In the era of precision medicine, biologicals demonstrate how therapies can be personalized and directed against new targets. This type of therapy includes different molecules such as growth factors, immune modulators, vaccines, and monoclonal antibodies (mAbs). In recent years, biologicals have been increasingly developed and authorized, although their use in children is limited compared to that in adults, due to the complexity of the pharmacokinetics and pharmacodynamics of the involved proteins, as well as other factors, such as regulations governing clinical trials. Regardless, biologicals are used with efficacy in children to treat various diseases, including oncological, hematological, atopic, and rheumatological diseases. In parallel with the increased use of biologicals, there has been an increase in the unwanted effects of these agents. This paper aims to provide physicians with a practical approach to differentiate between the types of reactions to biologicals in children, especially mAbs, based on the frequency of use, for a comprehensive allergy workup. Starting from a clinical case (i.e., phenotype), specific biomarkers of the involved molecular mechanism (i.e., endotype) are described, providing the reader with currently known instruments to guide the diagnosis. Finally, practical limitations, preventive measures, and unmet needs were discussed by a panel of experts.
Primary hyperparathyroidism (PHPT) in the pediatric population is a rare but clinically important endocrine disorder that poses significant diagnostic and therapeutic challenges. In contrast to adult PHPT, which is often detected incidentally, pediatric patients are frequently symptomatic at diagnosis, with manifestations reflecting prolonged exposure to hypercalcemia and elevated parathyroid hormone levels. Neonatal forms, particularly neonatal severe hyperparathyroidism, represent life-threatening conditions requiring prompt biochemical recognition and urgent intervention. The heterogeneity of clinical presentation and the rarity of the disease contribute to delayed diagnosis and increased risk of end-organ complications. Although hereditary syndromes are proportionally more frequent in children than in adults, sporadic PHPT remains the most common etiology in pediatric patients and is typically caused by a single parathyroid adenoma. Genetically determined forms, including multiple endocrine neoplasia syndromes, hyperparathyroidism–jaw tumor syndrome, and calcium-sensing receptor-related disorders, are often associated with multiglandular disease, earlier onset, and a higher risk of persistence or recurrence. Biochemical confirmation remains the cornerstone of PHPT diagnosis, while diagnostic imaging plays an important role in preoperative localization and surgical planning. High-resolution cervical ultrasound is the preferred first-line imaging modality in pediatric patients due to its excellent diagnostic performance and absence of ionizing radiation. Functional and advanced cross-sectional imaging techniques should be applied in a stepwise manner in selected cases with inconclusive first-line imaging or suspected ectopic disease, balancing diagnostic yield against radiation exposure. Surgical management remains the definitive treatment for pediatric PHPT. The extent of surgery is determined by disease etiology, localization findings, and intraoperative assessment, with focused parathyroidectomy favored in sporadic single-gland disease and more extensive approaches required in genetically determined forms. This review highlights a structured diagnostic and therapeutic pathway for pediatric PHPT, emphasizing the integration of biochemical testing, imaging strategies, genetic evaluation, and individualized surgical management to optimize outcomes and reduce long-term morbidity.
Various systemic and topical medications can induce ocular and periocular cutaneous adverse effects (AEs), ranging from mild to severe. These AEs may lead to ocular surface (OS) damage and, in some cases, life-threatening complications. Drug-induced ocular adverse reactions are generally classified into two primary categories: toxic reactions and/or allergic hypersensitivity reactions, which can be IgE or non-IgE-mediated. Systemic antibiotics, antivirals, and anticonvulsants can trigger adverse reactions that may involve the OS. Drugs like antihistamines, beta-blockers, antipsychotics, antidepressants, and isotretinoin are linked to dry eye disease. Topical treatments-including antibiotics, antiglaucoma medications, preservatives, contact lens solutions, and cosmetics-may elicit allergic or toxic ocular diseases. Recent evidence implicates ocular surface AEs in patients undergoing biological treatments for oncological diseases and atopic dermatitis. Epidermal growth factor receptor inhibitors, used in the treatment of several cancers, have been associated with conjunctivitis, meibomitis, dry eye, periocular skin changes, and trichomegaly. Similarly, dupilumab, the first biologic approved for treating moderate-to-severe atopic dermatitis, has also been linked to OS disease with blepharoconjunctivitis. This position paper provides a comprehensive overview of the clinical presentations, diagnostic approaches, and treatment strategies for drug-induced ocular AEs, integrating the latest literature and clinical guidelines.
Protein arginine methyltransferase 9 (PRMT9) is part of the PRMT family, and it is suspected to function in pathways relevant to neurodevelopment. It is thought to participate in alternative splicing through interactions with the splicing factor SF3B2 (SAP145). In this study, we report 26 families (35 individuals) with bi-allelic loss-of-function variants in PRMT9, implicating PRMT9 in an autosomal-recessive human disease. Individuals primarily present with a neurodevelopmental disorder characterized by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia. The mutation spectrum includes 26 different variants such as frameshifting indels, nonsense variants, missense variants, and two copy-number variants. Mapping of the disease-causing missense variants onto the crystal structure of PRMT9 revealed that several of the variants reside within the catalytically active module of PRMT9, likely impairing its methyltransferase activity and resulting in a loss of function. In skin fibroblasts derived from affected individuals, we observed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Moreover, transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals. Altogether, our findings implicate bi-allelic PRMT9 loss-of-function variants as causal for neurodevelopmental disorders.
