Decreased bone mineral density in Costello syndrome

• Published in: Molecular genetics and metabolism Vol. 111; no. 1; pp. 41 - 45
• Main Authors: Leoni, Chiara, Stevenson, David A., Martini, Lucilla, De Sanctis, Roberto, Mascolo, Giovanna, Pantaleoni, Francesca, De Santis, Sara, La Torraca, Ilaria, Persichilli, Silvia, Caradonna, Paolo, Tartaglia, Marco, Zampino, Giuseppe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2014
• Subjects: 25-Hydroxyvitamin D 2 - blood; Absorptiometry, Photon - methods; Adolescent; Adult; Body Composition - physiology; Body Mass Index; Bone Density - physiology; Bone mineral density; Case-Control Studies; Child; Costello syndrome; Costello Syndrome - physiopathology; Female; Femur - diagnostic imaging; Femur Neck - diagnostic imaging; HRAS; Humans; Lumbar Vertebrae - diagnostic imaging; Male; NF1; Noonan syndrome; RASopathies; Young Adult; NS; FN-BMD; RASopathies; CFCS; DXA; WBLH; CS; Noonan syndrome; Costello syndrome; NF1; BMD; S-BMD; Bone mineral density; L-BMD; F-BMD; HRAS; subtotal bone mineral density; femoral neck bone mineral density; femur bone mineral density; lumbar bone mineral density; dual-energy X-ray absorptiometry; neurofibromatosis type 1; cardiofaciocutaneous syndrome; whole body less head
• ISSN: 1096-7192; 1096-7206; 1096-7206
• DOI: 10.1016/j.ymgme.2013.08.007

Costello syndrome (CS) is a multisystemic disorder characterized by postnatal reduced growth, facial dysmorphism, cardiac defects, cognitive impairment, skin and musculo-skeletal anomalies, and predisposition to certain cancers. CS is caused by activating germline mutations in the HRAS proto-oncogene. Similar to what is observed in other RASopathies, CS causative HRAS mutations promote enhanced signal flow through the RAF–MEK–ERK and PI3K–AKT signaling cascades. While decreased bone mineralization has been documented in other RASopathies, such as neurofibromatosis type 1 and Noonan syndrome, systematic studies investigating bone mineral density (BMD) are lacking in CS. Dual-energy X-ray absorptiometry (DXA) was utilized to assess BMD and body composition (fat and fat-free mass) in a cohort of subjects with molecularly confirmed diagnosis of CS (n=9) and age-matched control individuals (n=29). Using general linear regression, subtotal body (total body less head), lumbar, femoral neck and femur BMD parameters were compared considering age, sex, body mass index (BMI) and Tanner stage. Blood and urine biomarkers of bone metabolism were also assessed. All individuals with CS showed significantly lower mean values of subtotal, lumbar and femoral neck BMD compared to the control group (p≤0.01). Similarly, mean total body mass and fat-free mass parameters were lower among the CS patients than in controls (p<0.01). Low 25-OH vitamin D concentration was documented in all individuals with CS, with values below the reference range in two patients. No significant correlation between vitamin D levels and BMD parameters was observed. CS belongs to a family of developmental disorders, the RASopathies, that share skeletal defects as a common feature. The present data provide evidence that, similar to what is recently seen in NF1 and NS, bone homeostasis is impaired in CS. The significant decrease in BMD and low levels of vitamin D documented in the present cohort, along with the risk for pathologic fractures reported in adult individuals with CS, testifies the requirement for a preventive treatment to alleviate evolutive complications resulting from dysregulated bone metabolism. •Patients with Costello syndrome exhibit decreased bone mineral density•RAS signaling contributes to the control of bone homeostasis•Patients with Costello syndrome have low levels of vitamin D•Vitamin D supplementation may improve bone density and reduce fracture risk in adults