Alternative titles; symbols
ORPHA: 284973, 558, 60030, 91387; DO: 0070234;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p24.1 | Loeys-Dietz syndrome 2 | 610168 | Autosomal dominant | 3 | TGFBR2 | 190182 |
A number sign (#) is used with this entry because Loeys-Dietz syndrome-2 (LDS2) is caused by heterozygous mutation in the TGFBR2 gene (190182) on chromosome 3p24.
Loeys-Dietz syndrome-2 (LDS2) is an autosomal dominant connective tissue disorder characterized by hypertelorism, cleft palate or bifid uvula, and arterial tortuosity. Arterial aneurysms are aggressive, with intracranial aneurysms leading to subarachnoid hemorrhage, and risk of aortic dissection is high (summary by Law et al., 2006, Chung et al., 2014).
For a general phenotypic description and a discussion of genetic heterogeneity of Loeys-Dietz syndrome, see LDS1 (609192).
Boileau et al. (1990) described a large French family in which multiple members in an autosomal dominant pedigree pattern exhibited some of the skeletal and cardiovascular features of the Marfan syndrome (154700) but lacked ocular abnormalities. Boileau et al. (1993) considered that the patients fulfilled criteria for the MASS (mitral valve, aortic, skeleton, and skin) phenotype (see 157700), but might represent a distinct clinical entity. The proband was a man who died at age 39 years from aortic dissection. Necropsy showed dilatation of the ascending aorta at the level of the sinuses of Valsalva. Other members demonstrated aortic dilatation on echocardiograms as well as mitral valve prolapse. The father of one of these patients died suddenly at the age of 35 years. Another member of the family died suddenly of aortic dissection at age 29 years. One girl died at the age of 9 years after complaining of chest pain.
Dietz et al. (1995) felt that the clinical presentation of the family described by Boileau et al. (1993) failed to meet the diagnostic criteria for Marfan syndrome and that the assignment of 'affected' status was sometimes arbitrary. The salient phenotype in the French family was that of ascending aortic dissection affecting individuals in their mid-thirties. Most of these individuals were deceased and no tissue was available for study. Only 1 person with a dissection contributed a sample, but no further phenotypic description was provided. No individual in this pedigree had documented involvement of the skin, eye, lung, or dura; only the skeletal and cardiovascular systems were involved. Boileau et al. (1995) defended their case-by-case phenotype determination on the basis of reexamination and clinical developments. See also comment of Gilchrist (1994).
Hasham et al. (2003) described a 4-generation family of Swiss-German heritage in which multiple members had thoracic aortic aneurysms and dissection but no ocular or skeletal features of Marfan syndrome.
Pannu et al. (2005) described 4 unrelated families with thoracic aortic aneurysms leading to type A dissections who also had descending aortic disease and aneurysms of other arteries. One of these families was the one reported by Hasham et al. (2003).
Loeys et al. (2005) described 10 families with an aortic aneurysm syndrome characterized by hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity with ascending aortic aneurysm and dissection. Other findings included craniosynostosis, structural brain abnormalities, mental retardation, congenital heart disease, and aneurysms with dissection throughout the arterial tree. The syndrome showed variable clinical expression.
Loeys et al. (2006) assigned patients with 'typical' craniofacial manifestations of LDS, including those from the 10 families described in the report of Loeys et al. (2005), to the type 1 category.
Watanabe et al. (2008) evaluated the parents of a patient with LDS associated with a heterozygous mutation in the TGFBR2 gene. Analysis of the paternal DNA indicated that the father was somatic mosaic for the mutation, with the mutation detected in 52%, 25%, 0%, and 35% of leukocytes, buccal cells, hair root cells, and nails, respectively. Clinical examination of the father did not reveal any features of LDS, including bifid uvula, narrow palate, micrognathia, marfanoid habitus, or arachnodactyly, and echocardiography in the father was normal. The information was useful for genetic counseling in this family.
Kirmani et al. (2010) reported 2 male patients with Loeys-Dietz syndrome, age 17 years and 26 years, respectively, who had a significant history of low bone mineral density and multiple low-impact fractures. Kirmani et al. (2010) noted that 4 of 40 patients reported by Loeys et al. (2006) had 'osteoporosis with multiple fractures at a young age,' and suggested that skeletal fragility and increased fracture risk might be features of LDS.
