Danilo Fintini

Purpose To investigate the prevalence, classification, and clinical impact of genetic variants in leptin–melanocortin (MC4R) pathway- and ciliopathy related genes, and in some key neurodevelopmental and pleiotropic genes whose dysfunction may cause hyperphagia in a sample of youths with severe obesity regardless of age of obesity onset and presence of hyperphagia. Methods Cross-sectional evaluation of patients consecutively referred for severe obesity having had prior next-generation sequencing targeting genes of interest as for the Rare Obesity Advanced Diagnosis (ROAD) program gene panel. Variants were classified according to guidelines as likely benign (LB), pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VOUS). Clinical and metabolic features were compared across groups of controls (mutant negative and LB carriers), VOUS, and LP/P carriers. Results A total of 164 patients were included: 91 patients (54.5%) carried at least one variant. Most variants were heterozygous and classified as VOUS (n = 82, 89%); 10 patients (11%) had LP/P variants. Genes most frequently associated with LP/P findings included MC4R (n = 2), ALMS1 (n = 3), and CEP290 (n = 2). No significant differences were found across groups in obesity degree, lipid profile, glucose metabolism, or behavioural symptoms. A non-significant trend toward earlier onset of obesity was observed in the LP/P group. Conclusion Children with severe obesity often carry gene variants in the leptin–MC4R pathway or associated to ciliopathies, which appear even in cohorts unselected for early onset or hyperphagia. Their clinical significance remains uncertain. Although genetic testing may inform clinical stratification and personalised treatment, its integration into the diagnostic workup of severe obesity should currently be restricted to specialised obesity clinics and research contexts. Findings highlight the need for improved interpretation of LP and VOUS through functional studies and long-term phenotyping.

Children and adolescents frequently experience fractures related to accidental injuries; however, fractures may also result from non-accidental trauma in abused children or from underlying bone fragility due to primary or secondary osteoporosis. In pediatric patients with fragility fractures diagnosis and treatment may be delayed. This document aims to provide clinicians with a practical approach to the diagnosis and management of fragility fractures in children and adolescents. Between November 2024 and June 2025, a group of Italian pediatric endocrinologists with expertise in bone and mineral metabolism held regular online meetings to discuss key issues related to the diagnosis and management of pediatric bone fragility and developed experts opinion statements based on clinical experience and a review of the relevant literature. The expert panel formulated consensus statements on the clinical management of children and adolescents with fragility fractures. Seven main areas were addressed: 1) definition of fragility fractures and pediatric osteoporosis; 2) diagnostic approach; 3) main causes of primary and secondary osteoporosis; 4) assessment of the potential for spontaneous recovery from bone fragility; 5) management of bisphosphonate therapy; 6) other therapeutic options; 7) conservative measures. The diagnosis of osteoporosis in pediatric patients should follow a clinically oriented approach. Genetic testing plays a crucial role in identifying primary forms of osteoporosis. Vertebral reshaping may occur in some patients with secondary osteoporosis. Bisphosphonates represent the mainstay of treatment in children and adolescents with bone fragility. Conservative measures aimed at optimizing bone strength may be beneficial in selected cases.

Objective: To evaluate the long-term effectiveness of laparoscopic sleeve gastrectomy (LSG) in pediatric and transition age patients with Prader–Willi syndrome (PWS). Design: Single-center, longitudinal, retrospective cohort study. Methods: We reviewed the electronic health records of 110 patients with PWS and 268 subjects undergoing LSG. We included 16 patients with PWS and severe obesity (PWS-LSG) and 32 matched non-syndromic patients with obesity (OB-LSG), both undergoing LSG, and 16 patients with PWS receiving lifestyle intervention only (PWS-LS). The primary endpoint was ΔBMI-SDS% at 5 years. Results: In PWS-LSG, BMI-SDS decreased from 5.18 to an early nadir at 1-2 years (median ΔBMI-SDS% ∼−26%), then partially rebounded to 4.75 at 5 years, with ΔBMI-SDS% −16.9% (P = .012). Conventional metrics confirmed this attenuated response, with %BMI change −2.8% and absolute ΔBMI-SDS −1.10 at 5 years. In OB-LSG, BMI-SDS declined from 4.95 to 2.24, with larger and more sustained improvement (ΔBMI-SDS% −57.4%; P < .001 within-group; P = .002 vs PWS-LSG), corresponding to a %BMI change −40.1% and absolute ΔBMI-SDS −2.81 at 5 years. In PWS-LS, BMI-SDS increased from 2.25 to 3.19 (ΔBMI-SDS% + 36.4%, P = .003). The mean number of obesity-related comorbidities decreased in PWS-LSG (2.69 ± 1.66 to 1.94 ± 1.18; P = .041) and in OB-LSG (1.25 ± 0.88 to 0.56 ± 0.76; P < .001), but increased in PWS-LS (1.56 ± 0.96 to 2.44 ± 1.32; P = .004). Conclusion: In PWS, LSG produces clinically relevant early weight loss with partial maintenance at 5 years, but markedly attenuated long-term benefit compared with non-syndromic peers. Nevertheless, when interpreted against the progressive worsening of obesity and cardiometabolic comorbidities observed with lifestyle intervention alone, LSG appears to modify disease trajectory in PWS.

