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Clin Genet. 2017 Mar;91(3):458-462. doi: 10.1111/cge.12838. Epub 2016 Sep 13.

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

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Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, Hôpitaux de Paris, Paris, France.
Centre Hospitalier Intercommunal Toulon-La Seyne-sur-Mer, Service de Génétique Médicale, Toulon, France.
Centre de Référence National Syndromes de Marfan et apparentés, Hôpitaux de Paris, Hôpital Bichat-Claude-Bernard, Paris, France.
Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
Paris Cardiovascular Research Centre, INSERM, U970, Paris, France.


Syndromic thoracic aortic aneurysm and dissection (TAAD) can suggest Marfan, vascular Ehlers-Danlos or Loeys-Dietz (LDS) syndromes. Several of the TGFβ-pathway-related genes predispose to different types of LDS. Heterozygous loss-of-function variations in TGFβ2 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 TGFβ2 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 TGFβ2 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.


Loeys-Dietz syndrome type 4; Phenotypic variability; diffuse vascular lesions; transforming-growth-factorβ (TGFβ) signaling pathway

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