Clinical Genetics, Medical Genetics, Human Genetics, Pedaitrics
81
Scopus Publications
Scopus Publications
9q34.11 Microduplications Encompassing SET Gene Are Associated With Neurodevelopmental Disorder and Recurrent Dysmorphisms Alessandro De Falco, Marie Vincent, Gaëlle Vieville, Marjolaine Gauthier, Klaus Dieterich, et al. American Journal of Medical Genetics Part A, 2026 Copy number variants (CNV) are a major cause of neurodevelopmental disorders. Novel CNV syndromes may still be unrecognized. We report a 9q34.11 microduplication syndrome characterized by neurodevelopmental impairment and recurrent facial anomalies. Following the identification of a de novo 9q34.11 microduplication involving the SET and SPTAN1 genes in an 11‐year‐old girl with speech delay, intellectual disability, and behavioral abnormalities, we identified 13 additional patients with overlapping duplications. Besides the neurodevelopmental disorder, clinical features observed among affected individuals included recurrent dysmorphic features, such as midface hypoplasia and thin lips. The minimal region of overlap among these cases contained the SET gene, suggesting that its triplosensitivity may play a role in the observed phenotypes.
Non-Convulsive Status Epilepticus and Mild Neurodevelopmental Phenotype in a Female with a Novel p.Thr657Ala Variant in the GRIA3 Gene Alfonso Rubino, Giorgia Bruno, Gabriella Errichiello, Fabio Acquaviva, Daniele De Brasi, et al. Children, 2025 Background: The GRIA3 gene encodes the GluA3 subunit of AMPA-type glutamate receptors, which are crucial for excitatory neurotransmission in the central nervous system. Pathogenic GRIA3 variants cause X-linked neurodevelopmental disorders of varying severity, including developmental delay, behavioral abnormalities, and epilepsy. Case Summary: Here, we present the case of a seven-year-old female patient presenting with developmental delay, spastic gait, and non-convulsive status epilepticus (NCSE), who was found to carry a novel de novo GRIA3 missense variant (c.1969A > G; p.Thr657Ala). The EEG revealed high-amplitude diffuse rhythmic theta/delta activity consistent with NCSE. A brain MRI showed transient cortical and thalamic T2-FLAIR hyperintensities, likely postictal. Metabolic investigations were unremarkable. Following intensive treatment with levetiracetam and midazolam, the patient gradually recovered to her baseline neurological status. Genetic Finding: Whole-exome sequencing (WES) identified a novel de novo variant in GRIA3, c.1969A > G; p.Thr657Ala, involving the replacement of threonine with alanine at position 657 within the coding region. Significance: This case expands the clinical and molecular spectrum of GRIA3-related disorders, demonstrating that females with de novo variants may experience severe epilepsy. This is the first reported case of NCSE in a female patient with a GRIA3 variant.
Unusual Onset of Hereditary Hemorrhagic Telangiectasia Due to Somatic Mutational Mosaicism: Case Report and Review of the Literature Virginia Mirra, Margherita Rosa, Cristina Fontanella, Martina Mancuso, Fabio Antonelli, et al. Children, 2025 Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu–Osler–Weber syndrome, is a disorder of angiogenesis characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. This rare autosomal dominant disorder is caused by pathogenic variants in the ENG and ACVRL1 genes, and only 1–3% of case variants occur in SMAD4. HHT clinical manifestations include telangiectasias, epistaxis, and arteriovenous malformations in multiple organ systems. Clinical diagnosis is based on Curaçao Criteria. Here, we describe a pauci-symptomatic 10-year-old girl with an orbital and sinus infectious disease. Her clinical history was unremarkable, except for sporadic, self-limiting epistaxis episodes. She showed finger clubbing and low oxygen saturation levels on pulse oximetry, suggesting a chronic lung disease, and a large lung arteriovenous malformation. She also developed acute neurological symptoms, with evidence of multiple cerebral abscess lesions on MRI. HHT was therefore suspected and confirmed by genetic analysis, which revealed a de novo pathogenic variant in the ENG gene [c.1183G>T p.(Glu395Ter)] found in only 15% of the reads from NGS analysis, performed on peripheral blood lymphocytes, indicating a possible mutational mosaicism. This case outlines that HHT could present with unusual clinical symptoms highlighting the importance of diagnosis using both clinical criteria and genetic test.
