Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). Approximately 75% of affected individuals have LDS type I with craniofacial manifestations (ocular hypertelorism, bifid uvula/cleft palate, craniosynostosis); approximately 25% have LDS type II with cutaneous manifestations (velvety and translucent skin; easy bruising; widened, atrophic scars). LDSI and LDSII form a clinical continuum. The natural history of LDS is characterized by aggressive arterial aneurysms (mean age at death 26.1 years) and high incidence of pregnancy-related complications including death and uterine rupture.

The diagnosis of LDS is based on characteristic clinical findings in the proband and family members and molecular genetic testing of TGFBR1 and TGFBR2, the only two genes known to be associated with LDS. No differences in phenotype are observed between individuals with mutations in TGFBR1 and TGFBR2.

LDS is inherited in an autosomal dominant manner. Approximately 25% of individuals diagnosed with LDS have an affected parent; approximately 75% of probands have LDS as the result of a de novo gene mutation. Each child of an individual with LDS has a 50% chance of inheriting the mutation and the disorder. Prenatal diagnosis for pregnancies at increased risk for LDS is possible if the disease-causing mutation in the family is known.

The major cardiovascular manifestations of thoracic aortic aneurysms and aortic dissections (TAAD) include: (1) dilatation of the ascending thoracic aorta at the level of the sinuses of Valsalva or ascending aorta or both; and (2) dissections of the thoracic aorta involving either the ascending (Stanford type A dissections) or descending aorta (Stanford type B). Rarely an aneurysm involving the descending thoracic aorta is observed. Vascular manifestations can be the only findings. In the absence of surgical repair of the ascending aorta, affected individuals typically have progressive enlargement of the ascending aorta leading to an acute aortic dissection. The age of onset and presentation of the aortic disease are highly variable, as are the other vascular diseases and features associated with the aortic disease.

TAAD is diagnosed using different imaging modalities such as echocardiography, computed tomography (CT), magnetic resonance imaging (MRI), or angiography. Up to 20% of individuals with TAAD have a first-degree relative with thoracic aortic disease. Familial TAAD (FTAAD) is diagnosed based on the presence of dilatation and/or dissection of the thoracic aorta, absence of clinical features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome, and presence of a positive family history of TAAD. TGFBR2, TGFBR1, MYH11, ACTA2, MYLK, SMAD3, and two loci on other chromosomes, AAT1 (FAA1) and AAT2 (TAAD1), are associated with familial TAAD. Rarely, FTAAD can also be caused by FBN1 mutations. Further locus heterogeneity is evident: to date, only about 20% of familial TAAD is accounted for by mutations in known genes.

Familial TAAD is primarily inherited in an autosomal dominant manner with variable expression and decreased penetrance. The majority of individuals with familial TAAD have an affected parent. The children of an affected parent have an up to 50% chance of inheriting the genetic predisposition to TAAD. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.