Clinical features in a family with an R460H mutation in transforming growth factor   receptor 2 gene

Abstract

Objectives: To describe the clinical findings and natural history in 22 carriers of an R460H mutation in the transforming growth factor b receptor 2 gene (TGFbR2) from a five-generation kindred ascertained by familial aortic dissection. Methods: 13 of the confirmed carriers were interviewed and examined, and information about the remaining carrier was obtained from medical records. Clinical information about deceased individuals was obtained, when possible, from postmortem reports, death certificates and medical records. Results: There have been eight sudden deaths; the cause of death was aortic dissection in all six cases in which a postmortem examination was performed. Three individuals had undergone aortic replacement surgery. Dissection had occurred throughout the aorta, and in one case in the absence of aortic root dilatation. Subarachnoid haemorrhage, due to a ruptured berry aneurysm, had occurred in two individuals. Four gene carriers and one deceased family member who were investigated had tortuous cerebral blood vessels. One had tortuous vertebral arteries, two had tortuous carotid arteries and one a tortuous abdominal aorta. Two individuals were found to have a brachiocephalic artery aneurysm and a subclavian artery aneurysm, respectively. Conclusions: Despite the predisposition to aortic dilatation and dissection, individuals did not frequently manifest the skeletal features of Marfan syndrome, with the exception of joint hypermobility. No one individual had ocular lens dislocation. Striae and herniae were common. There was some overlap with Ehlers-Danlos syndrome type 4, OMIM 130050, with soft translucent skin, which is easily bruised. Other features were arthralgia, migraine and a tendency to fatigue easily, varicose veins and prominent skin striae. This family provides further evidence that mutations in TGFbR2 cause a distinct syndrome that needs to be distinguished from Marfan syndrome to direct investigation and management of patients and shows the natural history, spectrum of clinical features and variable penetrance of this newly recognised condition.

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

“…The mutational hotspot at the p.R460 residue in TAAD2 suggested a positive phenotype-genotype correlation, and this observation was supported by the discovery of another family with p.R460H that was initially diagnosed as having TAAD2 and, later, as having a distinctive condition with cardiovascular findings consistent with TAAD2, together with arterious tortuosity and aneurysm (Law et al 2005(Law et al , 2006.…”

Association of the TGF-β receptor genes with abdominal aortic aneurysm

“…20 Mutations in these genes are responsible for Marfan syndrome type II (OMIM 154705), 13 Loeys-Dietz syndrome (OMIM 609192) 14,15 and thoracic aortic aneurysms leading to type A dissections (TAA; OMIM 608967). 16,17 Marfan syndrome type I is clinically similar to Marfan type II syndrome, but it is caused by mutations in the fibrillin-1 gene. 21 Fibrillin-1 encodes the structural ECM protein fibrillin-1, which is thought to regulate the availability of active TGF-b by binding to TGF-b in its latent form.…”

“…12 Dysregulated TGF-bsignaling by mutations in the receptor genes, TGFBR1 and TGFBR2, causes thoracic aortic aneurysm (TAA) syndromes, including Marfan syndrome type II (OMIM 154705), 13,14 Loeys-Dietz syndrome (OMIM 609192), 14,15 and thoracic aortic aneurysms leading to type A dissections. 16,17 Although these syndromes are clinically distinct, their phenotypes overlap, with TAA and aortic dissections as the common denominator. In families with TAA caused by mutations in the TGFBR2 gene, family members had aneurysms at different locations of the vascular system.…”

“…Most affected members had TAA of the ascending aorta but some also had aneurysms of the descending aorta, the carotid, brachiocephalic, subclavian or popliteal arteries whereas others had ruptured or unruptured IA. 17,18 Furthermore, detailed characterization revealed that half of the probands with Loeys-Dietz aortic aneurysm syndrome not only had TAA but also aneurysms at different locations, mainly consisting of AAA and aneurysms of head and neck. 15 It is therefore conceivable that dysregulated TGF-b signaling has a role in aneurysm formation in general.…”

Marfan syndrome: clinical diagnosis and management

“…6 -8 These 'Marfan syndrome type 2' (MIM 154705) 9 families seem less likely to have ectopia lentis. TGFBR2 mutations at the R460 codon have also been described in families with the chromosome 3-linked form of familial thoracic ascending aortic aneurysm 10,11 (FTAA3, MIM 608967), and TGFBR1 and 2 mutations are found in Loeys -Dietz syndromes type 1 and 2. 12,13 To make the diagnosis of Marfan syndrome more consistent and of more prognostic value, the Berlin diagnostic criteria of 1988 were revised and the clinical features codified as the Ghent nosology in 1996.…”