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Title: Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome

Author
item CAO, FELICIA - Baylor College Of Medicine
item LU, LINCHAO - Baylor College Of Medicine
item ABRAMS, STEVEN - University Of Texas At Austin
item HAWTHORNE, KELI - University Of Texas At Austin
item TAM, ALLISON - Children'S Nutrition Research Center (CNRC)
item JIN, WEIDONG - Baylor College Of Medicine
item DAWSON, BRIAN - Children'S Nutrition Research Center (CNRC)
item SHYPAILO, ROMAN - Children'S Nutrition Research Center (CNRC)
item LIU, HAO - Baylor College Of Medicine
item LEE, BRENDAN - Children'S Nutrition Research Center (CNRC)
item NAGAMANI, SANDESH - Texas Children'S Hospital
item WANG, LISA - Baylor College Of Medicine

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/3/2017
Publication Date: 5/3/2017
Citation: Cao, F., Lu, L., Abrams, S.A., Hawthorne, K.M., Tam, A., Jin, W., Dawson, B., Shypailo, R., Liu, H., Lee, B., Nagamani, S.C.S., Wang, L.L. 2017. Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome. Human Molecular Genetics. doi:10.1093/hmg/ddx178.

Interpretive Summary: Rothmund-Thomson syndrome (RTS) is a rare inherited genetic disorder that affects many parts of the body. About two-thirds of RTS cases are due to a mutation in a gene called RECQL4. Individuals with RTS can typically have a distinctive skin rash, small stature, sparse hair, skeletal abnormalities, decreased bone mass, and increased risk for certain cancers. The extent and the mechanisms behind the more generalized metabolic bone disease and low bone density in RTS have not been studied in detail. We studied 29 individuals with RTS, focusing on their metabolic bone status. We measured bone density, calcium kinetics, and bone remodeling. We found that individuals with RTS had low bone density. We also found that low bone density in the presence of certain variants in the RECQL4 gene led to an increased fracture risk. Calcium metabolism looked to be normal. We also studied a specific type of mouse with skeletal anomalies that mimic those seen in humans with RTS. The mouse model suggested that the skeletal involvement is likely due to lower levels of bone formation as opposed to bone loss. This leads to lower bone volume in these mice. This is the largest study to date evaluating metabolic bone disease in individuals with RTS. These findings are important and our results have important implications for the management of low bone mass.

Technical Abstract: Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, small stature, sparse hair, skeletal abnormalities, increased risk of osteosarcoma, and decreased bone mass. To date, there has not been a comprehensive evaluation of the prevalence and extent of metabolic bone disease in RTS. Furthermore, the mechanisms that result in this phenotype are largely unknown. In this report, we provide a detailed evaluation of 29 individuals with RTS with respect to their metabolic bone status including bone mineral density, calcium kinetics studies, and markers of bone remodeling. We show that individuals with RTS have decreased areal bone mineral density. Additionally, we demonstrate that the presence of pathogenic variants in RECQL4 and low bone mineral density correlate with the history of increased risk of fractures. Using a RECQL4-deficient mouse model that recapitulates skeletal abnormalities seen in individuals with RTS, we demonstrate that generalized skeletal involvement is likely due to decreased osteogenesis. Our findings are clinically relevant as they may help in the risk stratification of patients with RTS and also in the identification of individuals who may benefit from additional surveillance and management of metabolic bone disease.