Paola Giordano

Cystic fibrosis (CF) is a multisystem genetic disorder in which malnutrition has historically been a major determinant of disease severity. The advent of CFTR modulators has significantly altered the nutritional and functional profile of CF patients. This systematic review, conducted following PRISMA guidelines and registered on PROSPERO, summarizes studies published from 2012 to 2025 that evaluated the impact of CFTR modulators on nutritional status, body composition, and respiratory function, with a particular focus on the relationship between BMI changes and FEV₁. Seventeen studies including both pediatric and adult populations were identified and analyzed. All studies reported significant increases in BMI following modulator therapy, ranging from +0.9 to +1.6 kg/m² after 6–12 months of elexacaftor/tezacaftor/ivacaftor (ETI), accompanied by improvements in FEV₁ of 7–13 percentage points. Weight gain was primarily due to increases in fat mass (60–75%). Improvements in albumin, prealbumin, and vitamin levels, along with reductions in C-reactive protein (CRP) and fecal calprotectin, reflected systemic metabolic recovery. However, a marked increase in overweight and obesity (up to 40%), together with increased visceral adiposity, has also been observed. Overall, CFTR modulators result in significant nutritional and functional improvements, highlighting the need for strategies that prioritize overall metabolic health rather than weight gain alone.

Background: The aim of this study was to identify patient clusters based on acute symptom profiles and individual characteristics most likely to develop pediatric post-acute sequelae of SARS-CoV-2 infection (PASC), as well as clusters among patients with PASC based on post-acute sequelae and associated characteristics. Methods: This multicenter cohort study in 12 Italian pediatric units enrolled patients aged 0–17 years within three months of a laboratory-confirmed SARS-CoV-2 infection. Participants who completed at least two surveys developed by the ISARIC over one year were analyzed. PASC was defined per WHO criteria. Multiple Correspondence Analysis and Hierarchical Clustering were performed. Results: Of 1137 children enrolled, 850 (76%) completed at least two surveys. The most prevalent age group was older children (6–11 years) (46%); adolescents (12–17) and young children (0–5) were numerically similar. Males were more represented (51.9%), except for the adolescent group (45.1%). PASC occurred in 32.8% of participants, with the distribution of sequelae types varying by age. Clustering in COVID-19 cases identified three clusters: young children mainly presented with respiratory symptoms and with a higher risk of hospitalization, while older children were spared in both acute and post-acute phases. Adolescents, particularly females, reported more pronounced acute symptoms and developed PASC more frequently. Clustering analysis of cases with PASC identified three clusters, confirming these age-related patterns. Young children still exhibited respiratory sequelae, and older children confirmed good recovery with minimal complications, while adolescents, especially females, remained the most affected subgroup, reporting persistent neuropsychological sequelae such as fatigue and insomnia. Conclusions: Findings support age-tailored follow-up, emphasizing respiratory monitoring for young children and targeted neuropsychological care for adolescents, particularly girls.

Pediatric type 1 diabetes (T1D) disrupts musculoskeletal development during critical windows of growth, puberty, and peak bone mass accrual. Beyond classic micro- and macrovascular complications, accumulating evidence shows a dual burden of diabetic bone disease—reduced bone mineral density, microarchitectural deterioration, and higher fracture risk—and diabetic myopathy, characterized by loss of muscle mass, diminished strength, and metabolic dysfunction. Mechanistically, chronic hyperglycemia, absolute or functional insulin deficiency, and glycemic variability converge to suppress PI3K–AKT–mTOR signaling, activate FoxO-driven atrogenes (atrogin-1, MuRF1), and impair satellite-cell biology; advanced glycation end-products (AGEs) and RAGE signaling stiffen extracellular matrix and promote low-grade inflammation (IL-6, TNF-α/IKK/NF-κB), while oxidative stress and mitochondrial dysfunction further compromise the bone–muscle unit. In vitro, ex vivo, and human studies consistently link these pathways to lower BMD and trabecular/cortical quality, reduced muscle performance, and increased fractures—associations magnified by poor metabolic control and longer disease duration. Prevention prioritizes tight, stable glycemia, daily physical activity with weight-bearing and progressive resistance training, and optimized nutrition (adequate protein, calcium, vitamin D). Treatment is individualized: supervised exercise-based rehabilitation (including neuromuscular and flexibility training) is the cornerstone of skeletal muscle health. This review provides a comprehensive analysis of the mechanisms underlying the impact of type 1 diabetes on musculoskeletal system. It critically appraises evidence from in vitro studies, animal models, and clinical research in children, it also explores the effects of prevention and treatment.

