Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Loeys-Dietz Syndrome (LDS) [Q25.4]

OMIM-Nummer: 609192, 608967, 190181 (TGFBR1), 610168, 601380, 190182 (TGFBR2)

Dr. rer. nat. Karin Mayer, Dr. med. Imma Rost

Scientific Background

The Loeys-Dietz (aortic aneurysm) syndrome (LDS) was first described in 2005 and represents the most important differential diagnosis to the Marfan syndrome (MFS). Both syndromes display aortic root dilation or dissection, skeletal abnormalities and dural ectasia. Hypertelorism, craniosynostosis, cleft palate or bifid uvula as well as arterial tortuosity are not found in the Marfan syndrome; however, they are characteristic for Loeys-Dietz syndrome. About 75% of all LDS patients suffer from this LDS type 1. So far, lens luxation has not been observed in Loeys-Dietz syndrome. It is occasionally accompanied by intellectual disability, which is untypical for Marfan syndrome. 

LDS type 2 describes a subtype of Loeys-Dietz syndrome without craniofacial abnormalities affecting 25% of all patients and is characterized by abnormalities of the skin such as soft and translucent skin with atrophic scar formation and easy bruising. The clinical signs and symptoms of LDS type 2 overlap with the vascular type of the Ehlers-Danlos syndrome (EDS type IV): they both display uterine ruptures, aneurysm and dissections of the cerebral, thoracic and abdominal arteries; however, mutations in the COL3A1 gene or the typical changes in the type III collagen are not present.

The fact that the course of the aortic aneurysms is more aggressive in both LDS types than it is in Marfan syndrome and that dissections are likely to occur even without significant vascular dilation is of prognostic significance. The Loeys-Dietz syndrome has an autosomal dominant pattern of inheritance; 25% of all patients have a positive family history. The frequency is not known. 

It is caused by mutations in the genes for the transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2 gene). The cytokine-initiated TGFβ signal transduction plays a key role in the development of vessels and the craniofacial system. Both FBN1 mutations as well as TGFBR1 and 2 mutations activate the TGFβ signal transduction and lead to a disorganization of the elastic fibers in the media of the aortic wall. Clinical criteria do not allow a prediction on whether a mutation in TGFBR1 or TGFBR2 is present. Mutations in both genes were found in or also directly at the kinase domain; however, with a frequency of 75%, TGFBR2 mutations are more common than TGFBR1 mutations, which occur with a frequency of 25%. The detection rate of mutations in patients with classic LDS is 95%; in the Marfan-like syndrome without the full range of signs and symptoms it is approximately 10% and in TAAD approximately 5%.