Decreased bone mineral density in Costello syndrome.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Center for Rare Diseases, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy; Division of Medical Genetics, Department of Pediatrics, University of Utah, UT, USA.
Chiara
C
Leoni
Division of Medical Genetics, Department of Pediatrics, University of Utah, UT, USA.
David A
DA
Stevenson
Center for Rare Diseases, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy.
Lucilla
L
Martini
Center for Rare Diseases, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy.
Roberto
R
De Sanctis
Center for Rare Diseases, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy.
Giovanna
G
Mascolo
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Francesca
F
Pantaleoni
Center for Rare Diseases, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy.
Sara
S
De Santis
Center for Rare Diseases, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy.
Ilaria
I
La Torraca
Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, Rome, Italy.
Silvia
S
Persichilli
Department of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy.
Paolo
P
Caradonna
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Marco
M
Tartaglia
Center for Rare Diseases, Department of Pediatrics, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address: gzampino@rm.unicatt.it.
Giuseppe
G
Zampino
D015652:25-Hydroxyvitamin D 2 / Q000097:blood*; D015502:Absorptiometry, Photon / Q000379:methods*; D000293:Adolescent; D000328:Adult; D001823:Body Composition / Q000502:physiology*; D015992:Body Mass Index; D015519:Bone Density / Q000502:physiology*; D016022:Case-Control Studies; D002648:Child; D056685:Costello Syndrome / Q000503:physiopathology*; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging; D005272:Femur Neck / Q000000981:diagnostic imaging; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging; D008297:Male; D000090063:Proto-Oncogene Mas; D055815:Young Adult
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015652:25-Hydroxyvitamin D 2
BMD; Bone mineral density; CFCS; CS; Costello syndrome; DXA; F-BMD; FN-BMD; HRAS; L-BMD; NF1; NS; Noonan syndrome; RASopathies; S-BMD; WBLH; bone mineral density; cardiofaciocutaneous syndrome; dual-energy X-ray absorptiometry; femoral neck bone mineral density; femur bone mineral density; lumbar bone mineral density; neurofibromatosis type 1; subtotal bone mineral density; whole body less head