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A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2024) | Viewed by 11219

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Prof. Dr. Consolato M. Sergi

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1. Division of Anatomic Pathology, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
2. Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
Interests: gastrointestinal/biliary diseases; metabolic diseases; congenital heart disease; mitochondrial DNA-related cardiomyopathies; carcinogenesis (bone/liver)
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Angelo Ravelli

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Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DiNOGMI), University of Genoa, Genoa, Italy
Interests: childhood rheumatic diseases; lupus nephritis; autoantibodies

Dr. Luca Pio

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Department of Surgery, St. Jude Children’s Research Hospital, MS 133, 262 Danny Thomas Place, Memphis, TN 38105, USA
Interests: pediatric surgical oncology; neuroblastoma; robotic surgery; translational surgery; precision surgery; image-guided surgery
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Living in Liguria, gathering that the sea may be a metaphor for the human condition is not difficult. The Nobel Prize winner for literature (1975), Eugenio Montale, was born in Genoa in 1896 and spent his childhood and youth between his hometown and the picturesque village of Monterosso, in Cinque Terre. Paraphrasing Mengaldo here, the ego feels almost pulled in by the sea, and simultaneously, it is ejected and confined to the land-dwelling. Montale’s collection “Ossi di Seppia” is an evocation and allegory of the misery and marginalization of the human condition, which moved Giovanni De Toni into action.

Two years before Montale won his Nobel Prize for literature, Giovanni de Toni, an outstanding pediatrician and director of one of the largest children’s hospitals worldwide, passed away. Born in Venice in 1895, Giovanni De Toni was an Italian pediatrician. Known internationally for describing the so-called De Toni–Fanconi–Debré syndrome, he was a prominent figure in Italy, so much so that the Department of Pediatric Sciences of the University of Genoa bears his name. With his wife, Prof. Dr. De Toni also launched the “Villa Santa Chiara” in Genoa to assist disabled children. In 1933, he described a new type of pathology later known as “De Toni–Fanconi–Debré syndrome”. The disease established a cornerstone in vitamin D-resistant rickets. Later, he characterized children affected by hyperosteogenesis and was an authentic innovator in auxologic studies. According to many scholars, De Toni identified a form of infantile cortical hyperostosis, also studied in 1945 by John Caffey and William Silverman (the so-called “Caffey–De Toni disease”). In 1942, Prof. De Toni assumed the director position at the Istituto Gaslini, where he creatively transformed the approach to pediatric healthcare by instituting a free outpatient clinic within the hospital. His prominence rose during the tuberculosis epidemic, as he was the forerunner in detecting a cure with streptomycin. In the 1950s, Giovanni De Toni was remembered as a fervent breastfeeding supporter. On 1 November 1965, the pediatrician left his role at the pediatric institution. He subsequently became president of the Italian Society of Pediatrics (SIP), a position he held from 1966 to the time of his death in Genoa on 8 January 1973. This Special Issue is dedicated to his legacy at the Gaslini Children’s Hospital and to his descendants, Ettore and Teresa, who followed in his footsteps on the scientific journey.

Prof. Dr. Consolato M. Sergi
Prof. Dr. Angelo Ravelli
Dr. Luca Pio
Guest Editors

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soft tissue sarcomas
neuroblastoma

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Published Papers (11 papers)

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15 pages, 4670 KiB

Open AccessArticle

Functions of Hemp-Induced Exosomes against Periodontal Deterioration Caused by Fine Dust

by Eunhee Kim, Yoonjin Park, Mihae Yun and Boyong Kim

Int. J. Mol. Sci. 2024, 25(19), 10331; https://doi.org/10.3390/ijms251910331 - 25 Sep 2024

