Comparison of Clinical Presentations and Outcomes Between Patients With TGFBR2 and FBN1 Mutations in Marfan Syndrome and Related Disorders

Abstract

Background-TGFBR2 mutations were recognized recently among patients with a Marfan-like phenotype. The associated clinical and prognostic spectra remain unclear. Methods and Results-Clinical features and outcomes of 71 patients with a TGFBR2 mutation (TGFBR2 group) were compared with 50 age-and sex-matched unaffected family members (control subjects) and 243 patients harboring FBN1 mutations (FBN1 group). Aortic dilatation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% versus 79%, respectively) but was highly variable. The incidence and average age for thoracic aortic surgery (31% versus 27% and 35Ϯ16 versus 39Ϯ13 years, respectively) and aortic dissection (14% versus 10% and 38Ϯ12 versus 39Ϯ9 years) were also similar in the 2 groups. Mitral valve involvement (myxomatous, prolapse, mitral regurgitation) was less frequent in the TGFBR2 than in the FBN1 group (all PϽ0.05). Aortic dilatation, dissection, or sudden death was the index event leading to genetic diagnosis in 65% of families with TGFBR2 mutations, versus 32% with FBN1 mutations (Pϭ0.002). The rate of death was greater in TGFBR2 families before diagnosis but similar once the disease had been recognized. Most pregnancies were uneventful (without death or aortic dissection) in both TGFBR2 and FBN1 families (38 of 39 versus 213 of 217; Pϭ1). Seven patients (10%) with a TGFBR2 mutation fulfilled international criteria for Marfan syndrome, 3 of whom presented with features specific for Loeys-Dietz syndrome. Conclusions-Clinical

Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome

“…Similar to MFS, a great variability in aortic dilatation is observed amongst patients (11). When undetected and untreated, a dilatation could evolve into dissection or rupture, and has been observed as young as 3 months (32).…”

“…LDS patients most often present with cardiovascular features first, while this is not the case for MFS (11). The remainder of LDS patients often first show skeletal or joint symptoms (11,30).…”

“…However, great variability in rate of dilatation is observed between affected individuals. As a consequence of the dilatation at the aortic root, aortic regurgitation might develop (11). The dilation might evolve towards an aneurysm, which in turn can lead to a type A dissection or rupture (12).…”

Loeys–Dietz syndrome is a specific phenotype and not a concomitant of any mutation in a gene involved in TGF-β signaling

“…Many patients with mutations in TGFBR1, TGFBR2, SMAD3, and TGFB2 do not have a phenotype consistent with LDS nor do they have an aggressive arterial disease. 4,5 Although arterial involvement beyond the aortic root is established for TGFBR1, TGFBR2, and SMAD3, there is no evidence that TGFB2 mutations cause arterial disease to the same extent. Osteoarthritis and neurological features can be associated with mutations in SMAD3 but not with the other genes.…”

“…4 Most importantly, patients with LDS often show a widespread and aggressive vasculopathy (arterial tortuosity, aneurysms throughout the arterial tree, dissections at young ages and at relatively small vascular dimensions that do not infer risk or provoke surgery in MFS, and many other conditions). Within 1 year (in 2006), a second publication expanded the phenotypic spectrum of LDS to include individuals with TGFBR1 or TGFBR2 mutations with a similarly diffuse and aggressive vascular phenotype but only subtle or even absent craniofacial and/or skeletal manifestations.…”