Open Access Highly Accessed Case report

Further delineation of Loeys-Dietz syndrome type 4 in a family with mild vascular involvement and a TGFB2 splicing mutation

Marco Ritelli1, Nicola Chiarelli1, Chiara Dordoni1, Stefano Quinzani1, Marina Venturini2, Roberto Maroldi3, Piergiacomo Calzavara-Pinton2 and Marina Colombi1*

Author Affiliations

1 Division of Biology and Genetics, Department of Molecular and Translational Medicine, Medical Faculty, University of Brescia, Viale Europa 11, Brescia 25123, Italy

2 Department of Dermatology, University Hospital Spedali Civili, Brescia, Italy

3 Department of Radiology, University of Brescia, Brescia, Italy

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BMC Medical Genetics 2014, 15:91  doi:10.1186/s12881-014-0091-8

Published: 28 August 2014

Abstract

Background

The Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder characterized by thoracic aortic aneurysm and dissection and widespread systemic connective tissue involvement. LDS type 1 to 4 are caused by mutations in genes of the TGF-β signaling pathway: TGFBR1 and TGFBR2 encoding the TGF-β receptor (LDS1 and LDS2), SMAD3 encoding the TGF-β receptor cytoplasmic effector (LDS3), and TGFB2 encoding the TGF-β2 ligand (LDS4). LDS4 represents the mildest end of the LDS spectrum, since aneurysms are usually observed in fourth decade and the progression of the disease is slower than in the other forms.

Case presentation

We report the clinical and molecular findings of an LDS4 Italian family. Genetic testing included TGFBR1, TGFBR2, SMAD3, and TGFB2 analysis by Sanger sequencing. In order to verify the effect of the identified splice mutation, RT-PCR analysis was performed.

The proband, a 57-year-old woman, showed high palate, hypoplasic uvula, easy bruising, joint hypermobility, chronic pain, scoliosis, multiple relapsing hernias, dural ectasia, and mitral valve prolapse. Magnetic resonance angiography revealed tortuosity and ectasia of carotid, vertebral, cerebral, and segmental pulmonary arteries. Arterial aneurysm and dissection never occurred. Her 39- and 34-year-old daughters presented with a variable degree of musculoskeletal involvement. Molecular analysis disclosed the novel c.839-1G>A splice site mutation in the TGFB2 gene. This mutation activates a cryptic splice acceptor site in exon 6 leading to frameshift, premature termination codon and haploinsufficiency (p.Gly280Aspfs*41).

Conclusions

Our data confirm that loss-of-function mutations in TGFB2 gene do not always lead to aggressive vascular phenotypes and that articular and skeletal signs are prevalent, therefore suggesting that LDS4 must be considered in patients with sparse signs of LDS and related disorders also in the absence of vascular events.

Keywords:
Loeys-Dietz syndrome type 4; TGFB2; TGF-ß2; Splicing mutation