Disabella et al. (2006) reported 3 probands with a phenotype comprising cardioskeletal anomalies but without major ocular signs described as 'Marfan syndrome type II.' One proband was a 27-year-old man with aortic dilation, mitral valve prolapse, severe pectus excavatum, pes planus, arachnodactyly, scoliosis, and left lumbar gibbus. The ocular and nervous systems did not show major signs, although he had mild myopia. His affected father had died at age 40 from aortic dissection. The second proband was a 24-year-old woman with aortic root dilation, mitral valve prolapse, scoliosis, spondylolisthesis, arachnodactyly, pectus excavatum, pes cavus, joint hypermobility, and high-arched palate with crowded teeth. Her ocular system was not involved. Family history revealed that her father and a paternal aunt both died from aortic root dissection at age 37 and 45, respectively. The aunt reportedly had ocular involvement. The third proband was a 4-year-old girl with aortic root dilation, aortic valve incompetence, pulmonary dilation, and mitral valve prolapse immediately after birth. The skeletal habitus was suggestive of Marfan syndrome. The ocular system was not involved.
Loeys et al. (2006) commented that 'prior studies have suggested that some TGFBR2 mutations are present in families whose members have classic Marfan's syndrome ... or familial thoracic aortic aneurysm and dissection. Many of these families had findings that were atypical for these diagnoses, including cervical-spine instability, dysmorphic facies, patent ductus arteriosus, and cardiac septal defects in patients designated as having Marfan's syndrome, and clinically significant skeletal abnormalities and aneurysms with primary dissections distant from the thoracic aorta in those designated as having familial thoracic aortic aneurysm and dissection. All these features have been associated with the Loeys-Dietz syndrome phenotype. In our experience, all patients with TGFBR mutations have had clinical features that can be used to discriminate the Loeys-Dietz syndrome from Marfan's syndrome or from familial thoracic aortic aneurysm and dissection. Some features of both types are subtle and may have been overlooked (e.g., bifid uvula and skin findings) or missed in the absence of specialized imaging (e.g., arterial tortuosity) on examination of the families described as having Marfan's syndrome or familial thoracic aortic aneurysm and dissection. A reevaluation of these families might shed light on this important issue.'
Ades (2008) described the evolution of craniofacial features in 7 patients with LDS type 2 and proven mutations in the TGFBR1 or TGFBR2 genes. Most patients had dolichocephaly, a tall broad forehead, frontal bossing, high anterior hairline, hypoplastic supraorbital margins, a 'jowly' appearance in the first 3 years of life, translucent and redundant facial skin that was most pronounced in the periorbital area, prominent upper central incisors in late childhood/adulthood, and an open-mouthed myopathic face. The adult faces appeared prematurely aged. Although not exclusive to the LDS type 2 phenotype, Ades (2008) suggested that recognition of these facial features and their evolution might assist in the differentiation of some cases of LDS type 2 from related clinical entities.
In a male infant with molecularly confirmed LDS type 2 and typical features of the disorder, Chung et al. (2014) identified novel features, including brachydactyly, camptodactyly, syndactyly, and absent distal phalanges. The patient also had an umbilical hernia and a quadricuspid pulmonary valve.
In 30 patients with Loeys-Dietz syndrome, 6 with a mutation in TGFBR1 and 24 with a mutation in TGFBR2, Sheikhzadeh et al. (2014) analyzed imaging findings for the presence of dural ectasia and compared them to 60 age- and sex-matched patients with Marfan syndrome (MFS; 154700) and mutations in FBN1 (134797). The authors observed a similar frequency and severity of dural ectasia in LDS and MFS, and suggested that it was a highly sensitive but not specific sign of both diseases. Analysis of other documented features in these patients corroborated that arterial tortuosity, aneurysms of nonaortic arterial vessels, patent ductus arteriosus, bifid uvula, and increased craniofacial severity indices are seen only in LDS patients, whereas ectopia lentis and myopia greater than 3 diopters are seen only in MFS patients.
In the family reported by Boileau et al. (1993), Collod et al. (1994) demonstrated linkage to markers in the region 3p25-p24.2. Linkage analysis by Boileau et al. (1993) had excluded both FBN1 (134797) and FBN2 (612570) as the site of the mutation in the family they described. After the linkage was established, Boileau et al. (1995) used haplotype analysis to identify nonpenetrance and to refine the map position. Collod et al. (1996) excluded the FBLN2 gene (135821), which maps to 3p25-p24, as the basis of the disorder in this family.
In a 4-generation family in which multiple members had thoracic aortic aneurysms and dissection (TAAD) but no ocular or skeletal features of Marfan syndrome, Hasham et al. (2003) excluded known loci for familial thoracic aneurysm and conducted a genomewide scan. Using DNA from 51 family members, they found linkage of the phenotype with 26 markers located in a 30-cM region on 3p. Multipoint analysis demonstrated a maximum lod score of 4.27 at marker D3S2336, and haplotype analysis defined a critical 25-cM region at 3p25-p24 between D3S3701 and D3S1211. The authors designated this locus TAAD2. Hasham et al. (2003) commented that the variable expression and decreased penetrance of this and other familial aortic aneurysm loci make it necessary to continue to monitor aortic dimensions throughout an at-risk individual's lifetime, and to do so even if the parent is unaffected.
