Research

Mol Med Rep. 2025 Mar;31(3):81. doi: 10.3892/mmr.2025.13446. Epub 2025 Jan 31.

ABSTRACT

Cartilage‑hair hypoplasia (CHH) is an autosomal recessive form of metaphyseal chondrodysplasia caused by RNA component of mitochondrial RNA processing endoribonuclease (RMRP) gene variants; however, its molecular etiology remains unclear. Whole‑exome sequencing was performed to detect possible pathogenic variants in a patient with a typical short stature and sparse hair. A co‑segregation analysis was also conducted and variants in the family members of the patient were confirmed by Sanger sequencing. A novel compound heterozygous variant in RMRP (NR_003051.4: n.‑21_‑2dup and n.197C>T) was identified in the affected patient. Data from 2 years and 4 months of follow‑up showed a positive effect of growth hormone (GH) therapy on height. Subsequently, two gene expression profiles associated with CHH were obtained from the EMBL‑EBI ENA and ArrayExpress databases. Differentially expressed genes between patients with CHH and healthy controls were selected using R software and were subjected to core analysis using ingenuity pathway analysis (IPA) software. IPA core analysis showed that the ‘cell cycle checkpoints’ was the most prominent canonical pathway, and the top enriched diseases and functions included various types of cancer, immunological diseases, development disorders and respiratory diseases. The integrative analysis displayed that RMRP can regulate the aberrant expression of downstream targets mainly via the transcription factor TP53, which results in the inhibition of ‘cell cycle checkpoints’; eventually, functions associated with the CHH phenotype, such as ‘growth failure or short stature’ are activated. In conclusion, novel disease‑causing genetic variants of RMRP expand the genetic etiology of CHH, which must be clinically differentiated from achondroplasia. The findings of the present study provide new insights into the mechanisms underlying CHH.

PMID:39886981 | DOI:10.3892/mmr.2025.13446

Leuk Lymphoma. 2025 Jan 28:1-15. doi: 10.1080/10428194.2025.2456970. Online ahead of print.

ABSTRACT

Over the past two decades, there has been a continuous improvement in outcome for patients with indolent lymphoma (iNHL) resulting in a gradual accumulation of survivors. While life expectancy in the current era approaches that of the lymphoma-free population, patients continue to experience lifelong complications of the disease and its treatment affecting general health, emotional, psychological and social wellbeing, relationships, employment, finances, and fitness. Contemporary care models while suited to the management of lymphoma are often lacking when it comes to identification and management of these additional needs. Given improvements in physical survival achieved over the past decades, it is timely for us to focus on other issues affecting patient wellbeing including immunodeficiency and infection, second cancers, cardiovascular disease, bone health, psychological wellbeing, and sexual health. Many of these aspects are in the domain of the primary care physician; however, there is limited guidance on how these issues should be addressed. It is now time for us to engage our patients, their caregivers, and other healthcare providers in care aspects beyond the lymphoma diagnosis, so they can anticipate a rich and full life, free from both direct and indirect consequences of the lymphoma diagnosis.

PMID:39876569 | DOI:10.1080/10428194.2025.2456970

Wiad Lek. 2024;77(12):2475-2480. doi: 10.36740/WLek/197084.

ABSTRACT

OBJECTIVE: Aim: To investigate the effect of succinic acid on the humoral component of the immune system in rats.

PATIENTS AND METHODS: Materials and Methods: The study was conducted on two groups of mature non-linear white rats (males) of similar weight (200-270 g, aged 6-8 months), with 5 animals in each group. The control group was fed a standard diet with free access to water throughout the experiment. Rats in the experimental group were subcutaneously injected with a 0,1% solution of succinic acid in a liposomal emulsion at a dose of 20 cm³ for five days. The state of the humoral component of the immune system was assessed by measuring serum immunoglobulins A, M, and G using solid-phase enzyme-linked immunosorbent assay. Circulating immune complexes were determined in a 40% solution of polyethylene glycol.