Viewed by 516

Abstract

Although fine dust is linked to numerous health issues, including cardiovascular, neurological, respiratory, and cancerous diseases, research on its effects on oral health remains limited. In this study, we investigated the protective effects of mature hemp stem extract-induced exosomes (MSEIEs) on periodontal cells exposed to fine dust. Using various methods, including microRNA profiling, PCR, flow cytometry, immunocytochemistry, ELISA, and Alizarin O staining, we found that MSE treatment upregulated key microRNAs, such as hsa-miR-122-5p, hsa-miR-1301-3p, and hsa-let-7e-5p, associated with vital biological functions. MSEIEs exhibited three primary protective functions: suppressing inflammatory genes while activating anti-inflammatory ones, promoting the differentiation of periodontal ligament stem cells (PDLSCs) into osteoblasts and other cells, and regulating LL-37 and MCP-1 expression. These findings suggest that MSEIEs have potential as functional biomaterials for applications in pharmaceuticals, cosmetics, and food industries. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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18 pages, 601 KiB

Open AccessArticle

Association of the Single Nucleotide Polymorphisms rs11556218, rs4778889, rs4072111, and rs1131445 of the Interleukin-16 Gene with Ovarian Cancer

by Rafał Watrowski, Eva Schuster, Toon Van Gorp, Gerda Hofstetter, Michael B. Fischer, Sven Mahner, Stefan Polterauer, Robert Zeillinger and Eva Obermayr

Int. J. Mol. Sci. 2024, 25(19), 10272; https://doi.org/10.3390/ijms251910272 - 24 Sep 2024

Viewed by 429

Abstract

Single nucleotide polymorphisms (SNPs) of the IL-16 gene have been reported to influence the risk of several cancers, but their role in ovarian cancer (OC) has not been studied. Using the restriction fragment length polymorphism (PCR-RFLP) method, we examined four IL-16 SNPs: rs11556218 (T > G), rs4778889 (T > C), rs4072111 (C > T), and rs1131445 (T > C) in blood samples from 413 women of Central European descent, including 200 OC patients and 213 healthy controls. Among the patients, 62% were postmenopausal, 84.5% were diagnosed in late stages (FIGO IIb-IV), and 73.5% had high-grade serous OC (HGSOC). Minor allele frequencies in controls were 9.2% for rs11556218 (G allele), 13.7% for rs4778889 (C allele), 10.4% for rs4072111 (T allele), and 32.3% for rs1131445 (C allele). We found significant associations of rs11556218 (G vs. T allele: OR 2.76, 95% CI 1.84–4.14, p < 0.0001) with elevated OC risk in the whole cohort (p < 0.001) and in both premenopausal (p < 0.001) and postmenopausal (p = 0.001) subgroups. These associations remained significant across heterozygote (p < 0.001), dominant (p < 0.001), and overdominant (p < 0.001) models. IL-16 rs4778889 was associated with OC risk predominantly in premenopausal women (p < 0.0001 in almost all models). In the whole cohort, the C allele was associated with OC risk (OR 1.54, CI 95% 1.06–2.23, p = 0.024), and the association of rs4778889 was significant in dominant (p = 0.019), overdominant (p = 0.033), and heterozygote (p = 0.027) models. Furthermore, rs4778889 was linked with HGSOC (p = 0.036) and endometriosis-related OC subtypes (p = 0.002). No significant associations were found for rs4072111 or rs1131445 (p = 0.81 or 0.47, respectively). In conclusion, rs11556218 and rs4778889 SNPs are associated with OC risk, especially in premenopausal women. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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13 pages, 3580 KiB

Open AccessArticle

Novel Function of Osteocalcin in Chondrocyte Differentiation and Endochondral Ossification Revealed on a CRISPR/Cas9 bglap–bglap2 Deficiency Mouse Model

by Xiang-Fang Yu, Bin Teng, Jun-Feng Li, Jian V. Zhang, Zhe Su and Pei-Gen Ren

Int. J. Mol. Sci. 2024, 25(18), 9945; https://doi.org/10.3390/ijms25189945 - 15 Sep 2024

