Loeys-Dietz Syndrome 3

A number sign (#) is used with this entry because of evidence that Loeys-Dietz syndrome-3 (LDS3) is caused by heterozygous mutation in the SMAD3 gene (603109) on chromosome 15q.

For a general phenotypic description and a discussion of genetic heterogeneity of Loeys-Dietz syndrome, see LDS1A (609192).

Clinical Features

Van de Laar et al. (2011) studied 3 unrelated Dutch families with arterial aneurysms, dissections, and/or early-onset osteoarthritis. The largest family was a 4-generation pedigree in which 12 of 22 affected individuals presented with aneurysms of the aorta, primarily at the sinus of Valsalva, but also involving the abdominal aorta and/or other arteries such as the splenic, common iliac, mesenteric, renal, vertebral, or main pulmonary artery. There was a strong history of sudden death between 35 and 69 years of age, primarily due to dissection and/or rupture of the aorta, which sometimes occurred in mildly dilated aortas. Arterial tortuosity of the cerebral, thoracic, and/or abdominal arterial tree was present in the majority of cases. Other congenital heart disease was present as well, including mitral valve abnormalities, and 5 normotensive individuals had idiopathic mild to moderate predominantly concentric left ventricular hypertrophy. Craniofacial abnormalities in affected individuals were mild and included hypertelorism, abnormal palate and/or uvula, and dental malocclusion. In contrast to other aneurysm syndromes, most affected individuals also presented with early-onset osteoarthritis, with radiologically proven osteoarthritis of 1 or more joints at a mean age of 42 years, primarily involving the knees, spine, and/or thumb base. Intervertebral disc abnormalities of the cervical and lumbar discs were commonly seen, and were detected as early as 12 years of age. The osteoarthritic changes in the hands and wrists involved the scaphotrapeziotrapecoidal, first carpometacarpal, and occasionally the metacarpophalangeal joints; in contrast with classic hand osteoarthritis, the proximal and distal interphalangeal joints were not affected. In addition, umbilical and/or inguinal hernias, velvety skin, and striae were recurring features. Varices or thread veins presented at a young age and were resistant to therapy. Ophthalmologic examination in 10 cases revealed no abnormalities. Aortic tissue that was obtained at surgery or postmortem from affected individuals in 2 of the families showed a variable degree of disorganization of the tunica media with fragmentation and loss of elastic fibers, as well as characteristic mucoid medial degeneration and accumulation of collagen in the media. The authors designated the disorder aneurysms-osteoarthritis syndrome (AOS).

Regalado et al. (2011) reported 5 families with mutation in the SMAD3 gene. One family, TAA549, had been reported by Regalado et al. (2011). That family had a frameshift mutation in exon 5 of the SMAD3 gene (603109.0004). Regalado et al. (2011) identified 3 additional SMAD3 mutations in 4 families. These families all segregated thoracic aortic aneurysm as an autosomal dominant trait. Some members of the family also had abdominal aortic aneurysms, iliac artery aneurysms, and intracranial aneurysms. Only 2 of 6 who were imaged had arterial tortuosity of the cerebral vessels. Seven of 25 patients reported osteoarthritis, and 2 of 25 reported degenerative disc or joint disease. In the 5 families, there were 31 individuals carrying SMAD3 mutations and 11 obligate carriers. Among these 42 individuals, 21 individuals presented with thoracic aortic aneurysm and/or dissection, 4 with intracranial aneurysm or subarachnoid hemorrhage, 2 with abdominal aortic aneurysm, and 2 with bilateral iliac aneurysms. The average age at presentation of disease was 45.1 years (42 years for thoracic aortic dissection and 51 years for intracranial aneurysms or subarachnoid hemorrhage). Regalado et al. (2011) concluded that SMAD3 mutations are responsible for 2% of familial thoracic aortic aneurysms with dissection.

