCAL1 gene that encodes protein involved in chromatin remodelling. SIOD is an ultra-rare condition, with an incidence of ~1 per 1-3 million live births; data on its genetic and clinical features are scarce. We conducted a retrospective study of 21 paediatric patients with SIOD diagnosed in our centre during the years 2003-2023. The most common extra-renal clinical features were short stature, osseous dysplasia, multiple stigmas, and leukopenia. Proteinuria of varying severity was observed in 16 cases. The five-year overall survival rate (OS) was 89% (95% CI 77-100%), and the ten-year OS was 10%. Next-generation sequencing (NGS) revealed the following PSVs in SMARCAL1 in 19 patients: c.355_500del, c.2542G>T, c.2290C>T, c.2562del, c.2533_2534del, c.1582A>C, c.1933C>T, c.1010T>C, c.1736C>T, c.2070dup, c.2551A>T, c.2149_2150dup, c.939delC, and c.1451T>A; the most common was c.2542G>T, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state. According to microsatellite analysis, it is a “founder mutation” in Russia.

PMID:40004207 | DOI:10.3390/ijms26041744

Biomedicines. 2025 Jan 31;13(2):323. doi: 10.3390/biomedicines13020323.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is a rare genetic disorder that causes primary immunodeficiency. In addition to increasing infection susceptibility in various bodily systems, several ocular manifestations have been described in males. This condition is well described in males, due to its X-linked recessive inheritance. However, here we present, to our knowledge, the first cases of X-linked CGD chorioretinitis in female carriers, possibly due to skewed X-inactivation (lyonization).

METHODS: Comprehensive multimodal imaging, including color fundus photography, short-wavelength autofluorescence, and spectral domain optical coherence tomography (OCT), was conducted. Functional assessment was completed with full-field electroretinogram (ff-ERG).

RESULTS: This report details two sisters with X-linked CGD carrier status, both presenting chorioretinal lesions on fundoscopy. Observed features included punched-out chorioretinal lesions, perivascular atrophy, and peripheral pigment changes. Autofluorescence imaging confirmed hypoautofluorescent areas correlating with chorioretinal atrophy, and OCT revealed retinal collapse and ellipsoid zone loss in one sibling. Despite these structural changes, visual function remained stable with minimal progression over time. Subsequent serial ERGs did not show progression.

CONCLUSIONS: The findings highlight that skewed X-inactivation may contribute to retinal changes in asymptomatic CGD carriers, underscoring the need for awareness of potential ocular manifestations in X-linked genetic disorders in female carriers.

PMID:40002738 | DOI:10.3390/biomedicines13020323

BMC Pediatr. 2025 Feb 26;25(1):139. doi: 10.1186/s12887-025-05458-2.

ABSTRACT

BACKGROUND: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), also known as autoimmune polyendocrine syndrome type I (APS-I) is an inborn error of immunity (IEI) with an immune dysregulation phenotype, mainly characterized by endocrine and non-endocrine manifestations including adrenal insufficiency, chronic mucocutaneous candidiasis, and ectodermal dystrophy. Renal disorders seem to be a significant morbidity in APECED patients, requiring further investigations.

METHODS: The literature search was conducted in PubMed, Web of Science, and Scopus databases using relevant keywords, and included articles were systematically reviewed regarding the clinical and immunological features. APECED patients with at least one nephrological complication were included.

RESULTS: Ninety-three APECED patients from 30 studies were identified. More than half of the patients (38,52%) presented nephrocalcinosis. The second and third most prevalent renal complications were tubulointerstitial nephritis (TIN) (23,31%), and hypertension (13,18%), respectively. Other less frequent renal disorders including renal tubular acidosis (RTA) glomerulonephritis were also reported among patients. Additionally urinary tract infections (UTI), were also common among cases (15,20.5%).

CONCLUSIONS: Renal complications in APECED represent a significant issue that should be monitored and considered in managing these patients to preserve renal function and improve patients’ outcomes.

PMID:40000975 | DOI:10.1186/s12887-025-05458-2

Toxics. 2025 Jan 27;13(2):100. doi: 10.3390/toxics13020100.

