Phenotypic variability and diffuse arterial lesions in a family with Loeys–Dietz syndrome type 4

<jats:p>Syndromic thoracic aortic aneurysm and dissection (<jats:styled-content style="fixed-case">TAAD</jats:styled-content>) can suggest Marfan, vascular Ehlers–Danlos or Loeys–Dietz (<jats:styled-content style="fixed-case">LDS</jats:styled-content>) syndromes. Several of the <jats:styled-content style="fixed-case">TGFβ</jats:styled-content>‐pathway‐related genes predispose to different types of <jats:styled-content style="fixed-case">LDS</jats:styled-content>. Heterozygous loss‐of‐function variations in <jats:italic>TGF</jats:italic>β<jats:italic>2</jats:italic> have been shown to be responsible for a novel form of syndromic TAAD associated with an impairment of the mitral valve and cerebrovascular disease called Loeys–Dietz syndrome type 4 (LDS4). We report the clinical characterization of a LDS4 French family with sudden deaths and diffuse vascular lesions, caused by a frameshift mutation in <jats:italic>TGF</jats:italic>β<jats:italic>2</jats:italic> gene: c.[995del]; p.(Leu332TrpfsTer27). Clinical characteristics include aneurysm of aortic sinus, skeletal and cutaneous features compatible with a syndromic form of TAAD (joint hypermobility, scoliosis, and easy bruises), intracranial aneurysms and rare mitral valve involvement. Iliac aneurysms, systemic medium caliber arteries dissections, and mild developmental delay were present in the family, and have not been described in LDS4. Phenotypic variability was also an important finding, including absence of clinical vascular events at advanced age in one case. Our data expand the phenotype of LDS4: we confirm that <jats:italic>TGF</jats:italic>β<jats:italic>2</jats:italic> mutations are responsible for true LDS syndrome with non‐specific features of connective tissue disorders and diffuse vascular lesions. Adapted vascular follow up and prevention has to be proposed for these patients.</jats:p>