This report presents the systemic phenotypes of Loeys–Dietz syndrome that were caused by a novel TGFBR2 mutation (R381P) in a Japanese case. The systemic vascular phenotypes of this case indicate the strong penetrance as well as the dominant effects of the heterozygous missense mutation.
The TGFBR2 gene encodes transforming growth factor-beta receptor II (70/80 kDa), a membrane-bound, serine/threonine kinase domain-containing protein. This protein forms a heterodimeric complex with another receptor protein, thereby activating the downstream signaling molecules, such as SMAD proteins, upon stimulation by TGF-beta ligands. Previous studies showed that the majority of pathogenic TGFBR2 mutations were identified in the exons encoding the protein kinase domain [1–3]. In vitro studies suggested that such mutations disturbed not only the kinase activity of TGFBR2, but also internalization process of the receptor, suggesting the dominant effects of heterozygous mutations. Given that the R381P mutation in this case (Figure 3A) was also located at the kinase domain of TGFBR2, we speculated that the mutation caused deleterious effects on both its kinase activity and the receptor internalization. An angiotensin II receptor antagonist, losartan, has been recently shown to down-regulate the expression of TGFBRs, and thus proved to be effective in preventing the progressive aortic dilation and development of aneurysm in Marfan and Loeys-Dietz syndromes. A large cohort, including the present case, is thus needed to monitor its efficacy and side effects, thereby elucidating prognostic factors and contraindications of the therapies.
It is well known that prevention of aortic dilation is a vital issue for the long-term survival of patients with Loeys-Dietz syndrome. On the other hand, there are no reports clearly demonstrating the association of Marfan or Loeys-Dietz syndrome with neurovascular complications [7, 8]. Nonetheless, recent reports showed sporadic cases with intracranial aneurysm as well as tortuosity of carotid arteries in this disorder [7, 9, 10]. Given the progressive nature of the cardiovascular phenotypes of Loeys–Dietz syndrome, one could argue that only severely affected cases may experience such late-onset neurovascular complications. It also remains to be determined whether the enlarged perivascular lumens in this case (Figure 5A-C) are associated with the neurovascular phenotypes of Loeys-Dietz syndrome. Future studies will address the issues of their genotype-phenotype correlations, particularly on their comorbidity with neurovascular complications. Large cohorts with serial imaging studies can be considered to determine whether certain genotypes may correlate to their specific phenotypes.