The transmission pattern of LDS2 in families 1 and 6 reported by Loeys et al. (2005) was consistent with autosomal dominant inheritance. The heterozygous mutation in the TGFBR2 gene that was identified in patient 2 with LDS2 by Kirmani et al. (2010) occurred de novo.
Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-beta receptor-2 (TGFBR2; 190182) in a Japanese individual with a diagnosis of Marfan syndrome led Mizuguchi et al. (2004) to consider TGFBR2 as the gene underlying the phenotype in the French family reported by Boileau et al. (1993). In affected members of this family, Mizuguchi et al. (2004) identified a 1524G-A mutation in TGFBR2 causing a synonymous amino acid substitution (Q508Q; 190182.0004) resulting in abnormal splicing. In 4 unrelated probands, Mizuguchi et al. (2004) identified 3 other missense mutations in TGFBR2 that led to loss of function of TGF-beta signaling activity on extracellular matrix formation. These results showed that heterozygous mutations in TGFBR2, a putative tumor-suppressive gene implicated in several malignancies, are also associated with inherited connective tissue disorders.
Loeys et al. (2005) considered TGFBR2 as a candidate gene for LDS because TGF-beta signaling has a prominent role in vascular and craniofacial development in mouse models (Azhar et al., 2003, Sanford et al., 1997) and because conditional knockout of TGFBR2 in neural crest cells caused cleft palate and calvaria defects (Ito et al., 2003). Loeys et al. (2005) sequenced all exons of the TGFBR2 gene and identified heterozygous mutations (190182.0008-190182.0013) in 6 of 10 families with LDS. Of these 10 patients, 8 showed hypertelorism, 2 cleft palate, and 2 craniosynostosis. No mutations in TGFBR2 were found in the 4 other families with a clinically indistinguishable phenotype. Therefore, Loeys et al. (2005) sequenced all exons of the TGFBR1 gene (190181) and found a unique missense mutation in each family.
Pannu et al. (2005) sequenced 8 coding exons of the TGFBR2 gene using genomic DNA from 80 unrelated familial cases with TAAD. They found 2 TGFBR2 missense mutations (190182.0014, 190182.0015) in 4 unrelated families. Affected family members also had descending aortic disease and aneurysms of other arteries. Strikingly, both mutations affected an arginine residue at position 460 in the intracellular domain, suggesting a mutation 'hotspot.' Assessment of linked polymorphisms suggested that these families were not distantly related. Structural analysis of the TGFBR2 serine/threonine kinase domain revealed that R460 is strategically located within a highly conserved region of this domain and that the amino acid substitutions resulting from these mutations will interfere with the receptor's ability to transduce signals. They estimated that germline TGFBR2 mutations are responsible for the inherited predisposition to familial TAAD in 5% of cases.
Loeys et al. (2006) identified a total of 52 families with LDS, including the 10 described by Loeys et al. (2005). Loeys et al. (2006) found mutations in TGFBR2 in 27 probands with LDS type 1. The other 13 probands with LDS1 had mutations in TGFBR1 (190181). Overall, they found 29 mutations in TGFBR2 and 13 in TGFBR1. Of the 30 new probands whose phenotype was consistent with LDS type 1, 21 had mutations in TGFBR2.
In a Japanese boy with clinical findings reported as Shprintzen-Goldberg syndrome (SGS; 182212), Kosaki et al. (2006) identified heterozygosity for a splice site mutation in the TGFBR2 gene (190182.0016). Because the patient had a bifid uvula and sigmoid configuration of the brachycephalic left common carotid and left subclavian arteries, Robinson et al. (2006) suggested that the diagnosis of Loeys-Dietz syndrome would also be appropriate for this patient.
In 2 male patients with LDS who had a significant history of low bone mineral density and multiple low-impact fractures, Kirmani et al. (2010) identified 2 different heterozygous mutations in the TGFBR2 gene, respectively (see, e.g., 190182.0005).
The 3 probands reported by Disabella et al. (2006) carried 3 distinct heterozygous missense mutations in the TGFBR2 gene. All 3 mutations, in exon 5, affected evolutionarily conserved residues of the serine/threonine kinase domain (e.g., 190182.0015). One of the mutations occurred at residue R460.