Van de Laar et al. (2012) presented clinical data on 45 patients with aneurysms-osteoarthritis syndrome from 8 families with 8 different SMAD3 mutations. The 45 patients had a mean age of 45 years, including 6 children aged 9 to 17 years. All had at least 1 sign of the disorder. Among adult patients, 54% had presented with joint complaints with age of onset 18 to 61 years, and 46% presented with cardiovascular abnormalities with an age range of 20 to 66 years. Sudden death, aortic aneurysms, and severe mitral valve insufficiency were the most common presentation. In 3 patients the diagnosis of Marfan syndrome (154700) was made at the time of presentation on the basis of revised Ghent criteria. All 6 children were referred for initial evaluation after the disorder had been diagnosed in the family. Among the children, a 12-year-old patient presented with knee and lower back pain and imaging showed agenesis of the anterior cruciate ligaments, osteochondritis dissecans of the knee, and severe intervertebral disc degeneration. A 17-year-old boy also showed severe intervertebral disc degeneration at multiple levels, and a 16-year-old boy had tenodesis of the first metacarpophalangeal joint. Overall, 89% of patients had cardiovascular anomalies, including aneurysm or tortuosity (83%), ventricular hypertrophy (18%), atrial fibrillation (24%), mitral valve anomalies (50%), and congenital heart malformation (9%), including atrial septal defect, persistent ductus arteriosus, pulmonary valve stenosis, and bicuspid aortic valve. Osteoarthritis in at least 1 joint was present in 96% with variable joints involved; however, 77% presented with spine osteoarthritis, 92% with intervertebral disc degeneration, 56% with osteochondritis dissecans, and 85% with painful joints. Pes planus was present in 91%, and scoliosis in 61%. A minority had other skeletal anomalies associated with this phenotype, including dolichostenomelia, long slender fingers, camptodactyly, pectus deformity, and protrusio acetabulae. Hypertelorism was present in 31%; abnormal palate in 54%; abnormal uvula in 52%; velvety skin in 62%; migraine or severe headache in 50%; and varices in 58%. Other anomalies were present in a minority of patients.

Van de Laar et al. (2012) noted that atrial fibrillation and ventricular hypertrophy had not previously been reported in LDS and that both are uncommon in Marfan syndrome. They suggested that patients presenting with arterial tortuosity and symptoms of osteoarthritis, as well as those with osteoarthritis who have a family history of arterial disease or sudden death should have SMAD3 as the first gene screened. They recommended x-ray examination of the knees, total spine, and hands, particularly in thoracic aortic aneurysm disease patients with a family history of joint complaints or abnormalities.

Mapping

In a 4-generation Dutch family in which 22 individuals had arterial aneurysms and dissections and/or early-onset osteoarthritis, van de Laar et al. (2011) performed genomewide linkage analysis and obtained a lod score of 3.6 on chromosome 15q. Fine mapping narrowed the gene locus to a 12.8-Mb region between markers D15S155 and D15S980.

Molecular Genetics

In a 4-generation Dutch family with arterial aneurysms and dissections and/or early-onset osteoarthritis mapping to chromosome 15q22.2-q24.2, van de Laar et al. (2011) analyzed the candidate gene SMAD3 and identified heterozygosity for a missense mutation (603109.0001) that segregated with the disease. Analysis of SMAD3 in 99 patients with thoracic aortic aneurysms and dissections and Marfan-like features, who were known to be negative for mutation in the FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes, revealed 2 additional probands with heterozygous SMAD3 mutations (603109.0002; 603109.0003).

Regalado et al. (2011) reported 4 new mutations in SMAD3 in 5 families with thoracic aortic and other aneurysms with dissection.

Van de Laar et al. (2012) screened 393 patients with aneurysms but without mutation in FBN1, TGFBR1, or TRGBR2 for mutations in SMAD3 and identified 45 patients from 8 families with 8 different SMAD3 mutations, 5 of which were novel. The novel mutations included 1 nonsense, 2 missense, and 2 frameshift mutations.