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.

Cardio‐facio‐cutaneous syndrome (CFCS) is a rare disorder characterized by distinctive craniofacial appearance, cardiac, neurologic, cutaneous, and musculoskeletal abnormalities. It is due to heterozygous mutations in BRAF, MAP2K1, MAP2K2, and KRAS genes, belonging to the RAS/MAPK pathway. The role of RAS signaling in bone homeostasis is highly recognized, but data on bone mineral density (BMD) in CFCS are lacking. In the present study we evaluated bone parameters, serum and urinary bone metabolites in 14 individuals with a molecularly confirmed diagnosis of CFCS. Bone assessment was performed through dual X‐ray absorptiometry (DXA); height‐adjusted results were compared to age‐ and sex‐matched controls. Blood and urinary bone metabolites were also analyzed and compared to the reference range. Despite vitamin D supplementation and almost normal bone metabolism biomarkers, CFCS patients showed significantly decreased absolute values of DXA‐assessed subtotal and lumbar BMD (p ≤ 0.05), compared to controls. BMD z‐scores and t‐scores (respectively collected for children and adults) were below the reference range in CFCS, while normal in healthy controls. These findings confirmed a reduction in BMD in CFCS and highlighted the importance of monitoring bone health in these affected individuals.

Background: The diagnosis of acute appendicitis (AA) remains challenging, especially in pediatrics, because early symptoms are not specific, and the younger the patient the more difficult their interpretation is. There is a large degree of agreement between pediatric surgeons on the importance of an early diagnosis to avoid complicated acute appendicitis (CAA) and its consequences. The aim of this study is to assess if Interleukin 6 (IL-6) could enhance the sensitivity (Sn) and specificity (Sp) of the currently available and routinely performed diagnostic tools in case of suspected AA in pediatric patients. Materials and Methods: A prospective observational study was conducted including patients who underwent appendectomy between November 2020 and March 2022. We divided patients into three groups: not inflamed appendix (group NA), not complicated AA (group NCAA), and complicated AA (group CAA). We compared the mean values of white blood cells (WBC), neutrophils, fibrinogen, ferritin, aPTT, INR, C-reactive protein (CRP), IL-6, and CRP between the three groups. Then we evaluated Sn, Sp, and odds ratio (OR) of IL-6 and CRP alone and combined. Results: We enrolled 107 patients operated on for AA (22 in Group NA, 63 in Group NCAA, and 21 in group CAA). CRP levels resulted in a significant increase when comparing CAA with NA (p = 0.01) and CAA with NCAA (p = 0.01), whereas no significance was found between NA and NCAA (p = 0.38). A statistically significant increase in average IL-6 levels was found when comparing NCAA with NA (p = 0.04), CAA with NA (p = 0.04), and CAA with NCAA (p = 0.02). Considering CRP alone, its Sn, Sp, and OR in distinguishing NA from AA (both NCAA and CAA together) are 86%, 35%, and 33,17, respectively. Similarly, Sn, Sp, and OR of IL-6 alone are 82%, 54%, and 56, respectively. Combining CRP and IL-6 serum levels together, the Sn increases drastically to 100% with an Sp of 40% and OR of 77. Conclusions: Our study may suggest an important role of IL-6 in the detection of AA in its early stage, especially when coupled with CRP.