Factor XI (FXI) deficiency, or hemophilia C, is a rare bleeding disorder resulting from reduced levels or dysfunctional FXI protein due to mutations in the F11 gene. This study investigated the correlation between FXI activity levels, F11 genotype, and bleeding phenotypes. Clinical and genetic characteristics of 93 individuals from southern Italy diagnosed with congenital FXI deficiency, including 39 index cases and their relatives, were evaluated. FXI:C plasma levels were measured. Sanger sequencing of F11 was performed, and the pathogenicity of variants identified was assessed using in silico tools. FXI activity levels ranged widely (1–69%), with most cases being heterozygous and showing moderate deficiency. Only 12 individuals had severe FXI deficiency, typically associated with homozygosity or compound heterozygosity. Bleeding symptoms varied from mild to severe and occurred in 31% of subjects, though only a minority of those with severe deficiency experienced spontaneous or surgery-related bleeding. Sanger sequencing revealed 24 distinct F11 gene variants, predominantly missense mutations, with three novel variants (p.Val89*, p.Leu306Pro, and p.Trp515Gly). Common mutations included p.Glu135* and p.Glu315Lys. Variants were distributed across the gene, with no domain-specific clustering. No clear genotype–phenotype correlation was observed. FXI levels alone did not reliably predict bleeding risk, highlighting the influence of additional factors such as age, gender, and clinical history. This study reinforces the allelic and clinical heterogeneity of FXI deficiency and the limited utility of FXI:C levels alone for predicting bleeding severity. Further research is needed to clarify the complex genotype–phenotype relationships in FXI deficiency.

Cystic fibrosis (CF) is a multisystemic genetic disorder caused by dysfunctional CF transmembrane conductance regulator (CFTR) protein, leading to impaired chloride and bicarbonate transport. Advances in care have increased patient lifetime, revealing chronic complications such as CF-related bone disease (CFBD), characterized by low bone mineral density and increased fracture risk. CFBD results from a complex interplay of factors including chronic inflammation, nutritional deficiencies, hormonal imbalances, and impaired glucose metabolism. Pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, and IL-8) promote osteoclastogenesis, disrupting bone remodeling via the RANK/RANKL/OPG pathway. In vivo murine and in vitro studies have elucidated the pathogenic mechanisms underlying CFBD, highlighting CFTR’s role in bone cell function. Diagnosis is based on clinical evaluation, bone densitometry, and laboratory assessments of bone metabolism markers. In this narrative review we highlight the recent scientific evidence on the etiopathogenesis and the current strategies for management of CFBD.

Background: Factor XI (FXI) deficiency, or hemophilia C, is a rare bleeding disorder resulting from reduced levels or dysfunctional FXI protein due to mutations in the F11 gene. Aim of the Study: This study investigated the correlation between FXI activity levels, F11 genotype and bleeding phenotypes Methods: Clinical and genetic characteristics of 93 individuals from southern Italy diagnosed with congenital FXI deficiency, including 39 index cases and their relatives were evaluated. FXI:C plasma levels were measured. Sanger sequencing of F11 was performed and pathogenicity of variants identified was assessed using in silico tools. Results: FXI activity levels ranged widely (1–69%), with most cases being heterozygous and showing moderate deficiency. Only 12 individuals had severe FXI deficiency, typically associated with homozygosity or compound heterozygosity. Bleeding symptoms varied from mild to severe and occurred in 31% of subjects, though only a minority of those with severe deficiency experienced spontaneous or surgery-related bleeding. Sanger sequencing revealed 24 distinct F11 gene variants, predominantly missense mutations, with three novel variants (p.Val89*, p.Leu306Pro, and p.Trp515Gly). Common mutations included p.Glu135* and p.Glu315Lys. Variants were distributed across the gene, with no domain-specific clustering. No clear genotype-phenotype correlation was observed). Conclusions: FXI levels alone did not reliably predict bleeding risk, highlighting the influence of additional factors such as age, gender, and clinical history. The study reinforces the allelic and clinical heterogeneity of FXI deficiency and the limited utility of FXI:C levels alone for predicting bleeding severity. Comprehensive risk assessment models integrating clinical and molecular data are necessary for optimal patient management. Further research is needed to clarify the complex genotype–phenotype relationships in FXI deficiency.

