Chromosome 16p11.2 deletions: another piece in the genetic puzzle of childhood obesity

Ipercaloric diet and reduced physical activity have driven the rise in the prevalence of childhood obesity over a relatively short time interval. Family and twin studies have led to the conclusion that the strong predicitve value of parental body mass index (BMI) mainly stems from genetic rather than environmental factors. Whereas the common polygenic obesity arises when an individual genetic make-up is susceptible to an environment that promotes energy consumption over energy expenditure, monogenic obesity, on the contrary, is the obesity associated with a single gene mutation, which is sufficient by itself to cause weight gain in a food abundant context. Genes involved in the leptin-melanocortin pathway are often mutated in these cases. The cumulative prevalence of monogenic obesity among children with severe obesity is about 5%

X-linked hypophosphatemic rickets. What the orthopedic surgeon needs to know

Purpose: X-linked hypophosphatemic rickets (XLH) is a rare genetic disease characterized by an increase in fibroblast growth factor 23 (FGF23) expression. The skeleton is one of the systems most affected and deformities of the lower limbs are one of the first reasons for consulting an orthopedic surgeon. The aim of the present study was to offer practical advice for a comprehensive orthopedic approach to XLH. Materials: A literature search was conducted in PubMed, a freely available and cost-effective database. The articles included in the study were discussed by a research group with specific expertise in bone metabolism and pediatric deformities, in order to answer three fundamental questions and thus provide the orthopedic specialist with guidance on XLH: (1) How should the physician complete the diagnosis of XLH?; (2) When might a surgical procedure be recommended?; (3) What kind of surgical procedure should be performed? Results: Sixty-three articles were included and discussed by the research group. Conclusions: A correct and timely diagnosis of XLH is essential to appropriately manage affected patients. To complete this diagnosis a detailed medical history of the patient, a comprehensive clinical and radiographic evaluation, and specific biochemical tests are needed. Pharmacological treatment is based on supplementation of both phosphate and vitamin D, however, a monoclonal antibody that inactivates FGF23 (burosumab), has recently been introduced with promising results. Orthopedic surgery is needed in cases of moderate or severe deformities, to allow physiological growth and prevent early osteoarthritis and gait alterations. Surgical options are osteotomies and hemiepiphysiodesis, which is preferred whenever possible. Three different devices for temporary hemiepiphysiodesis are available (staples, transphyseal screws and tension band plates). Obviously, surgical procedures need an appropriate medical therapy to be effective. In conclusion, the diagnosis, treatment and follow-up of XLH require a multidisciplinary approach and a comprehensive evaluation of anamnestic, clinical and radiographic data

Bioavailable Vitamin D in Obese Children: The Role of Insulin Resistance.

Context: Studies examining vitamin D levels in association with childhood obesity usually do not consider the effect of insulin on vitamin D–binding protein and do not calculate the unbound, bioavailable vitamin D. Objective: This study aimed to evaluate in a group of children 1) the concentrations of both total 25-hydroxyvitamin D and bioavailable fraction, and 2) the potential role of insulin resistance in modulating the concentrations of bioavailable vitamin D. Design, Setting, and Patients or Other Participants: This was a cross-sectional study at a University Pediatric Department in which 63 obese children and 21 lean controls were enrolled. Main Outcome Measures: Total 25-hydroxyvitamin D and vitamin D–binding protein were measured, twosingle-nucleotide polymorphisms in the coding region of the vitaminD–binding protein (rs4588 and rs7041) were studied, and the vitamin D bioavailable fraction was calculated. Results: Obese children showed total 25-hydroxyvitamin D levels lower compared with nonobese children (21.36.7 ng/mL vs 29.611.7 ng/mL; P.0004). Bioavailable 25-hydroxyvitaminDlevels were not different among the two groups (3.1 1.6 ng/mL vs 2.6 1.2 ng/mL; P .05). Insulinresistant children showed higher bioavailable levels of 25-hydroxyvitamin D compared with noninsulin- resistant children (3.4 1.4 ng/mL vs 2.0 0.9 ng/mL; P .013) and an inverse correlation between insulin resistance and vitamin D–binding protein was found (r: 0.40; P .024). Conclusions: Obese children present levels of bioavailable 25-hydroxyvitamin D similar to those of normal-weight children due to reduced concentration of vitamin D–binding protein. The insulin resistance could play a role in this reduced concentrat

Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets

Background and objective: X-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia. Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions. Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few. In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. Methods: Five Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8–1.2 mg/kg, s. c. QW2). Burosumab was continued for 12–48 months and, once discontinued, patients were followed-up for 6–12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3–6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. Results: At entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (P[dbnd]NS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. Discussion: Our data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH

