Germline TGF‐β receptor mutations and skeletal fragility: A report on two patients with Loeys–Dietz syndrome

Abstract

Loeys-Dietz syndrome (LDS, OMIM # 609192) caused by heterozygous mutations in TGFBR1 and TGFBR2 has recently been described as an important cause of familial aortic aneurysms. These patients have craniofacial and skeletal features that overlap with the Marfan syndrome (MFS), and more importantly, have significant vascular fragility as is seen in MFS and Ehlers-Danlos syndrome Type IV (EDS-IV). The skeletal phenotype with respect to low bone mineral density and skeletal fragility is not clear. We present two patients with LDS with significant skeletal fragility. The first is a 17-year-old male who had talipes equinovarus, diaphragmatic and inguinal and herniae, aortic root dilatation necessitating surgical repair, craniofacial and skeletal dysmorphism consistent with LDS, and a history of numerous fragility fractures leading to significant skeletal deformity. He was found to be heterozygous for a c.923T > C transition in exon 4 of TGFBR2. The second is a 26-year-old male with submucous cleft palate, talipes equinovarus, pectus excavatum requiring surgery, inguinal hernia, and aneurysms in the ascending aorta, abdominal aorta, carotid, subclavian, vertebral and brachial arteries requiring surgical repairs. He also had craniofacial and skeletal dysmorphism consistent with LDS, multiple fractures in childhood, low bone mineral density, and was found to be heterozygous for a c.1561 T > C transition in exon 7 of TGFBR2. These case studies highlight the importance of paying close attention to fractures and bone density in patients with LDS. Osteopenia or osteoporosis may become increasingly important issues as earlier detection and treatment of the vascular complications of LDS improves life expectancy in these patients.

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 .…”

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.…”

Targeted next-generation sequencing makes new molecular diagnoses and expands genotype–phenotype relationship in Ehlers–Danlos syndrome

“…[26] The fourth variant, in TGFBR1 (ID 475) was in a patient with Other HDCT, bone fragility and a systolic murmur (and normal COL1A1/2). This variant was reported previously as a VUS associated with bicuspid aortic valve, [27] and bone fragility is a recent addition to the LDS clinical spectrum, [28] so this variant may underlie some of our patient's features but the evidence is less clear.…”