Loeys–Dietz syndrome is a rare congenital disorder characterized by loose connective tissue [1, 2]. As a variant form of Marfan syndrome, affected individuals exhibit progressive vascular diseases such as dilation of the aortic root, aortic dissection and valvular insufficiency [1–3]. In addition to these common phenotypes, patients with Loeys–Dietz syndrome manifest distinct anomalies, such as ocular hypertelorism, high-arched palate, bifid uvula, scoliosis and clubfoot [1, 2].

Vascular complications in Loeys–Dietz syndrome are known to progress more rapidly than those in Marfan syndrome [2, 3]. Hence the precise diagnosis of Loeys–Dietz syndrome is a critical issue in the long-term management of affected individuals. In this report, we present a Japanese boy with Loeys–Dietz syndrome who carried a novel mutation in the TGFBR2 gene. This study highlights the moderate to severe vascular phenotypes that resulted from an R381P mutation in TGFBR2.

MR imaging was performed using a 3.0T system (Intera Achieva; Philips Medical Systems, Best, Netherlands). Polymerase chain reaction (PCR) amplifying the coding exons of TGFBR2 (chr3:30647994–30735633) was performed as previously described [1, 2, 4]. Sequencing reactions were performed with the BigDye® Terminator v3.1 cycle sequencing kit (Life Technologies, Grand Island, NY, U.S.A.) according to the manufacturer’s protocol.

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.

This study was conducted in compliance with the institutional review board at Kyushu University Hospital. Written informed consent was obtained from the patient’s parents for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.