RESULTS: Results: Under the influence of succinic acid in liposomal emulsion the content of class A immunoglobulins increased by 44,0% (p<0.01) compared to rats in the control group. The activation of class A immunoglobulin synthesis points to the provision of local immunity of the mucous membranes in the rat’s body. The content of class M immunoglobulins increased by 61,0% (p<0.001) compared to the control group rats. This high activity of class M immunoglobulins indicates their rapid activation in the body of rats in response to primary contact with succinic acid in liposomal emulsion. The content of class G immunoglobulins increased by 36,0% (p<0.05) compared to the control group rats. No clinical deviations from physiological norms were observed in the rats after the use of succinic acid in liposomal emulsion. After the use of succinic acid in liposomal emulsion in the experimental group of rats, the concentration of CICs increased by 15,0% (p<0.05) compared to the control group rats. In our case, the increase in CIC levels is not correlated with clinical manifestations but is a consequence of increased levels of class M and G immunoglobulins.

CONCLUSION: Conclusions: The succinic acid in liposomal emulsion activates the production of class A, M, G immunoglobulins, circulating immune complexes, it prevents the development of secondary immunodeficiency and has a positive impact on the humoral branch of the immune system in rats.

PMID:39874332 | DOI:10.36740/WLek/197084

Front Immunol. 2025 Jan 13;15:1517543. doi: 10.3389/fimmu.2024.1517543. eCollection 2024.

ABSTRACT

Activated PI3K delta syndrome (APDS) is a primary immunodeficiency that is caused by mutations in the PI3K signalling pathway resulting in either gain-of-function or loss-of-function phenotypes of APDS 1 and 2. Malignancy is one of the most serious complications associated with APDS patients, with the most commonly occurring of these being lymphoma, and is the most common cause of death in APDS patients. Management of APDS is complex and variable due to the heterogeneous nature of the disease and ranges from antimicrobial and immunosuppressant agents to haematopoetic stem cell transplantation. More recently, an increasing level of interest has been shown in the use of more targeted agents such as PI3Kδ-specific inhibitors. Here, we provide expert perspective on the suspected causality of a case of lymphoma observed in a 20-year-old female patient who was included in a clinical trial of leniolisib, a PI3K inhibitor.

PMID:39872539 | PMC:PMC11770023 | DOI:10.3389/fimmu.2024.1517543

Tremor Other Hyperkinet Mov (N Y). 2025 Jan 20;15:4. doi: 10.5334/tohm.992. eCollection 2025.

ABSTRACT

BACKGROUND: Ataxia-telangiectasia (Louis-Bar syndrome) is a rare genetic disorder characterized by progressive ataxia, ocular telangiectasias, immunodeficiency and increased cancer risk due to impaired DNA repair.

PHENOMENOLOGY SHOWN: Thorough clinical and subsequently radiological examination in a 19-year-old woman with a history of previously undiagnosed, progressive gait ataxia since early childhood, diffuse large B-cell lymphoma and severe combined immunodeficiency revealed the eponymous features of the disease, ocular telangiectasias and cerebellar atrophy, enabling targeted genetic testing.

EDUCATIONAL VALUE: Ocular telangiectasias represent an important clue for a diagnosis of ataxia-telangiectasia in young patients with progressive ataxia, implicating awareness of increased malignancy risk and treatment of immunodeficiency.

HIGHLIGHTS: Ataxia-telangiectasia is a rare genetic disorder characterized by its eponymous features, progressive cerebellar ataxia and ocular telangiectasias. These signs can help in establishing an early diagnosis, hence preventing, or addressing secondary complications of the disease caused by impaired DNA repair, such as malignancies, immunodeficiency, and increased radiation sensitivity.

PMID:39867503 | PMC:PMC11758811 | DOI:10.5334/tohm.992

Cell Mol Biol Lett. 2025 Jan 26;30(1):12. doi: 10.1186/s11658-025-00691-0.