ABSTRACT

Fluorene-9-bisphenol (BHPF) has been increasingly used as a bisphenol A substitute in the synthesis of various products. Previous studies have suggested that BHPF can be released from plastic bottles into drinking water, and BHPF accumulation has been reported to cause various adverse effects in humans. Nevertheless, the impact of BHPF exposure on endometrial epithelial cells remains largely unexplored. Here, we investigated the effects of exposure to different concentrations of BHPF on endometrial cells and used integrated metabolomic and transcriptomic methods to elucidate the underlying molecular mechanisms. Our results revealed significant associations between specific metabolites and genes, indicating that low-concentration exposure to BHPF affects endometrial epithelial cells by targeting pathways related to primary immunodeficiency, in which the key genes are IL7R and PTPRC. High-concentration exposure to BHPF decreased cell viability by regulating the purine metabolism pathway, as well as dysregulating the expression of PGM1, PDE3B, AK9, and ENTPD8. Our study highlights that the health risk of BHPF exposure to endometrial epithelial cells is concentration-dependent and that integrated analysis of metabolomic and transcriptomic data not only revealed the biological effects of BHPF and its underlying mechanisms, but also provided key candidate target genes for further exploration.

PMID:39997915 | DOI:10.3390/toxics13020100

J Allergy Clin Immunol Glob. 2025 Jan 11;4(2):100407. doi: 10.1016/j.jacig.2025.100407. eCollection 2025 May.

ABSTRACT

BACKGROUND: Emerging evidence suggests that inborn errors of immunity (IEI) are underdiagnosed among underserved populations. However, there remains a lack of national studies evaluating diagnostic disparities in IEI.

OBJECTIVE: We examined disparities in the timely IEI diagnosis and related health outcomes.

METHODS: A retrospective analysis was performed of a US national claims database (years 2007 to 2021). Participants included patients diagnosed with an “unspecified immune deficiency” (uID) and presented with IEI-related symptoms, who later received an IEI diagnosis (n = 1429). We quantified the diagnostic interval from clinical suspicion (uID) to IEI diagnosis and examined its association with sociodemographic factors and related health outcomes.

RESULTS: The median (interquartile range) diagnostic interval was 369 (126-808) days. Diagnostic interval was 14% longer among patients residing in predominantly non-White neighborhoods, compared with those in predominantly White neighborhoods (P = .04), despite having more severe IEI-related symptoms at uID diagnosis and significantly more health care encounters for pneumonia (incidence rate ratio, 2.24; 95% confidence interval, 1.40-3.70) and sepsis (incidence rate ratio, 2.15; 95% confidence interval, 1.21-3.99) in the year after uID diagnosis. Residence in neighborhoods with greater deprivation was also associated with more severe IEI-related symptoms and greater health care utilization in the year after uID diagnosis. Older age was associated with longer diagnostic interval (P < .001). Longer diagnostic interval was associated with a longer interval to receiving IgR therapy (hazard ratio, 0.64; 95% confidence interval, 0.49-0.83).

CONCLUSION: We observed significant racial and socioeconomic disparities in the timeliness of IEI diagnosis and IEI-related outcomes. Further studies are needed to address the underlying factors contributing to diagnostic inequity.

PMID:39991621 | PMC:PMC11847075 | DOI:10.1016/j.jacig.2025.100407

Front Immunol. 2025 Feb 6;16:1550380. doi: 10.3389/fimmu.2025.1550380. eCollection 2025.

ABSTRACT

Hereditary angioedema (HAE) is a rare genetic disease, characterized by transient and self-limiting episodes of subcutaneous or submucosal swelling that spontaneously resolve within two to five days. The most common form of HAE, HAE-C1-INH, is caused by deleterious mutations in the SERPING1 gene, encoding the C1-Inhibitor protein, and its diagnosis is confirmed by decreased C1-INH function. Distinctively from other genetic forms of HAE, up to 15-20% of HAE-C1-INH cases are sporadic caused by de novo mutations. Here, we report a patient with apparently sporadic HAE-C1-INH. The patient had compatible clinical symptoms and a markedly low C1-INH function, and the parents showed normal values of C4 and normal C1-INH function. In the patient, we identified a novel splice site mutation in SERPING1 (c.890-1G>C) and, by cDNA analysis, we confirmed its pathogenicity. Despite normal C1-INH function in the parents, we found that the mother was, unexpectedly, a mutation carrier. The inverted profile of the Sanger peaks compared with the patient, strongly suggested the presence of gonosomal mosaicism in the mother. We confirmed and quantified the mosaicism in different tissues by high depth NGS-based deep amplicon sequencing, showing a similar frequency of the variant ranging from 17 to 23%. In this study, we present the first case of gonosomal mosaicism in a family with a single child affected with HAE-C1-INH from unaffected parents. Our results underscore the importance of parental genetic testing in all patients, regardless of whether the parents are affected, and highlights the implications of gonosomal mosaicism for genetic counseling.

PMID:39981253 | PMC:PMC11839619 | DOI:10.3389/fimmu.2025.1550380

SAGE Open Med. 2025 Feb 19;13:20503121251320849. doi: 10.1177/20503121251320849. eCollection 2025.