Viewed by 604

Abstract

Endochondral ossification is the process by which cartilage is mineralized into bone, and is essential for the development of long bones. Osteocalcin (OCN), a protein abundant in bone matrix, also exhibits high expression in chondrocytes, especially hypertrophic chondrocytes, while its role in endochondral ossification remains unclear. Utilizing a new CRISPR/Cas9-mediated bglap–bglap2 deficiency (OCN^em) mouse model generated in our laboratory, we provide the first evidence of OCN’s regulatory function in chondrocyte differentiation and endochondral ossification. The OCN^em mice exhibited significant delays in primary and secondary ossification centers compared to wild-type mice, along with increased cartilage length in growth plates and hypertrophic zones during neonatal and adolescent stages. These anomalies indicated that OCN deficiency disturbed endochondral ossification during embryonic and postnatal periods. Mechanism wise, OCN deficiency was found to increase chondrocyte differentiation and postpone vascularization process. Furthermore, bone marrow mesenchymal stromal cells (BMSCs) from OCN^em mice demonstrated an increased capacity for chondrogenic differentiation. Transcriptional network analysis implicated that BMP and TGF-β signaling pathways were highly affected in OCN^em BMSCs, which is closely associated with cartilage development and maintenance. This elucidation of OCN’s function in chondrocyte differentiation and endochondral ossification contributes to a more comprehensive understanding of its impact on skeletal development and homeostasis. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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22 pages, 6264 KiB

Open AccessArticle

Identification and Validation of STC1 Act as a Biomarker for High-Altitude Diseases and Its Pan-Cancer Analysis

by Qiong Li, Zhichao Xu, Qianhui Gong and Xiaobing Shen

Int. J. Mol. Sci. 2024, 25(16), 9085; https://doi.org/10.3390/ijms25169085 - 21 Aug 2024

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Abstract

High-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), are closely related to an individual’s ability to adapt to hypoxic environments. However, specific research in this field is relatively limited, and further biomarker research and clinical trials are needed to clarify the exact role and potential therapeutic applications of key genes in high-altitude diseases. This study focuses on the role of the STC1 gene in high-altitude diseases and explores its expression patterns in different types of cancer. By using gene expression data analysis and functional experiments, we identified STC1 as a key gene affecting the development of altitude sickness. In addition, we also conducted expression and mutation analysis on STC1 in various cancer samples and found significant differences in the expression of this gene in 13 types of malignant tumors, which is associated with the hypoxic state in the tumor microenvironment. In addition, STC1 is significantly associated with patient prognosis and influences tumor immunity by mediating six types of immune cells (CD8+T cells, CD4+T cells, neutrophils, macrophages, monocytes, and B cells) in the tumor microenvironment. The expression and diagnostic value of STC1 were confirmed through GEO datasets and qPCR testing, indicating consistency with the results of bioinformatics analysis. These results indicate that STC1 is not only an important factor in the adaptive response to high-altitude diseases but may also play a role in the adaptation of cancer to low-oxygen environments. Our research provides a new perspective and potential targets for the discovery of biomarkers for high-altitude diseases and cancer treatment. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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17 pages, 6037 KiB

Open AccessArticle

SOX2, JAGGED1, β-Catenin, and Vitamin D Receptor Expression Patterns during Early Development and Innervation of the Human Inner Ear

by Petra Mikulić, Marin Ogorevc, Marin Petričević, Dean Kaličanin, Robert Tafra, Mirna Saraga-Babić and Snježana Mardešić

Int. J. Mol. Sci. 2024, 25(16), 8719; https://doi.org/10.3390/ijms25168719 - 9 Aug 2024

Viewed by 980

Abstract

Sensorineural hearing loss can be caused by lesions to the inner ear during development. Understanding the events and signaling pathways that drive inner ear formation is crucial for determining the possible causes of congenital hearing loss. We have analyzed the innervation and expression of SOX2, JAGGED1, β-catenin (CTNNB1), and vitamin D receptor (VDR) in the inner ears of human conceptuses aged 5 to 10 weeks after fertilization (W) using immunohistochemistry. The prosensory domains of the human inner ear displayed SOX2 and JAGGED1 expression throughout the analyzed period, with SOX2 expression being more extensive in all the analyzed timepoints. Innervation of vestibular prosensory domains was present at 6 W and extensive at 10 W, while nerve fibers reached the base of the cochlear prosensory domain at 7–8 W. CTNNB1 and VDR expression was mostly membranous and present during all analyzed timepoints in the inner ear, being the strongest in the non-sensory epithelium. Their expression was stronger in the vestibular region compared to the cochlear duct. CTNNB1 and VDR expression displayed opposite expression trends during the analyzed period, but additional studies are needed to elucidate whether they interact during inner ear development. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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14 pages, 13074 KiB

