• Letizia Camerota, Marco Ritelli, Anita Wischmeijer, Silvia Majore, Valeria Cinquina, Paola Fortugno, Rosanna Monetta, Laura Gigante, Marfan Syndrome Study Group Tor Vergata University HospitalHuman Genetics Institute, Department of Life, Health, and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy. sangiuolo@med.uniroma2.it., Federica Carla Sangiuolo, Giuseppe Novelli, Marina Colombi, and Francesco Brancati.
• Human Genetics Institute, Department of Life, Health, and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy. letizia.camerota@guest.univaq.it.
• Genes (Basel). 2019 Sep 28; 10 (10).

AbstractLoeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.

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