Alterations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been associated with primary osteoporosis, leading to recurrent low-trauma fractures. Heterozygous carriers typically show a milder phenotype, with reduced bone mass starting in early childhood. In this paper, we described the clinical features and therapeutic outcomes of a cohort of 7 children (5 males) harboring different variants in the LPR5 gene. Eight heterozygous variants of the LRP5 gene were identified (6 missense, 2 nonsense), two of which were likely pathogenic. One male patient was compound heterozygous, carrying two different variants, including p.(Arg570Gln), previously reported as pathogenic in homozygous form, and exhibited a more severe phenotype consistent with Osteoporosis-Pseudoglioma Syndrome, including vitreoretinal abnormalities. At initial presentation, most patients had a history of low-trauma long bone fractures, or spontaneous vertebral fractures, and bone/joint pain. Five of them received bisphosphonate therapy and one patient also received denosumab. No new fractures occurred during follow-up (9 months-4 years). Bone mineral density (BMD) increased in all patients (3-103%, mean: 55%), and partial vertebral reshaping was described. No adverse effects were reported. This pediatric case series highlights the phenotypic variability of LRP5 gene variants, and underscores the efficacy of bisphosphonate therapy in improving BMD and reducing fracture risk. However, while bisphosphonates remain the standard of care, further research is needed on precision therapies that target Wnt signaling and other pathways affected by LRP5 gene alterations.

Background: Currently, there is a lack of data regarding the reliability of different anthropometric, instrumental, and biochemical indexes in detecting metabolic syndrome (MetS) in pediatric patients with Prader–Willi syndrome (PWS). Therefore, this study aimed to compare the accuracy of different indices to identify the simplest and most accurate predictor of MetS in this at-risk population. Methods: We conducted a multicenter study involving 124 children and adolescents with PWS (61 males and 63 females), aged 13.6 ± 3.7 years. For each participant, we assessed all components of MetS, defined according to either the Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS) study or the International Diabetes Federation (IDF) criteria, based on age. The following indexes were calculated: Body Mass Index (BMI), BMI standard deviation score (BMI-SDS), tri-ponderal mass index, body mass fat index, fat mass index, fat-free mass index, body shape index, visceral adiposity index, waist-to-height ratio, cardiometabolic index, total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio, and triglycerides/HDL-C (TG/HDL-C) ratio. Results: MetS was identified in 24 subjects (9 females and 15 males), representing 19.4% of the sample. When comparing the receiver operating characteristic (ROC) curves, the TG/HDL-C ratio and cardiometabolic index demonstrated significantly better performance than the other indices in detecting MetS, with no difference between the two. As a result, we focused on the TG/HDL-C ratio since it is the simplest measure, requiring no additional anthropometric data compared to the cardiometabolic index. Additionally, applying age- and gender-specific thresholds can further improve its accuracy. Conclusions: The TG/HDL-C ratio, which requires only two standard biochemical markers, provides the same accuracy as more complex indexes in detecting MetS in children and adolescents with PWS, making it the optimal predictor for MetS in this population.

Purpose X-linked hypophosphatemia (XLH) is a rare hereditary skeletal disorder that may be very disabling and significantly impacting the quality of life throughout the lifespan. The aim of this document was to inform stakeholders about the lifelong impact, management, and treatment of individuals with XLH, especially focusing on the new therapeutic approach with burosumab. Methods From October 2023 to April 2024, a multidisciplinary working group of Italian experts on bone and mineral metabolism convened periodic online meetings. Statements were formulated identifying the most relevant studies, including randomized controlled trials, international guidelines based on GRADE criteria, and systematic reviews, and the experts’ opinions. Results The panel of experts provided "consensus statements" on the clinical management of individuals with XLH across lifespan. Five main issues were identified: (1) clinical and biochemical diagnosis of individuals with XLH and monitoring of the progression of the disease; (2) effects of conventional treatment with phosphate supplements and active vitamin D metabolites; (3) effects of the treatment with burosumab; (4) multidisciplinary approach and management of individuals with XLH; (5) consensus statement for transition from pediatric to adult care in individuals with XLH. Conclusion Individuals with XLH often experience unmet needs throughout life; a multidisciplinary approach involving different specialists, is recommended. The new treatment with burosumab can provide an effective and safety therapeutic option in reducing the burden of the disease in both children and adults. Therefore, awareness about the XLH disease should be increased among stakeholders. The criteria and reimbursement policies of burosumab should be revised.