Acute Otomastoiditis in Children: An Observational Study on the Role of Mastoid Morphology in the Development of Intracranial Complications Camilla Russo, Simone Coluccino, Marco Sarno, Antonia Pascarella, Alida Casale, et al. Journal of Clinical Medicine, 2025 Background: Acute otomastoiditis (AOM) may occasionally progress to severe intracranial complications in children. While immunological and microbiological factors have been studied, the role of temporal bone anatomical variants remains less well-defined. The aim of this study is to investigate the prevalence of anatomical variants in pediatric patients with acute complicated otomastoiditis (ACOM) compared to those with uncomplicated ones (AUOM) and healthy controls (HC) and assess their potential association with intracranial complication patterns. Methods: This retrospective, single-center study reviewed clinical and neuroradiological data of patients aged 0–16 years admitted for AOM between 2018 and 2025. ACOM patients were compared to AUOM and HC groups (the latter undergoing neuroimaging for minor head trauma). Two experienced neuroradiologists evaluated imaging to identify anatomical variants involving the following: (1) sigmoid sinus and emissary veins; (2) tegmen tympani; and (3) mastoid pneumatization. Statistical analyses assessed prevalence differences across groups. Results: Among 282 AOM patients, 58 had intracranial complications. Anatomical variants were significantly more frequent in ACOM patients versus both AUOM and HC (p < 0.01). In this subgroup, vascular anatomical variants were notably associated with vascular or combined (vascular and infectious) complications; tegmen tympani and mastoid pneumatization variants showed no significant subgroup associations. Conclusion: Anatomical variants, particularly vascular anomalies of the sigmoid sinus and emissary veins, appear to increase pediatric AOM patients’ susceptibility to intracranial complications. Recognition of these configurations through early neuroimaging could aid risk stratification and improve diagnostic and therapeutic strategies.
Early Diagnosis and Follow-Up of a Novel Homozygous Mutation in SOST Gene in a Child with Recurrent Facial Palsy: A Case Report and Review of the Literature Fabio Acquaviva, Giorgia Bruno, Federica Palladino, Alfonso Rubino, Carmela Russo, et al. International Journal of Molecular Sciences, 2025 Recurrent facial palsy is a rare event in the pediatric population, mostly idiopathic or associated with common comorbidities or, rarely, observed in syndromic conditions. However, some cases are difficult to explain and need more accurate diagnostic approaches. In this work, we describe a pediatric case of recurrent facial palsy secondary to hyperostosis of the skull and narrowing of the neural foramina related to a SOST-related sclerosing bone dysplasia. To our knowledge, this is the first Italian case that is also related to a novel loss-of-function variant in the SOST gene. We highlight the clinical relevance of a proper early diagnosis and the need for correct monitoring of the clinical evolution, considering the natural history of the disease, to prevent/reduce severe neurological complications.