Enhanced Recovery After Surgery (ERAS) Protocol for Gastrectomy: A Tailored Program Developed at a Gastric Cancer Unit

Background Planning for and managing patients who follow multidisciplinary paths allow institutions to provide better care administration; greater collaboration among medical staff, patients, and their relatives; better patients education; reduced possible complications related to surgery and hospital stay; and increased patient adherence to the proposed treatments due to better information. The ERAS Society’s guidelines align in this direction, and many institutions are now looking to apply the suggestions contained in its items. This effort is especially important in surgical oncology. In this work, we report the experience of our center in developing tailored guidelines for patients undergoing gastrectomy based on evidence from the literature and adapted to address the availability of personnel and equipment in our institute. Methods A permanent institutional working group was established at St. Mary’s Hospital. Evidence‐based comprehensive research was conducted to find optimal perioperative care management for patients undergoing gastrectomy. Evidence and recommendations were thoroughly evaluated and considered together with the items from the ERAS Society’s guidelines. Results A complete patient pathway has been established from the first outpatient visit to discharge. All ERAS items were considered and adapted to our hospital’s care environment. Education, nutrition, anesthesiologist care, surgical approach, and ward organization are the main points of strength highlighted in the present work. Conclusion This proposed institutional evidence‐based protocol show comprehensive management for patients with gastric cancer eligible for enhanced surgical pathways

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study

: Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3-26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14-26) versus 10 (3-17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual, pituitary and neurological dysfunction. Despite an excellent overall survival, PFS rates are poor in OPGs with DS. These patients invariably present visual, neurological or endocrine sequelae. Therefore, functional outcomes and quality-of-life measures should be considered in prospective trials involving patients with OPGs, aiming to identify "high-risk" patients and to better individualize treatment

Impact of phosphodiesterase 8B gene rs4704397 variation on thyroid homeostasis in childhood obesity

ContextSeveral studies demonstrated that obese children have higher TSH than normal-weight children. The polymorphism rs4704397 in the phosphodiesterase 8B (PDE8B) gene showed an association with TSH.Objectivesi) To assess the effect of PDE8B on TSH in obese children; ii) to dissect the role of obesity degree in modulating this association; and iii) to stratify the individual risk to show hyperthyrotropinaemia according to PDE8B genotype.MethodsEight hundred and sixty-seven Italian obese children were investigated. Clinical data and thyroid hormones were evaluated and the PDE8B rs4704397 was genotyped.ResultsPDE8B A/A homozygous subjects showed higher TSH (P=0.0005) compared with A/G or G/G. No differences were found for peripheral thyroid hormones. Among A/A children, 22% had hyperthyrotropinaemia, compared with 11.6% of heterozygotes and 10.8% of G/G (P=0.0008). Consistently, A/A had an odds ratio (OR) to show abnormal TSH level of 2.25 (P=0.0004). Body mass index (BMI) appeared correlated with TSH (P=0.0001), but the strength of the effect of PDE8B on TSH was independent of BMI (P=0.1).Children were subdivided into six groups according to obesity degree and genotypes. PDE8B A/A with BMI SDS above 3 had the highest OR (OR 2.6, P=0.0015) to have hyperthyrotropinaemia, whereas G/G with BMI SDS below 3 showed the lowest possibilities (OR 0.3, P=0.005).ConclusionsWe have shown: i) in obese children, PDE8B is associated with TSH; ii) the interaction between adiposity and PDE8B on TSH is not synergistic, but follows an additive model; and iii) impact of this association in the stratification of individual risk to have hyperthyrotropinaemia

DICER1 Syndrome: A Multicenter Surgical Experience and Systematic Review

DICER1 syndrome is a rare genetic disorder that predisposes patients to the development of malignant and non-malignant diseases. Presently, DICER1 syndrome diagnosis still occurs late, usually following surgical operations, affecting patients' outcomes, especially for further neoplasms, which are entailed in this syndrome. For this reason, herein we present a multicenter report of DICER1 syndrome, with the prospective aim of enhancing post-surgical surveillance. A cohort of seven patients was collected among the surgical registries of Pediatric Surgery at the University of Pisa with the General and Oncologic Surgery of Federico II, University of Naples, and the Pediatric Surgery, Regina Margherita Hospital, University of Turin. In each case, the following data were analyzed: sex, age at diagnosis, age at first surgery, clinical features, familial, genetic investigations, and follow-up. A comprehensive literature review of DICER1 cases, including case reports and multicenter studies published from 1996 to June 2022, was performed. Eventually, the retrieved data from the literature were compared with the data emerging from our cohort of patients