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Cardio‐facio‐cutaneous syndrome (CFCS) is a rare genetic disorder belonging to the RASopathies, a group of developmental syndromes caused by upregulated RAS/MAPK signaling. Pathogenic variants affecting four genes, KRAS, BRAF, MAP2K1 and MAP2K2, encoding core signal transducers of the pathway, underlie the condition. Major clinical features include a distinctive facies, ectodermal and cardiac anomalies, reduced postnatal growth, intellectual disability, and musculoskeletal abnormalities. Similar to other RASopathies, reports of visual impairment, high refractive error, optic nerve pallor, and other ocular abnormalities have been anecdotally reported in the literature. The aim of our study is to report the prevalence of ophthalmologic abnormalities in a large monocentric cohort of individuals affected by CFCS and explore the occurrence of genotype–endophenotype correlations in this series of patients. We observed that BRAF mutations are associated to a higher prevalence of anisometropia >3D (11.8% vs. 0%) and high astigmatism (29.4% vs. 0%; both p < 0.001) while patients with mutations in other genes had a significantly higher prevalence of myopia >6 D (60% vs. 5.9%; p = 0.012). Pale optic disc was associated with higher prevalence of inferior oblique muscle (IO) overaction (33.3% vs. 0%) and lower prevalence of ptosis (0% vs. 11.8%; both p < 0.001). Combined exotropia, IO overaction and nystagmus were frequent in patients with pale optic nerve. Our findings might suggest the need for earlier ophthalmologic referral for CFCS patients due to high risk of amblyopia, especially those expressing BRAF mutations. [ABSTRACT FROM AUTHOR]

Herein, we report on an individual with molecularly confirmed diagnosis of NS showing asymptomatic enlarged spinal nerve roots, which are distinctive features of neurofibromatosis type 1. 3 Ando Y, Sawada M, Kawakami T, Morita M, Aoki Y. A patient with Noonan syndrome with a KRAS mutation who presented severe nerve root hypertrophy. Noonan syndrome (NS) belongs to RASopathies, a family of disorders caused by unregulated signaling through the RAS-MAPK pathway. [Extracted from the article]

Costello syndrome (CS) is a rare disorder affecting development and growth characterized by cancer predisposition and caused by mutations in HRAS proto‐oncogene. Somatic HRAS mutations drive bladder carcinogenesis. The aim of this study was to analyze prevalence and histological characterization of bladder cancer (BC) in a cohort of patients with CS to help clinicians plan effective management strategies. This study included 13 patients above 10 years of age with molecular diagnosis of CS. Screening cystoscopies (31 total procedures) were performed to exclude BC. Any lesion was analyzed through cold‐cup biopsy or trans‐urethral resection of the bladder. According to histology, patients were followed‐up with urinalysis and abdominal ultrasound yearly, and cystoscopies every 12–24 months. During study enrollment, bladder lesions (often multifocal) were detected in 11/13 patients. Histological analysis documented premalignant lesions in 90% of cystoscopies performed, epithelial dysplasia in 71%, and papillary urothelial neoplasm of low‐malignant potential in 19%. BC G1/low grade (Ta) were removed in 10%. Overall, 76% of patients showed a bladder lesion at first cystoscopy. The present findings document that individuals with CS aged 10 years and older have high prevalence of bladder lesions (premalignant/malignant), highlighting the importance of personalized screening protocols. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Medical professionals frequently underestimate stress level of parents/caregivers of patients with rare disorders as RASopathies, the latter might experience elevated stress levels, with their own health frequently overlooked despite significant responsibilities and hurdles encountered. The aim of this study is to assess the stress experienced by parents of individuals with Noonan syndrome and related conditions. Forty-eight parents (20 fathers; 28 mothers), among the 31 recruited families, completed the Italian version of the Parenting Stress Index-Short Form. Our study shows abnormally elevated scores (≥ 85° percentile) in 35.4% of parents. Data retrieved from subscales reveal a perception of a difficult child in 25% of cases, a dysfunctional parental-child interaction in 20.8%, a general parental distress in 10.4% of cases, and an elevated overall stress in 18.8% of parents. Questionnaires as the Parenting Stress Index-Short Form are valuable tools to evaluate stress in parents/caregivers of children with RASopathies. Evaluation by professionals is fundamental to support parents and caregivers in managing stressors and to enhance their quality of life and relationships. To prevent stress escalation and parents' burnout, an early assessment to tailor a timely treatment should be introduced as soon as possible as good clinical practice., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)