Increased fracture risk and low bone mineral density in patients with loeys–dietz syndrome

Abstract

Loeys-Dietz syndrome is a recently recognized connective tissue disorder with widespread systemic involvement. Little is known about its skeletal phenotype. Our goal was to investigate the risk of fracture and incidence of low bone mineral density in patients with Loeys-Dietz syndrome. We performed a cross-sectional, descriptive, survey-based study with subsequent chart review from July 2011 to April 2012. Fifty-seven patients (26 men, 31 women) with Loeys-Dietz syndrome confirmed by genetic testing completed the survey (average age, 25.3 years; range, 0.9-79.6 years). There were a total of 51 fractures (33 patients): 35 fractures in the upper extremities, 14 in the lower extremities, and two in the spine. Fourteen patients (24.6%) reported two or more fractures. There was a 50% risk of fracture by age 14 years. The incidence of any fracture in this cohort was 3.86 per 100 person-years. Seventeen patients had dual-energy X-ray absorptiometry scans available for review, 11 (64.7%) of whom had at least one fracture. Thirteen included lumbar spine absorptiometry reports; eight (61.5%) indicated low or very low bone mineral density. In the left hip, ten of 14 participants (71.4%) had low or very low bone mineral density. In the left femoral neck, nine of 13 participants (69.2%) had low or very low bone mineral density. The lowest Z- and T-scores were not associated with an increased number of fractures. Patients with Loeys-Dietz syndrome have a high risk of fracture and a high incidence of low bone mineral density.

High Prevalence of Cervical Deformity and Instability Requires Surveillance in Loeys-Dietz Syndrome

“…The surgical approaches and postoperative complications in our cohort reflect the bone fragility previously reported in Loeys-Dietz syndrome [23][24][25] . Although it is unclear specifically how aberrant TGF-b signaling affects bone development, it is speculated that it causes uncoupling of bone formation and resorption 25,26 . Pseudarthrosis and failure of fixation were particularly common complications and may reflect defects in bone mineralization and resorption 25 .…”

“…Although it is unclear specifically how aberrant TGF-b signaling affects bone development, it is speculated that it causes uncoupling of bone formation and resorption 25,26 . Pseudarthrosis and failure of fixation were particularly common complications and may reflect defects in bone mineralization and resorption 25 . Other common postoperative complications, including junctional kyphosis and instability, are likely the result of ligamentous laxity.…”

Loeys–Dietz syndrome: a primer for diagnosis and management

“…Patients with LDS have a higher incidence of fractures. A study by Sponseller and colleagues 54 of individuals with LDS 1/2 revealed a 50% risk of fracture by 14 years of age. Limited dual-energy X-ray absorptiometry data supported the findings, revealing that at least 60% of patients had low or very low bone mineral density in the spine, hip, and/or femoral neck.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…Polymorphisms in BMP2 and BMP4 are also linked to osteoporosis, low bone mineral density, and fragility fracture risk (Styrkarsdottir et al 2003;Ramesh Babu et al 2005), although a correlation between a SNP in BMP2 and osteoporosis remains to be confirmed (Medici et al 2006). Osteoporosis, which presents with a high risk of pathologic fractures and delayed bone healing, is also a feature of LDS, and appears to be particularly frequent and most severe in patients with heterozygous missense mutations in TGFBR1 or TGFBR2 (Kirmani et al 2010;Tan et al 2013). Given the dual roles of TGFb signaling in bone formation and resorption, and the paradoxical effects of LDS mutations on TGF-b signaling in vivo, the mechanisms leading to osteoporosis in LDS remain unclear.…”