Open AccessArticle

Ectopic Activation of Fgf8 in Dental Mesenchyme Causes Incisor Agenesis and Molar Microdontia

by Yu Wang, Jingjing Wang, Tian Xu, Shuhui Yang, Xinran Wang, Lei Zhu, Nan Li, Bo Liu, Jing Xiao and Chao Liu

Int. J. Mol. Sci. 2024, 25(13), 7045; https://doi.org/10.3390/ijms25137045 - 27 Jun 2024

Viewed by 612

Abstract

Putatively, tooth agenesis was attributed to the initiation failure of tooth germs, though little is known about the histological and molecular alterations. To address if constitutively active FGF signaling is associated with tooth agenesis, we activated Fgf8 in dental mesenchyme with Osr-cre knock-in allele in mice (Osr2-cre^KI; Rosa26R-Fgf8) and found incisor agenesis and molar microdontia. The cell survival assay showed tremendous apoptosis in both the Osr2-cre^KI; Rosa26R-Fgf8 incisor epithelium and mesenchyme, which initiated incisor regression from cap stage. In situ hybridization displayed vanished Shh transcription, and immunostaining exhibited reduced Runx2 expression and enlarged mesenchymal Lef1 domain in Osr2-cre^KI; Rosa26R-Fgf8 incisors, both of which were suggested to enhance apoptosis. In contrast, Osr2-cre^KI; Rosa26R-Fgf8 molar germs displayed mildly suppressed Shh transcription, and the increased expression of Ectodin, Runx2 and Lef1. Although mildly smaller than WT controls prenatally, the Osr2-cre^KI; Rosa26R-Fgf8 molar germs produced a miniature tooth with impaired mineralization after a 6-week sub-renal culture. Intriguingly, the implanted Osr2-cre^KI; Rosa26R-Fgf8 molar germs exhibited delayed odontoblast differentiation and accelerated ameloblast maturation. Collectively, the ectopically activated Fgf8 in dental mesenchyme caused incisor agenesis by triggering incisor regression and postnatal molar microdontia. Our findings reported tooth agenesis resulting from the regression from the early bell stage and implicated a correlation between tooth agenesis and microdontia. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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16 pages, 8895 KiB

Open AccessArticle

Zebrafish as a Human Muscle Model for Studying Age-Dependent Sarcopenia and Frailty

by Paula Aranda-Martínez, Ramy K. A. Sayed, José Fernández-Martínez, Yolanda Ramírez-Casas, Yang Yang, Germaine Escames and Darío Acuña-Castroviejo

Int. J. Mol. Sci. 2024, 25(11), 6166; https://doi.org/10.3390/ijms25116166 - 3 Jun 2024

Cited by 1 | Viewed by 1080

Abstract

Currently, there is an increase in the aging of the population, which represents a risk factor for many diseases, including sarcopenia. Sarcopenia involves progressive loss of mass, strength, and function of the skeletal muscle. Some mechanisms include alterations in muscle structure, reduced regenerative capacity, oxidative stress, mitochondrial dysfunction, and inflammation. The zebrafish has emerged as a new model for studying skeletal muscle aging because of its numerous advantages, including histological and molecular similarity to human skeletal muscle. In this study, we used fish of 2, 10, 30, and 60 months of age. The older fish showed a higher frailty index with a value of 0.250 ± 0.000 because of reduced locomotor activity and alterations in biometric measurements. We observed changes in muscle structure with a decreased number of myocytes (0.031 myocytes/μm² ± 0.004 at 60 months) and an increase in collagen with aging up to 15% ± 1.639 in the 60-month group, corresponding to alterations in the synthesis, degradation, and differentiation pathways. These changes were accompanied by mitochondrial alterations, such as a nearly 50% reduction in the number of intermyofibrillar mitochondria, 100% mitochondrial damage, and reduced mitochondrial dynamics. Overall, we demonstrated a similarity in the aging processes of muscle aging between zebrafish and mammals. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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Review