Jondeau et al. (2016) analyzed 176 patients with mutations in TGFBR1 and 265 with mutations in TGFBR2 and found similar survival rates, aortic risks, and prevalence of extraaortic features between the 2 groups. The authors noted that the observed survival rate, 80% at age 60 years, was much better than previously reported. However, TGFBR2 patients had a smaller aortic diameter prior to or at the time of dissection, including 6 women with a diameter of 45 mm or less who also exhibited low body surface area and severe extraaortic features; the authors proposed that preventive aortic surgery be considered at a diameter of 40 mm in the latter patients. Furthermore, 10% of patients with TGFBR1 or TGFBR2 mutations who underwent surgical repair of an aortic root aneurysm subsequently presented with dissections of the ascending aorta, suggesting that aortic replacement should include the entire ascending aorta when possible. In addition, aortic dissection was observed in 1.6% of pregnancies.
Loeys et al. (2005) reported that histologic analysis in LDS patients with mutations in TGFBR2 showed loss of elastin (130160) content and disarrayed elastic fibers in the aortic media similar to that in patients with classic Marfan syndrome. Structural analysis showed loss of intimate spatial association between elastin deposits and vascular smooth muscle cells. These characteristics were observed in young children and in the absence of inflammation, suggestive of a severe defect in elastogenesis rather than secondary elastic fiber destruction. In addition, they had previously observed a marked excess of aortic wall collagen in individuals with Marfan syndrome compared with age-matched controls; this collagen excess was accentuated in individuals with mutations in TGFBR2. As multiple collagens normally expressed in the aorta are derived from early-induced target genes of TGF-beta, including COL1A1 (120150) and COL3A1 (120180), these data were considered consistent with increased TGF-beta signaling.
Attias et al. (2009) compared clinical features and outcomes of 71 patients with TGFBR2 mutations to those of 243 patients with FBN1 mutations. Aortic dilation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% and 79%, respectively) but was highly variable; the incidence and average age for thoracic aortic surgery and aortic dissection were also similar in the 2 groups. Mitral valve involvement was less frequent in the TGFBR2 than in the FBN1 group (p less than 0.05 for myxomatous valve, prolapse, or mitral regurgitation). Aortic dilation, dissection, or sudden death was the index event leading to genetic diagnosis in 65% of families with TGFBR2 mutations, versus 32% with FBN1 mutations (p = 0.002). The rate of death was greater in TGFBR2 families before diagnosis, but similar once the disease was recognized. Most pregnancies were uneventful in both groups. Seven (10%) of the 71 patients with TGFBR2 mutations fulfilled the Ghent criteria for Marfan syndrome, including 2 with ectopia lentis, compared with 140 (58%) of 243 patients in the FBN1 group (p less than 0.0001); 3 patients in the TGFBR2 group fulfilled the diagnostic criteria for both Loeys-Dietz and Marfan syndromes. Noting that clinical outcomes were similar between treated patients from both groups, Attias et al. (2009) concluded that prognosis depends on clinical disease expression and treatment rather than simply the presence of a TGFBR2 mutation.
Tran-Fadulu et al. (2009) compared the clinical features of 30 affected individuals from 4 TAAD families with TGFBR1 mutations to those of 77 patients from 4 families previously reported with mutations in the TGFBR2 gene (Pannu et al., 2005) and found that the average age of onset of vascular disease was significantly younger in the TGFBR1 cohort compared to the TGFBR2 cohort (31.4 vs 45.6 years; p = 0.002). In addition, men in TGFBR1 families presented with vascular disease at a statistically significant younger age compared with affected women (23 vs 39 years; p = 0.019); the difference was not statistically significant in the TGFBR2 cohort (42 vs 50 years). Thoracic aortic aneurysm was the predominant vascular presentation in both cohorts of patients, but the TGFBR1 patients were twice as likely to present with vascular disease elsewhere (23% vs 8%, respectively; p = 0.039), and vascular disease presentation differed based on gender in the TGFBR1 families: all men but 1 presented with AAT, whereas half of the affected women presented with disease in other vascular beds, including abdominal aortic aneurysms and carotid and coronary artery dissections (p = 0.038). In a combined analysis of the families, there was no difference in overall survival; however, survival was significantly worse in men than in women in TGFBR1 families (p = 0.017) but not in TGFBR2 families. The data also suggested that individuals with TGFBR2 mutations were more likely to dissect at aortic diameters less than 5.0 cm than individuals with TGFBR1 mutations: 3 TGFBR2 patients had dissections with aortic diameters under 5.0 cm, whereas there were no dissections under 5.0 cm in TGFBR1 patients, who often had dramatically enlarged aortic diameters at dissection (6.5 cm to 14.0 cm) or repair (8.5 cm).
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