Background: Parvovirus B19 is the major cause of transient aplastic crisis in children with hereditary spherocytosis (HS) inhibiting erythropoiesis and leading to a severe drop in hemoglobin levels, requiring hospitalization and transfusional support. During the COVID-19 pandemic, the circulation of non-COVID respiratory viruses, such as parvovirus B19, initially declined but subsequently increased abruptly following the relaxation of containment strategies. Moreover, it remains unclear whether this has resulted in a rise in parvovirus B19-induced aplastic crises among individuals with HS. Methods: This retrospective, single-center study conducted at the Pediatric University Hospital of Bari (Italy) aims to describe the clinical characteristics and frequency of parvovirus B19-induced aplastic crises in pediatric patients with HS before and after the COVID-19 Public Health Emergency of International Concern (PHEIC, 30 January 2020–5 May 2023). The study was divided into four distinct periods: Period A: from 1 December 2018 to 31 December 2019, representing one year before the declaration of the PHEIC; Period B: from 1 June 2023 to 30 June 2024, representing one year after the cessation of the PHEIC; Period C: before 1 December 2018; Period D: from 1 January 2020 to 31 May 2023, which refers to the pandemic period. Results: A total of 30 patients (55% of the study population, n = 55) experienced a parvovirus B19-induced aplastic crisis. The frequency of these crises in Period B was significantly higher than in Period A (p < 0.0001). Conclusions: This study suggests a substantial increase in parvovirus B19-induced aplastic crises among children with HS following the COVID-19 outbreak indicating a potential impact of public health containment strategies on parvovirus B19 infection rates.

Childhood leukemia survivors are at risk of long-term complications. Data on bone remodeling in childhood acute lymphoblastic leukemia (ALL) are limited. This 2-year prospective longitudinal study investigated bone remodeling and bone turnover markers at diagnosis, during treatment, and until stopping treatment, in ALL patients < 18 years, to clarify the influence of leukemia itself and/or chemotherapy on bone. Methods: A total of 22 ALL children (12 males, age 5.5 ± 3.6 years) underwent blood sampling at the 5 time point (T0−T4). Osteoprotegerin (OPG), receptor-activator-NF-B-ligand (RANKL), osteocalcin (OC), C-terminal-telopeptide-type-I-collagen (CTX), bone-alkaline-phosphatase (bALP), tartrate-resistant acid-phosphatase-5b (TRACP5b), procollagen-type-I-N-terminal-propeptide (P1NP), Dickkopf-1 (DKK-1), and sclerostin were assessed. Data from patients at T0 were compared to a control group of healthy children. We used the principal component analysis (PCA) for statistics. Results: Levels of CTX, OC, P1NP, and bALP resulted lower in ALL children than controls (p = 0.009 for CTX and p < 0.001 for the others), also DKK1 and sclerostin (p < 0.0001 and p = 0.023). RANKL ed OPG were higher in patients. During T0−T4, CTX, OC, P1NP, TRACP5b, and bALP showed a significant increase, in particular at T0−T1 (end-of-induction). Less evident changes were detected onwards. Conclusions: The onset of leukemia has been revealed as a key point in determining a slowing of bone remodeling in ALL children.

Background/Objectives: Chronic non-bacterial osteomyelitis (CNO) is a rare autoinflammatory disease characterized by chronic sterile uni- or multifocal osteomyelitis. The treatment of CNO is mostly empirical and the outcome of the disease has not yet been standardized. The aims of this study were to correlate clinically active lesions with radiological signs of inflammation and to evaluate the outcomes in terms of symptoms and radiological signs with Whole Body Magnetic Resonance Imaging (WB-MRI) based on the treatment line used. Methods: A retrospective, observational cohort study of 20 CNO patients, recruited from a single tertiary center in southern Italy, was conducted. Patients included in the study were treated based on the “step-up” approach and were guided by the “treat-to-target” strategy as well as by the response to therapy. The outcome measure was stratified into four different groups, defined by a “Delphy consensus”, depending on the symptoms and the presence of bone lesions in WB-MRI, compared with the therapy carried out. Results: Pain was the most common presenting symptom of the disease. Only 15% of our patients reported long-term complications. WB-MRI was performed for each patient both at diagnosis and during follow-up. At onset, the site most affected by the disease was the tibia. All patients who reached a 5-year follow-up (30%, n = 6) achieved a complete disease remission. Conclusions: The standardized “step-up” treatment approach in our cohort proved effective in disease management with disease control or remission in nearly 90% of patients at one year from diagnosis.