ABSTRACT

Vacuolization of hematopoietic precursors cells is a common future of several otherwise non-related clinical settings such as VEXAS, Chediak-Higashi syndrome and Danon disease. Although these disorders have a priori nothing to do with one other from a clinical point of view, all share abnormal vacuolization in different cell types including cells of the erythroid/myeloid lineage that is likely the consequence of moderate to drastic dysfunctions in the ubiquitin proteasome system and/or the endo-lysosomal pathway. Indeed, the genes affected in these three diseases UBA1, LYST or LAMP2 are known to be direct or indirect regulators of lysosome trafficking and function and/or of different modes of autophagy. Furthermore, all three genes are highly expressed in the more mature myeloid cells pointing out their likely important function in these cells. LAMP2 deficiency for instance is known to be associated with alterations of lysosome architecture and function. It is thus well established that different cell types from Danon disease patients that harbor invalidating mutations in LAMP2 exhibit giant lysosomes containing undigested materials characteristic of defects in the fusion of lysosomes with autophagosomes, a feature also found in VEXAS and CHS. Other similarities regarding these three diseases include granulocyte and monocyte dysfunctions and a recurrent inflammatory climate. In the present review we discuss the possibility that some common clinical manifestations of these diseases, notably the hematopoietic ones are consecutive to a dysfunction of the endo-lysosomal pathway in myeloid/erythroid progenitors and in mature myeloid cells including neutrophiles, monocytes and macrophages. Finally, we propose reacidification as a way of reinducing lysosome functionalities and autophagy as a potential approach for a better management of these diseases.

PMID:39865233 | DOI:10.1186/s11658-025-00691-0

Zhonghua Bing Li Xue Za Zhi. 2025 Feb 8;54(2):203-209. doi: 10.3760/cma.j.cn112151-20241209-00838.

ABSTRACT

极早发炎症性肠病是6岁之前儿童发生的具有炎症性肠病样症状的一组疾病，包括真正的炎症性肠病和单基因炎症性肠病（mIBD），后者涉及多种与原发免疫缺陷相关基因。极早发炎症性肠病，包括mIBD，病理组织学表现多样，临床表现及临床治疗反应均存在不同。本文总结了近年认识的常见mIBD和极早发炎症性肠病的病理诊断进展。.

PMID:39863544 | DOI:10.3760/cma.j.cn112151-20241209-00838

BMC Infect Dis. 2025 Jan 25;25(1):120. doi: 10.1186/s12879-025-10488-3.

ABSTRACT

BACKGROUND: Mycobacterium avium complex (MAC) is a common pathogen causing non-tuberculous mycobacterial infections, primarily affecting the lungs. Disseminated MAC disease occurs mainly in immunocompromised individuals, such as those with acquired immunodeficiency syndrome, hematological malignancies, or those positive for anti-interferon-γ antibodies. However, its occurrence in solid organ transplant recipients is uncommon. Herein, we report a rare case of disseminated MAC disease following liver transplantation, which led to an obstructive mass in the intestinal tract that required differentiation from a malignant tumor.

CASE PRESENTATION: A 76-year-old woman, who had undergone living-donor liver transplantation 15 years earlier for primary biliary cirrhosis, presented with persistent fever and vomiting three months before admission. She had a history of pulmonary MAC diagnosed five years earlier but remained untreated due to stable lung lesions. Abdominal computed tomography (CT) during her current illness revealed new thickening at the jejuno-jejunal anastomosis site and enlarged mesenteric lymph nodes. Positron emission tomography-CT indicated increased uptake at these sites, suggesting a possible malignancy. Endoscopy revealed an elevated lesion with circumferential ulcers, leading to a suspicion of primary malignant lymphoma. However, biopsies showed CD68-positive histiocyte-like cells with numerous acid-fast bacilli, confirming disseminated MAC infection. Despite ongoing antimicrobial therapy, the patient’s intestinal lesions persisted, and she required prolonged hospitalization and interventions for bile drainage and enteral nutrition.