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30 pages, 1122 KiB

Open AccessReview

Sepsis Biomarkers: Advancements and Clinical Applications—A Narrative Review

by Rong-Rong He, Guo-Li Yue, Mei-Ling Dong, Jia-Qi Wang and Chen Cheng

Int. J. Mol. Sci. 2024, 25(16), 9010; https://doi.org/10.3390/ijms25169010 - 19 Aug 2024

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Sepsis is now defined as a life-threatening syndrome of organ dysfunction triggered by a dysregulated host response to infection, posing significant challenges in critical care. The main objective of this review is to evaluate the potential of emerging biomarkers for early diagnosis and accurate prognosis in sepsis management, which are pivotal for enhancing patient outcomes. Despite advances in supportive care, traditional biomarkers like C-reactive protein and procalcitonin have limitations, and recent studies have identified novel biomarkers with increased sensitivity and specificity, including circular RNAs, HOXA distal transcript antisense RNA, microRNA-486-5p, protein C, triiodothyronine, and prokineticin 2. These emerging biomarkers hold promising potential for the early detection and prognostication of sepsis. They play a crucial role not only in diagnosis but also in guiding antibiotic therapy and evaluating treatment effectiveness. The introduction of point-of-care testing technologies has brought about a paradigm shift in biomarker application, enabling swift and real-time patient evaluation. Despite these advancements, challenges persist, notably concerning biomarker variability and the lack of standardized thresholds. This review summarizes the latest advancements in sepsis biomarker research, spotlighting the progress and clinical implications. It emphasizes the significance of multi-biomarker strategies and the feasibility of personalized medicine in sepsis management. Further verification of biomarkers on a large scale and their integration into clinical practice are advocated to maximize their efficacy in future sepsis treatment. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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17 pages, 828 KiB

Open AccessReview

Exploring the Utility of Long Non-Coding RNAs for Assessing the Health Consequences of Vaping

by Ahmad Besaratinia, Hannah Blumenfeld and Stella Tommasi

Int. J. Mol. Sci. 2024, 25(15), 8554; https://doi.org/10.3390/ijms25158554 - 5 Aug 2024

Viewed by 1413

Abstract

Electronic cigarette (e-cig) use, otherwise known as “vaping”, is widespread among adolescent never-smokers and adult smokers seeking a less-harmful alternative to combustible tobacco products. To date, however, the long-term health consequences of vaping are largely unknown. Many toxicants and carcinogens present in e-cig vapor and tobacco smoke exert their biological effects through epigenetic changes that can cause dysregulation of disease-related genes. Long non-coding RNAs (lncRNAs) have emerged as prime regulators of gene expression in health and disease states. A large body of research has shown that lncRNAs regulate genes involved in the pathogenesis of smoking-associated diseases; however, the utility of lncRNAs for assessing the disease-causing potential of vaping remains to be fully determined. A limited but growing number of studies has shown that lncRNAs mediate dysregulation of disease-related genes in cells and tissues of vapers as well as cells treated in vitro with e-cig aerosol extract. This review article provides an overview of the evolution of e-cig technology, trends in use, and controversies on the safety, efficacy, and health risks or potential benefits of vaping relative to smoking. While highlighting the importance of lncRNAs in cell biology and disease, it summarizes the current and ongoing research on the modulatory effects of lncRNAs on gene regulation and disease pathogenesis in e-cig users and in vitro experimental settings. The gaps in knowledge are identified, priorities for future research are highlighted, and the importance of empirical data for tobacco products regulation and public health is underscored. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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27 pages, 1592 KiB