Purpose: The aim of the present review is to analyze dynamic interactions between nutrigenomics, environmental cues, and parental influence, which can all lead to children’s neophobic reactions and its persistence in time. Methods: We reviewed studies available on electronic databases, conducted on children aged from birth to 18 years. We also considered official websites of Italian Institutions, providing advice on healthy eating during infancy. Results: Modern day societies are faced with an eating paradox, which has severe and ever-growing implications for health. In face of a wider availability of healthy foods, individuals instead often choose processed foods high in fat, salt and sugar content. Economic reasons surely influence consumers’ access to foods. However, there is mounting evidence that food choices depend on the interplay between social learning and genetic predispositions (e.g., individual eating traits and food schemata). Neophobia, the behavioral avoidance of new foods, represents an interesting trait, which can significantly influence children’s food refusal. Early sensory experiences and negative cognitive schemata, in the context of primary caregiver–child interactions, importantly contribute to the priming of children’s food rejection. Conclusions: As neophobia strongly affects consumption of healthy foods, it will be relevant to rule definitively out its role in the genesis of maladaptive food choices and weight status in longitudinal studies tracking to adulthood and, in meanwhile, implement early in life effective social learning strategies, to reduce long-term effects of neophobia on dietary patterns and weight status. Level of evidence: Level II, controlled trials without randomization.

Context: Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. Objective: We determined serum levels of PAPP-As and STCs in association with IGF axis components in prepubertal and pubertal patients with PWS, also analyzing the effect of GH treatment. Methods: Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at 6 months of treatment in 11 children. Results: Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and they had higher concentrations of free IGF-I, IGFBP-5, and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and had increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs, and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. Conclusion: The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

Vitamin B12 (or cobalamin) is an essential vitamin for DNA synthesis, fatty acid and protein metabolism as well as other metabolic pathways fundamental to the integrity of cells and tissues in humans. It is derived from the diet and mostly stored in the liver. Its deficiency has been associated with metabolic derangements, i.e., obesity, glucose intolerance, increased lipogenesis and metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). However, data with regard to body weight across the whole spectrum (from underweight to severe obesity) in children and young individuals are scarce. The present study aims to describe the association between serum total vitamin B12 and body mass index (BMI) ranging from underweight to severe obesity in a large population of children, adolescents and young adults. This study also investigates associations with visceral adiposity, glucose and lipid metabolism and liver dysfunction. A cross-sectional, single-centre study was conducted at the Paediatrics and Endocrinology units of the ”Bambino Gesù Children Hospital”, a tertiary referral institution for eating disorders. Clinical charts were reviewed and 601 patients aged from 5 to 25 years were enrolled in order to analyse anthropometric, auxological, clinical, biochemical and liver ultrasound data using robust statistical approaches. Analyses were adjusted for potential confounders. A reduction in serum total B12 levels was associated with a linear increase in body weight, as expressed by WHO BMI SDS (r = −0.31, p < 0.001, BCa 95% −0.38, −0.24). Lower B12 levels were associated with higher waist circumference but only in pubertal girls (r = −0.33, p = 0.008, BCa 95% −0.53, −0.11). Hepatic insulin resistance was higher in males with lower B12 levels (B = −0.003 (−0.007, −0.0001), p = 0.039), but not in females, whereas whole-body insulin resistance was unaffected. Serum lipid profiles (total, HDL and LDL cholesterol and triglycerides) were not influenced by serum cobalamin levels. However, lower cobalamin levels were associated with higher grading of ultrasound-scored hepatic steatosis (p_trend = 0.035). Lastly, both AST and ALT showed a significant and direct correlation with total B12 levels in underweight (r = 0.22 and 0.24, p = 0.002 and p = 0.002 and <0.001). In conclusion lower vitamin B12 levels are associated with higher body weight, adiposity and with worse metabolic health in a large population of children, adolescents and young adults.