Loeys-Dietz syndrome 1 (LDS1; MIM 609192) and 2 (LDS2; MIM 610168) are caused by mutations in the TGFBR1 and TGFBR2 genes respectively. The reported phenotype is highly variable and overlaps considerably with Ehlers-Danlos syndrome IV (EDS IV; MIM 130050) or Marfan syndrome (MFS; MIM 154700). A high percentage of patients have aortic root aneurysm or other arterial aneurysms. Some have cardiac abnormalities including patent ductus or atrial septal defects. Many display arterial tortuosity. Skeletal defects may include hypertelorism, pectus defects, joint laxity, craniosynostosis, arachnodactyly, scoliosis, talipes equinovarus, camptodactyly and malar hypoplasia. Some have dural ectasia. Additional features may include uterine, spleen or bowel rupture, thin, translucent, hyperextensible or velvety skin with atrophic scars and easy bruising. Blue sclera and a bifid uvula have also been observed.

Loeys-Dietz syndrome 3 (LDS3; MIM 613795), also known as aneurysms-osteoarthritis syndrome (AOS), is an autosomal dominant disorder caused by mutations in the SMAD3 gene. SMAD3 is an important molecule in the TGFβ pathway. LDS3/AOS is characterized by cardiovascular, joint and skeletal anomalies. Cardiovascular findings include frequent aneurysms or dissections of the thoracic and abdominal aortas, as well as the carotid, basilar ophthalmic, coronary, iliac, superior mesenteric, vertebral, pulmonary and splenic arteries. Arterial tortuosity of the thoracic, abdominal and cerebral arteries may also be present. Other findings may include mitral valve abnormalities, atrial fibrillation, and left ventricular hypertrophy. Painful joints, early onset osteoarthritis, intervertebral disc degeneration, irregularly shaped vertebral bodies, spondylysis and/or spondylolisthesis, non-traumatic osteochondritis dissecans and meniscal lesions are common. In one study, joint complaints represented the primary presenting symptoms. The most common skeletal findings include pes planus, scoliosis, pectus carinatum or excavatum, long slender fingers and protrusion acetabulae. Abnormal palate and uvula, velvety skin, striae, varices, umbilical hernia, inguinal hernia and easy bruising are also frequent. SMAD3 mutations are estimated to be responsible for about 2% of LDS3/AOS cases. Penetrance is considered to be almost 100% but expression is variable.

Loeys-Dietz Syndrome 4 (LDS4; MIM 614816), also known as aneurysm, aortic and cerebral with arterial tortuosity and skeletal manifestations, is an autosomal dominant disorder caused by mutations in the TGFB2 gene.  This gene encodes transforming growth factor, beta 2.  The described vascular features include aortic aneurysms and dissections, aortic root dilation, bicuspid aortic valve, intracranial aneurysms and subarachnoid hemorrhage and arterial tortuosity.  Additional findings may include hypertelorism, bifid uvula, high arched palate, pectus deformity, arachnodactyly, scoliosis, flat or clubbed feet, thin skin with easy bruising and striae, and joint hyperflexibility.  These features overlap with Marfan syndrome but individual patients do not meet diagnostic Marfan syndrome criteria.  Ectopia lentis has not been detected in patients to date. 

 Loeys-Dietz Syndrome 5 (LDS5; MIM 615582) is caused by mutations in the TGFB3 gene. LDS5 overlaps clinically with Shprintzen-Goldberg and Marfan syndromes. The cardiovascular phenotype includes thoracic and/or abdominal aortic aneurysm and dissection, and mitral valve disease. Other common findings include cleft palate, bifid uvula, cervical spine instability, club foot, scoliosis, and skeletal overgrowth. 

Copy number variation (CNV) analysis of the Loeys-Dietz syndrome genes is also offered as a panel. Additionally, CTGT offers a comprehensive test (both NGS and CNV panels) for these genes. Panel genes are also offered as individual sequencing and deletion/duplication tests unless otherwise indicated.