ABSTRACT

INTRODUCTION: Bronchiectasis is a chronic respiratory disease caused by various respiratory and systemic conditions. It is now considered a potentially reversible disease, particularly when diagnosed early and managed with appropriate respiratory care strategies. Although rare in children, it typically develops in patients with recurrent lower respiratory tract infections. The etiology of bronchiectasis in children differs from that in adults. This study aims to identify the clinical features, causes, and outcomes of non-cystic fibrosis bronchiectasis in children at a tertiary center.

METHODS: A retrospective review was conducted among children with non-cystic fibrosis bronchiectasis who attended a university-affiliated hospital between January 2007 and December 2021. Clinical outcomes were assessed based on pulmonary function tests, exacerbation, and mortality.

RESULTS: The study included 35 children with non-cystic fibrosis bronchiectasis. The median age at diagnosis was 36 months (IQR: 24-170 months). Bronchiectasis was linked to underlying conditions in 22 cases (62.9%), such as primary immunodeficiency, chronic aspiration, and primary ciliary dyskinesia. Thirteen children had infectious-associated bronchiectasis (37.1%), with four cases related to pulmonary tuberculosis. At diagnosis, cystic bronchiectasis was most common (n = 17, 48.6%), followed by varicose (n = 13, 37.1%) and cylindrical bronchiectasis (n = 5, 14.3%). Pulmonary exacerbation occurred in 28 (80%) children, with a higher rate in noninfectious bronchiectasis than postinfectious bronchiectasis (90.9% vs 61.5%, p = 0.036). Hospitalization was required for 26 (77.1%) children, with a higher rate of noninfectious bronchiectasis than postinfectious bronchiectasis (86.3% vs 53.8%, p = 0.033).

CONCLUSIONS: Primary immune deficiency and chronic aspiration are the most common non-infective causes of non-cystic fibrosis bronchiectasis. Noninfectious bronchiectasis leads to higher exacerbation and hospitalization rates.

PMID:39980590 | PMC:PMC11840848 | DOI:10.1177/20503121251320849

Neurology. 2024 Apr 9;102(7_supplement_1):6859. doi: 10.1212/WNL.0000000000208137. Epub 2024 Apr 9.

ABSTRACT

OBJECTIVE: To report on a newborn infant with a homozygous mutation in the ACP5 gene associated with a type-1 interferonopathy, workup for possible mimics, and initiation of potentially disease-modifying immunotherapy.

BACKGROUND: Variations in the ACP5 gene causes Spondyloenchondrodysplasia with immunodeficiency (SPENCDI), a type I interferonopathy leading to multiorgan autoimmune sequalae due to increased interferon activity. The CNS is particularly susceptible resulting in developmental delay, intracranial calcification, white matter disease, atrophy, and spasticity. Herein we describe a newborn with a complex hematologic and immunologic presentation, and discuss mimics and differential diagnoses for type I interferonopathies.

DESIGN/METHODS: Retrospective chart review.

RESULTS: Petechiae on the face and trunk was noted at birth on a full-term infant boy born to consanguineous Afghani parents who previously had an infant and toddler die from unknown causes. Within 3 hours, the infant manifested full body petechiae and tachypnea. He underwent workup for familial hemophagocytic lymphohistiocytosis (due to high ferritin, D-dimer, LDH, among other abnormalities) and X-linked adrenoleukodystrophy (newborn screens indicated elevated very long chain fatty acids). Signal prolongation was observed on brain MRI within subcortical and deep white matter. On DOL 20 he was started on steroids with improvement in laboratory abnormalities but had rising liver enzymes with attempted wean of steroids. On DOL 54, trio whole exome sequencing indicated a homozygous mutation in the ACP5 gene concerning for SPENCDI, inherited from each parent. He was started on a JAK2 inhibitor, baricitinib, on DOL 68, discharged on DOL 137, meeting developmental milestones at follow up on DOL 167.

CONCLUSIONS: Presentation at birth of SPENCDI is extremely rare with only one other reported case of neonatal thrombocytopenia. As new therapies emerge with potential to impact disease course, genetic testing is indispensable. The impact of JAK2 inhibitors on preventing CNS injury and improving neurodevelopmental outcomes in type 1 interferonopathies remains to be determined. Disclosure: Dr. Varnet has nothing to disclose. Dr. Kayani has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurogene. The institution of Dr. Kayani has received research support from Neurogene. The institution of Dr. Kayani has received research support from NIH. Dr. Wang has nothing to disclose.

PMID:39977878 | DOI:10.1212/WNL.0000000000208137