Our study showed a high prevalence of insulin resistance in patients with nonfunctioning AI and suggests its possible involvement in AI growth.

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Although weight-recovery represents the main aim of treatment in AN, refeeding is associated with an increase in abdominal fat which might be responsible of the onset of insulin resistance. As BMI and weight-recovery were associated with impaired IS, they cannot be considered the only aim of treatment of AN.

Many scientific studies have revealed a trend towards an earlier onset of puberty and have disclosed an increasing number of children that display precocious puberty. As an explanation, some authors have considered the global socio-economic improvement across different populations, and other authors have considered the action of endocrine disrupting chemicals (EDCs). Among these, bisphenol A (BPA), an aromatic compound largely used worldwide as a precursor of some plastics and chemical additives, is well known for its molecular oestrogen-like and obesogenic actions. We reviewed the medical literature of the previous 20 years that examined associations between BPA exposure and the age of puberty in humans, considering only those referring to clinical or epidemiological data. Of 19 studies, only 7 showed a correlation between BPA and puberty. In particular, the possible disruptive role of BPA on puberty may be seen in those with central precocious puberty or isolated premature breast development aged 2 months to 4 years old, even if the mechanism is undefined. Some studies also found a close relationship between urinary BPA, body weight, and early puberty, which can be explained by the obesogenic effect of BPA itself. The currently available data do not allow establishment of a clear role for BPA in pubertal development because of the conflicting results among all clinical and epidemiological studies examined. Further research is needed to fully understand the potential role of exposure to EDCs and their adverse endocrine health outcomes.

Costello syndrome (CS) is a neurodevelopmental disorder with a distinctive musculoskeletal phenotype and reduced bone mineral density (BMD) caused by activating de novo mutations in the HRAS gene. Herein, we report the results of a prospective study evaluating the efficacy of a 4-year vitamin D supplementation on BMD and bone health. A cohort of 16 individuals ranging from pediatric to adult age with molecularly confirmed CS underwent dosages of bone metabolism biomarkers (serum/urine) and dual-energy X-ray absorptiometry (DXA) scans to assess bone and body composition parameters. Results were compared to age-matched control groups. At baseline evaluation, BMD was significantly reduced (p ≤ 0.05) compared to controls, as were the 25(OH)vitD levels. Following the 4-year time interval, despite vitamin D supplementation therapy at adequate dosages, no significant improvement in BMD was observed. The present data confirm that 25(OH)vitD and BMD parameters are reduced in CS, and vitamin D supplementation is not sufficient to restore proper BMD values. Based on this evidence, routine monitoring of bone homeostasis to prevent bone deterioration and possible fractures in adult patients with CS is highly recommended. K E Y W O R D S bone metabolism biomarkers, bone mineral density, Costello syndrome, patient-centered care, personalized medicine, RASopathies 1 | INTRODUCTION Costello syndrome (CS, OMIM #218040) is a rare multisystem disorder belonging to a family of syndromes affecting development and growth collectively known as the RASopathies. These rare diseases share the upregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway as a common pathogenetic mechanism (Aoki et al., 2016;Tartaglia & Gelb, 2010). This signaling cascade controls a wide array of cellular processes (e.g., proliferation, migration, Abbreviations: 25(OH)vitD, 25 hydroxy vitamin D; B-ALP, bone alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; CFCS, cardio-facio-cutaneous syndrome; CS, Costello syndrome; DXA, dual-energy X-ray absorptiometry; F-BMD, femur bone mineral density; FFM, fat free mass; FM, fat mass; FN-BMD, femoral neck bone mineral density; L-BMD, lumbar bone mineral density; MAPK, mitogen-activated protein kinase; NF1, neurofibromatosis type 1; NS, Noonan syndrome; PTH, parathyroid hormone; S-BMC, subtotal bone mineral content; S-BMD, subtotal bone mineral density; WBLH, whole body less head.