title: Germline TGF-beta 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.
authors.affiliation: Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota 55905, USA. kirmani.salman@mayo.edu
authors.forename: Salman
authors.initials: S
authors.lastname: Kirmani
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tebben
authors.forename: Aida N
authors.initials: AN
authors.lastname: Lteif
authors.forename: David
authors.initials: D
authors.lastname: Gordon
authors.forename: Bart L
authors.initials: BL
authors.lastname: Clarke
authors.forename: Theresa E
authors.initials: TE
authors.lastname: Hefferan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Yaszemski
authors.forename: Pamela S
authors.initials: PS
authors.lastname: McGrann
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Jay W
authors.initials: JW
authors.lastname: Ellison
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D001842:Bone and Bones / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D055947:Loeys-Dietz Syndrome / Q000235:genetics*; D008297:Male; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D018125:Receptors, Transforming Growth Factor beta