Open AccessReview

A Glimpse into Humoral Response and Related Therapeutic Approaches of Takayasu’s Arteritis

by Shuning Guo, Yixiao Tian, Jing Li and Xiaofeng Zeng

Int. J. Mol. Sci. 2024, 25(12), 6528; https://doi.org/10.3390/ijms25126528 - 13 Jun 2024

Viewed by 1088

Abstract

Takayasu’s arteritis (TAK) manifests as an insidiously progressive and debilitating form of granulomatous inflammation including the aorta and its major branches. The precise etiology of TAK remains elusive, with current understanding suggesting an autoimmune origin primarily driven by T cells. Notably, a growing body of evidence bears testimony to the widespread effects of B cells on disease pathogenesis and progression. Distinct alterations in peripheral B cell subsets have been described in individuals with TAK. Advancements in technology have facilitated the identification of novel autoantibodies in TAK. Moreover, emerging data suggest that dysregulated signaling cascades downstream of B cell receptor families, including interactions with innate pattern recognition receptors such as toll-like receptors, as well as co-stimulatory molecules like CD40, CD80 and CD86, may result in the selection and proliferation of autoreactive B cell clones in TAK. Additionally, ectopic lymphoid neogenesis within the aortic wall of TAK patients exhibits functional characteristics. In recent decades, therapeutic interventions targeting B cells, notably utilizing the anti-CD20 monoclonal antibody rituximab, have demonstrated efficacy in TAK. Despite the importance of the humoral immune response, a systematic understanding of how autoreactive B cells contribute to the pathogenic process is still lacking. This review provides a comprehensive overview of the biological significance of B cell-mediated autoimmunity in TAK pathogenesis, as well as insights into therapeutic strategies targeting the humoral response. Furthermore, it examines the roles of T-helper and T follicular helper cells in humoral immunity and their potential contributions to disease mechanisms. We believe that further identification of the pathogenic role of autoimmune B cells and the underlying regulation system will lead to deeper personalized management of TAK patients. We believe that further elucidation of the pathogenic role of autoimmune B cells and the underlying regulatory mechanisms holds promise for the development of personalized approaches to managing TAK patients. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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8 pages, 527 KiB

Open AccessCase Report

Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy

by Kioa L. Wijnsma, Anne M. Schijvens, Romy N. Bouwmeester, Lonneke A. M. Aarts, Lambertus (Bert) P. van den Heuvel, Charlotte A. Haaxma and Nicole C. A. J. van de Kar

Int. J. Mol. Sci. 2024, 25(14), 7604; https://doi.org/10.3390/ijms25147604 - 11 Jul 2024

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Abstract

Thrombotic microangiopathy (TMA) in association with RNA exosome encoding mutations has only recently been recognized. Here, we present an infant (female) with an EXOSC5 mutation (c.230_232del p.Glu77del) associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA. At the age of four months, she presented with signs of septic illness, after which she developed TMA. A stool culture showed rotavirus as a potential trigger. The patient received eculizumab once, alongside supportive treatment, while awaiting diagnostic analysis of TMA, including genetic complement analysis, all of which were negative. Eculizumab was withdrawn and the patient’s TMA recovered quickly. A review of the literature identified an additional four patients (age < 1 year) who developed TMA after a viral trigger in the presence of mutations in EXOSC3. The recurrence of TMA in one of these patients with an EXOSC3 mutation while on eculizumab treatment underscores the apparent lack of responsiveness to C5 inhibition. In conclusion, mutations in genes influencing the RNA exosome, like EXOSC3 and EXOSC5, characterized by neurodevelopment and neurodegenerative disorders could potentially lead to TMA in the absence of complement dysregulation. Hence, these patients were likely non-responsive to eculizumab. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy)

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A Commemorative Special Issue in Honor of Prof. Giovanni De Toni: A Pediatrician and Innovator at the Gaslini Children’s Hospital, Genoa, Italy

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