Expanding the Mutational Spectrum of TSPEAR in Ectodermal Dysplasia Type 14: A Familial Case Study Roberto Sirica, Alessandro Ottaiano, Daniele De Brasi, Simone Marcella, Fabio Acquaviva, et al. Genes, 2025 Background: Ectodermal dysplasia (ED) encompasses a heterogeneous group of genetic disorders affecting ectoderm-derived structures such as hair, teeth, nails, and sweat glands. Among these, variants in TSPEAR (Thrombospondin-type laminin G domain and epilepsy-associated repeats) have been implicated in autosomal recessive ED type 14 (OMIM 618180), predominantly manifesting with dental anomalies and hair dysplasia. However, the mutational spectrum of TSPEAR remains incompletely characterized. Methods: Two female siblings (ID#1 and ID#4) were clinically evaluated for ED. Genetic analysis, including next-generation sequencing (NGS) and Sanger validation, was conducted to identify TSPEAR variants. A segregation study confirmed inheritance patterns within the family. Results: Both affected siblings exhibited hallmark features of TSPEAR-related ED14, including oligodontia with dysmorphic, pointed maxillary central incisors. Hair thinning and cutaneous angiomas were predominant in ID#4. Genetic analysis identified two compound heterozygous variants in TSPEAR: c.543-1G>A, a splice-site variant likely to disrupt mRNA processing, and NM_144991.2:c.1251G>C(p.Gln417His), a missense variant with predicted deleterious effects. Segregation analysis confirmed maternal and paternal inheritance of the respective variants. A third sibling, ID#5, was identified as a heterozygous carrier without clinical manifestations. Conclusions: This study contributes to the expanding understanding of TSPEAR-related ED14 by providing novel genotype–phenotype correlations.
Diagnosis "upon the face": Good the first Margherita Rosa, Michele Biccardi, Giuseppina Bernardo Quaderni ACP, 2025 We describe the case of a 7-month-old infant with iatrogenic Cushing’s syndrome caused by the topical administration of clobetasol propionate. Since the admission, we hypothesized that the child’s phenotype and her hormonal profile, indicative of adrenal insufficiency, were secondary to corticosteroid administration. However, the diagnostic and therapeutic process became complicated and prolonged due to the language barrier and the family’s social and cultural context. A careful and clear medical history provided the resolution of this challenging case more than any other laboratory or instrumental investigation.
Refractory Chylothorax and Ventricular Hypertrophy Treated with Trametinib in a Patient with Noonan Syndrome: 18-Month Follow-Up Antonia Pascarella, Giuseppe Limongelli, Alessandro De Falco, Elia Marco Paolo Minale, Giangiacomo Di Nardo, et al. Children, 2024 RASopathies are a group of genetic syndromes caused by germline mutations in genes involved in the RAS/Mitogen-Activated Protein Kinase signaling pathway, which regulates cellular proliferation, differentiation, and angiogenesis. Despite their involvement at different levels of this pathway, RASopathies share overlapping clinical phenotypes. Noonan syndrome is the most prevalent RASopathy, with an estimated incidence of 1 in 2500 live births, and it is typically inherited in an autosomal dominant manner, with 50% of cases involving gain-of-function mutations in the PTPN11 gene. De novo mutations are common, accounting for 60% of cases. The phenotype of Noonan syndrome includes characteristic facial and physical features, congenital cardiac defects, lymphatic and cerebrovascular anomalies, renal malformations, hematological abnormalities, developmental issues, and an increased risk of cancer. Severe congenital cardiac defects and lymphatic abnormalities significantly impact prognosis, contributing to increased morbidity and mortality. Recent therapeutic advancements have introduced trametinib, an MEK1/2 inhibitor, for treating Noonan syndrome patients with severe cardiac and lymphatic complications. To assess its efficacy, here, we present a case of a newborn with Noonan syndrome who exhibited refractory chylothorax, ventricular hypertrophy, and pulmonary stenosis who was treated with trametinib. The patient demonstrated significant improvement in chylothorax and left ventricular hypertrophy, though pulmonary stenosis persisted. This case further confirms trametinib’s potential as a therapeutic option for severe Noonan syndrome complications, emphasizing the need for further clinical trials to optimize treatment protocols and evaluate long-term outcomes.
Scurvy in childhood: do not forget it Maria Simona Sabbatino, Federica De Seta, Daniele De Brasi, Claudio Santoro, Francesco Esposito, et al. Minerva Pediatrics, 2022
Thyroid transcription factor 1 phosphorylation is not required for protein kinase A-dependent transcription of the thyroglobulin promoter Cell Growth and Differentiation, 2000
