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

Objectives

To describe the clinical findings and natural history in 22 carriers of an R460H mutation in the transforming growth factor β receptor 2 gene (TGFβR2) 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 TGFβR2 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.In 1993, Boileau et al¹ reported on a large French family with a Marfan‐like disorder that did not map to fibrillin 1 gene (FBN1) or FBN2. A year later, this family was mapped to 3p24.2–25 and this was proposed as a second locus for Marfan syndrome² and the condition was designated Marfan syndrome type 2 (MFS2), OMIM 154705. Interestingly, a family with familial thoracic aortic aneurysms and dissections (TAAD2) have also been shown to map within this region.³The transforming growth factor β receptor 2 (TGFβR2) gene was implicated in the pathogenesis of Marfan syndrome when Mizuguchi et al⁴ reported on a Japanese patient who had a clinical diagnosis of Marfan syndrome together with a complex chromosomal rearrangement involving a breakpoint at 3p24.1, disrupting TGFβR2. They also found three missense mutations in four unrelated FBN1‐negative Marfan syndrome probands and a splice‐site mutation in the original French family, which had mapped to 3p24.2–25.².This report led us to reconsider a large family known to us with an autosomal dominant predisposition to aortic dissection, in which no FBN1 mutation was detected in affected members and linkage studies excluded the FBN1 locus.In 2005, Loeys et al⁵ reported Loeys–Dietz syndrome, OMIM 609192, consisting of hypertelorism, bifid uvula, cleft palate, arterial tortuosity and ascending aortic aneurysm and dissection due to mutations in TGFβR1 and TGFβR2. They found five missense mutations and a splice‐site mutation in TGFβR2 in members from six families, and four missense mutations in TGFβR1 in members from four families with a clinical phenotype indistinguishable from that seen in those with TGFβR2 mutations.Mutations at the R460 position in TGFβR2 have been reported in four unrelated families with TAAD2,⁶ and in one family with Marfan syndrome;⁷ three of the families had the R460H mutation present in our family, and Pannu et al⁶ proposed that this may be a mutation hotspot.Recently, there has been a report of a Korean with a de novo missense mutation in TGFβR2, with features consistent with Loeys–Dietz syndrome (fig 1​1).⁸Open in a separate windowFigure 1 A sketch of transforming growth factor β2 gene with mutations.TGFBR2, OMIM 190182, codes for a serine threonine kinase transmembrane receptor,⁹ which, in association with transforming growth factor β receptor 1 and the ligand, transforming growth factor β (TGFβ) is involved in the regulation of cellular processes and the formation of extracellular matrix.¹⁰ This pathway may be affected by fibrillin 1, which controls the activation of TGFβ.¹¹ Dysregulation of TGFβ activation has been implicated in the pathogenesis of Marfan syndrome.^12,13,14