A number sign (#) is used with this entry because of evidence that Loeys-Dietz syndrome-4 (LDS4) is caused by heterozygous mutation in the TGFB2 gene (190220) on chromosome 1q41.

Loeys-Dietz syndrome-4 (LDS4) is characterized by aortic aneurysm, with other variable features including arterial tortuosity, skeletal anomalies (e.g., pectus deformity, scoliosis, and arachnodactyly), and skin involvement (e.g., thin skin, easy bruising, striae). Mild craniofacial anomalies including retrognathia, high-arched palate, hypertelorism, and bifid uvula may be present. Tarlov cysts and dural ectasia have been reported (Lindsay et al., 2012, Boileau et al., 2012).

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

Lindsay et al. (2012) studied 8 families segregating autosomal dominant aortic aneurysm in association with variable other features, including hypertelorism, bifid uvula, pectus deformity, bicuspid aortic valve, arterial tortuosity, arachnodactyly, scoliosis, clubfeet, and thin skin with easy bruising and striae. Ectopia lentis was not observed. Histologic examination of aortic tissue from an affected family member showed elastic fiber fragmentation and higher collagen and proteoglycan deposition versus control.

Boileau et al. (2012) reported 2 large families segregating autosomal dominant thoracic aortic aneurysm and aortic dissection with decreased penetrance, along with intracranial aneurysm and subarachnoid hemorrhage. Additional features in affected individuals included arterial tortuosity, high-arched palate, pectus deformity, arachnodactyly, scoliosis, flat feet, joint hyperflexibility, skin striae, and dural ectasia. The median age at aortic disease presentation was 35 years, with the majority of affected family members presenting aneurysms at the level of the sinuses of Valsalva. Although features overlapping those of Marfan syndrome (MFS; see 154700) were found in some individuals, they were insufficient in any individual to meet the diagnostic criteria for MFS. Ectopia lentis was absent in these families. Histologic examination of aortic tissue from 2 affected individuals showed pathology typical for thoracic aortic disease, with fragmentation and loss of elastin fibers and accumulation of proteoglycans in the tunica media.

Gago-Diaz et al. (2014) reported a large 4-generation Spanish pedigree segregating autosomal dominant thoracic aortic aneurysm and dissection with or without bicuspid aortic valve. Affected members of the family presented some minor connective tissue disease signs such as joint laxity, scoliosis, flat feet, dolichocephaly, and high palate; however, none met standard diagnostic criteria for Marfan (154700), Ehlers-Danlos (see 130000), or Loeys-Dietz syndromes or any other described disorder of connective tissue. One affected member had a bicuspid aortic valve.

The transmission pattern of LDS4 in the families reported by Boileau et al. (2012) was consistent with autosomal dominant inheritance.

Lindsay et al. (2012) performed SNP array analysis in 2 unrelated probands with aortic aneurysm and MFS- and LDS-like features as well as mild developmental delay, and identified 2 unique heterozygous de novo chromosomal microdeletions at 1q41, both of which included the 'obvious' candidate gene TGFB2. Analysis of TGFB2 in 86 individuals with aneurysm who did not have mutations in FBN1 (134797), TGFBR1 (190181), or TGFBR2 (190182) revealed 6 different mutations in 6 probands (see, e.g., 190220.0001 and 190220.0002). Noting the substantial clinical and mechanistic overlap of this disorder with Loeys-Dietz syndrome (see 609192), Lindsay et al. (2012) suggested that categorizing it within the LDS spectrum would facilitate diagnosis and disease management.

Using genomewide linkage analysis followed by whole-exome sequencing in 2 unrelated families with an autosomal dominant thoracic aortic aneurysm syndrome, 1 from the US and 1 French, who were negative for mutation in known aneurysm-related genes, Boileau et al. (2012) identified a frameshift and a nonsense mutation in the TGFB2 gene (190220.0003 and 190220.0004) that segregated with disease in each family. Analysis of TGFB2 in 276 additional individuals with thoracic aortic disease, including 62 French probands and 74 French sporadic cases as well as 214 US probands from families with 2 or more members with thoracic disease, revealed a nonsense and a frameshift mutation respectively in 2 of the French familial cases. Analysis of aortic tissue from 2 affected individuals by quantitative PCR unexpectedly showed increased TGFB2 expression compared to controls; immunoblot analysis showed a corresponding increase in TGF-beta-2 proprotein levels in mutant aorta. Boileau et al. (2012) concluded that haploinsufficiency for TGFB2 predisposes to thoracic aortic disease and suggested that the initial pathway driving disease is decreased cellular TGF-beta-2 levels, leading to a secondary increase in TGF-beta-2 production in the diseased aorta.

Gago-Diaz et al. (2014) described a 4-generation Spanish family with aortic aneurysm and nonspecific minor connective tissue disease signs who segregated an arg348-to-cys mutation (R348C; 190220.0005) in the TGFB2 gene, which affects a residue evolutionarily conserved among mammals. Two unaffected individuals, ages 14 and 44 years, carried the mutation, suggesting possible later development or low penetrance, respectively.