CONCLUSION: This case underscores the importance of considering disseminated MAC as a potential complication in solid organ transplant recipients, even when a long period has passed since transplantation. Disseminated MAC can mimic malignancy, presenting with significant lesions causing intestinal obstruction. Awareness and thorough differential diagnosis are essential for timely and accurate management in such complex cases. The patient’s outcome emphasizes the need for vigilance in managing long-term immunosuppressed patients, particularly when they present with atypical infections.

PMID:39863833 | DOI:10.1186/s12879-025-10488-3

Genes (Basel). 2024 Dec 26;16(1):18. doi: 10.3390/genes16010018.

ABSTRACT

Background: The advent of next-generation sequencing (NGS) has revolutionized the analysis of genetic data, enabling rapid identification of pathogenic variants in patients with inborn errors of immunity (IEI). Sometimes, the use of NGS-based technologies is associated with challenges in the evaluation of the clinical significance of novel genetic variants. Methods: In silico prediction tools, such as SpliceAI neural network, are often used as a first-tier approach for the primary examination of genetic variants of uncertain clinical significance. Such tools allow us to parse through genetic data and emphasize potential splice-altering variants. Further variant assessment requires precise RNA assessment by agarose gel electrophoresis and/or cDNA Sanger sequencing. Results: We found two novel heterozygous variants in the coding region of the LYST gene (c.10104G>T, c.10894A>G) in an individual with a typical clinical presentation of Chediak-Higashi syndrome (CHS). The SpliceAI neural network predicted both variants as probably splice-altering. cDNA assessment by agarose gel electrophoresis revealed the presence of abnormally shortened splicing products in each variant’s case, and cDNA Sanger sequencing demonstrated that c.10104G>T and c.10894A>G substitutions resulted in a shortening of the 44 and 49 exons by 41 and 47 bp, respectively. Both mutations probably lead to a frameshift and the formation of a premature termination codon. This, in turn, may disrupt the structure and/or function of the LYST protein. Conclusions: We identified two novel variants in the LYST gene, predicted to be deleterious by the SpliceAI neural network. Agarose gel cDNA electrophoresis and cDNA Sanger sequencing allowed us to verify inappropriate splicing patterns and establish these variants as disease-causing.

PMID:39858566 | DOI:10.3390/genes16010018

J Clin Med. 2025 Jan 9;14(2):363. doi: 10.3390/jcm14020363.

ABSTRACT

Background/Objectives: The nuclear factor (NF)-kB essential modulator (NEMO) has a crucial role in the NFκB pathway. Hypomorphic IKBKG pathogenic variants cause ectodermal dysplasia with immunodeficiency (EDA-ID) in affected males. However, heterozygous amorphic IKBKG variants could be responsible for Incontinentia Pigmenti (IP) in female carriers. Typically, IP patients do not exhibit immunodeficiency, although hypomorphic variants might lead to immunodeficiency in female IP patients. Here, we report the case of an IKBKG female carrier, with no IP but an unexpected picture of immunodeficiency. She had a positive family history for the same genetic condition. Methods: We performed immunological, molecular, and functional analysis to evaluate NEMO contribution. Results: The patient was healthy until the age of 25 when severe asthma and Hashimoto thyroiditis occurred. She had HLAB27-positive ankylosing spondylitis, non-tubercular mycobacteriosis, and pulmonary aspergillosis infections. We found CD19+ B cell lymphopenia and T cell subset alterations. Sanger sequencing revealed a heterozygous IKBKG variant at position +1 of the 5′ UTR of the gene which disrupted the normal pre-mRNA splicing. We observed a decreased NEMO protein expression, a reduced level of mRNA, and a defective NF-κB pathway. Conclusions: These findings suggest a possible correlation between the partial loss of NEMO function and the immunodeficiency observed in this patient. This case could expand our understanding of NEMO deficiency in female carriers.

PMID:39860371 | DOI:10.3390/jcm14020363