The Loeys–Dietz syndrome

The Loeys–Dietz syndrome was first described in 2005 as an autosomal dominant syndrome (OMIM number 609192). It is characterised by aortic and peripheral aneurysms and arterial tortuosity, bifid uvula and/or cleft palate, and hypertelorism, and is caused by mutations in the genes for the transforming growth factor β receptors 1 or 2 (TGFBR1 at chromosome 9q33–q34 or TGFBR2 at chromosome 3p22).

The syndrome was first described in 10 families and is now found in an additional 42 families (Bart L Loeys and colleagues. N Engl J Med 2006;355: 788–98; see also editorial, ibid: 841–4). Of the 52 probands, 40 had all the features of the Loeys–Dietz syndrome and were categorised as having Loeys–Dietz syndrome type 1. Twelve were discovered on genetic screening of 40 patients who had a clinical diagnosis of vascular Ehlers–Danlos syndrome but did not have either the type III collagen abnormalities of Ehlers–Danlos syndrome or the craniofacial features of the Loeys–Dietz syndrome, although some had a bifid uvula. These 12 probands were categorised as having Loeys–Dietz syndrome type II. Of the 30 new probands with the type I syndrome, 21 had mutations in the TGFBR2 gene and 9 in the TGFBR1 gene; of the 12 with type II syndrome, 8 had TGFBR2 and 4 had TGFBR1 mutations. The phenotypes were similar for mutations in either gene.

The clinical features of the 40 probands with type I syndrome included aortic root aneurysm (98%), arterial tortuosity (84%), other aneurysms (52%), hypertelorism (90%), cleft palate or abnormal uvula (90%), other craniofacial features including craniosynostosis (48%) and blue sclerae (40%), and skeletal abnormalities including arachnodactyly (70%), pectus deformity (68%) and joint laxity (68%). Less common features included developmental delay, hydrocephalus and Arnold–Chiari malformation. The clinical features of type II Loeys–Dietz syndrome were those of vascular Ehlers–Danlos syndrome. Twelve women (5 with type I and 7 with type II syndrome) had 21 pregnancies, and 6 (1 with type I and 5 with type II) had major complications (aortic dissection in 4, uterine rupture in 2). Among 52 probands and 38 relatives with Loeys–Dietz syndrome, 27 died before or during the study period. The main causes of death were dissection of the thoracic or abdominal aorta, and the mean age at death was 26 (range 0.5–47) years. The mean age at death was lower in those with type I (22.6 v 31.8 years), and patients with more severe craniofacial features had earlier onset of cardiovascular events.

The differential diagnosis of Loeys–Dietz syndrome includes atypical Marfan syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysm and dissection. Genotyping of TGFBR may be needed to make the diagnosis. Animal research has led to the suggestion that TGFβ antagonists such as the angiotensin II type 1 receptor antagonist, losartan, might be beneficial in these syndromes and even in diabetic vascular disease. A trial of losartan versus β‐blockers in young people with Marfan syndrome and aortic aneurysms is in its early stages.