The Loeys-Dietz syndrome (LDS) is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement. As defined by Loeys et al. (2006), the disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula ... The Loeys-Dietz syndrome (LDS) is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement. As defined by Loeys et al. (2006), the disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS type 1 have craniofacial involvement consisting of cleft palate, craniosynostosis, or hypertelorism. Patients with LDS type 2 do not have these findings, but some have a bifid uvula. The natural history of both types is characterized by aggressive arterial aneurysms and a high rate of pregnancy-related complications. - Genetic Heterogeneity of Loeys-Dietz Syndrome LDS1A and LDS2A (608967) are both caused by mutation in the TGFBR1 gene; LDS1B (610168) and LDS2B (610380) are both caused by mutation in the TGFBR2 gene (190182). LDS1A and LDS1B are clinically indistinguishable, as are LDS2A and LDS2B. Another form of Loeys-Dietz syndrome (LDS3; 613795), which is associated with early-onset osteoarthritis, is caused by mutation in the SMAD3 gene (603109). LDS4 is caused by mutation in the TGFB2 gene (190220).
Furlong et al. (1987) described a male of normal height and intelligence with dolichocephaly, a high palate, dolichostenomelia, a mild scoliosis, L4-5 spondylolisthesis, long thorax, prominent pectus carinatum, camptodactyly, pes planus, mitral valve insufficiency, bilateral recurrent inguinal herniae, ... Furlong et al. (1987) described a male of normal height and intelligence with dolichocephaly, a high palate, dolichostenomelia, a mild scoliosis, L4-5 spondylolisthesis, long thorax, prominent pectus carinatum, camptodactyly, pes planus, mitral valve insufficiency, bilateral recurrent inguinal herniae, myopia with normal lenses, mitral valve prolapse, and a dilated aortic root which subsequently dissected at age 18 years. Features atypical for Marfan syndrome (154700) included multisutural craniosynostosis, ptosis, hypertelorism, and hypospadias. The patient of Lacombe and Battin (1993) had sagittal craniosynostosis, marfanoid habitus, cleft palate and micrognathia, and aortic root dilatation but normal height and intelligence. Pronounced craniofacial dysmorphism (scaphocephaly, facial asymmetry, unilateral ptosis, orbital dystopia, downslanting palpebral fissures) was reminiscent of that seen in Shprintzen-Goldberg syndrome (SGS; 182212). Other features included arachnodactyly, camptodactyly, kyphoscoliosis, and normal lenses. Megarbane and Hokayem (1998) described the osseous findings in a 16-year-old male with marfanoid habitus and craniosynostosis. Observations included dolichocephaly, malar hypoplasia, low set, posteriorly rotated ears, ptosis, downslanting palpebral fissures, and microretrognathia. Prominent pectus carinatum, kyphoscoliosis, and limited mobility at the elbows were present, as well as camptodactyly of the fourth and fifth fingers and fifth finger clinodactyly. Flat feet, long toes, and hallux valgus were observed. Echocardiography documented aortic root dilatation. Although early psychomotor development was delayed, intelligence was normal. The authors described radiologic abnormalities that included atlantooccipital joint dislocation, biconvex vertebral bodies, a fusion defect of the dorsal arches of L4 and L5, hypoplasia of the posterior arches of L5 and S1, and elongated diaphyses. Megarbane and Hokayem (1998) considered the clinical findings of their propositus to be similar to those reported by Furlong et al. (1987). Lacombe and Battin (1993) compared their case with that of Furlong et al. (1987) and 3 other cases. They suggested that the 5 patients might represent variable expressivity of the same syndrome with mental retardation as an inconstant feature, or that there may be 2 distinct syndromes, one with mental retardation (Shprintzen-Goldberg syndrome; 182212) and one without (Furlong syndrome). Megarbane and Hokayem (1998) noted similarities between Shprintzen-Goldberg syndrome and Furlong syndrome and proposed dividing craniosynostosis with marfanoid habitus into 2 types, nominating type 1 as Shprintzen-Goldberg syndrome and type 2 as those with normal intelligence, aortic root abnormalities, and mild skeletal dysplasia. Loeys et al. (2005) described 10 families with a previously undescribed aortic aneurysm syndrome characterized by hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity with ascending aortic aneurysm and dissection. The syndrome showed autosomal dominant inheritance and variable clinical expression. Other findings in multiple systems included craniosynostosis, structural brain abnormalities, mental retardation, congenital heart disease, and aneurysms with dissection throughout the arterial tree. Loeys et al. (2005) noted that some individuals with LDS had phenotypes that overlapped to some extent with that of Marfan syndrome (MFS; 154700), but none met the diagnostic criteria for MFS (De Paepe et al., 1996). All individuals with LDS had manifestations in multiple organ systems that are not associated with MFS. In these individuals, aneurysms tended to be particularly aggressive and to rupture at an early age or to be of a size not associated with high risk in MFS. From a management prospective, the distinction from MFS is neither ambiguous nor unimportant. Loeys et al. (2006) presented the clinical characteristics of the series of 40 probands, including the 10 previously described patients (Loeys et al., 2005). Besides the triad of hypertelorism, cleft palate or bifid uvula, and arterial tortuosity with aneurysms, patients in this group had additional cardiovascular, skeletal, and cutaneous findings. Neurocognitive signs included delayed development in 6 patients, hydrocephalus in 6 patients, and Arnold-Chiari malformation in 4 patients. When present, delayed development was not always associated with craniosynostosis or hydrocephalus, suggesting that learning disability is a rare primary manifestation. No patient had ectopia lentis, and few patients (18%) had dolichostenomelia. Loeys et al. (2006) stated that using 3-dimensional reconstruction of images from the head to the pelvis obtained by computed tomography with intravenous contrast material or magnetic resonance angiography, they identified aneurysms distant from the aortic root in 53% of their patients with LDS type 1; these aneurysms were not detected with the use of echocardiography. Most of these lesions were amenable to surgical repair. This imaging technique also detected arterial tortuosity, a finding of diagnostic importance. Loeys et al. (2006) noted that the natural history of both types of LDS among 52 probands was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type 1, as compared with those with type 2, underwent cardiovascular surgery earlier (mean age, 16.9 years vs 26.9 years) and died earlier (22.6 years vs 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular EDS.
In 4 families with Loeys-Dietz syndrome who did not carry a mutation in TGFBR2 (190182), Loeys et al. (2005) identified a unique missense mutation in TGFBR1 (190181). Two mutations occurred in the kinase domain, one occurred at the ... In 4 families with Loeys-Dietz syndrome who did not carry a mutation in TGFBR2 (190182), Loeys et al. (2005) identified a unique missense mutation in TGFBR1 (190181). Two mutations occurred in the kinase domain, one occurred at the junction of the glycine-serine-rich domain and kinase domain, and one occurred just past the kinase domain at the C terminus. Loeys et al. (2006) added observations on 30 new probands with a phenotype consistent with LDS type 1. Of the 30 newly identified probands, 9 had mutations in TGFBR1 and 21 had mutations in TGFBR2. Ades et al. (2006) found that 2 patients with a phenotype resembling Furlong syndrome were heterozygous for the same de novo missense mutation in the TGFBR1 gene (190181.0005). In 7 individuals referred with classic MFS in whom no mutation in fibrillin-1 (FBN1; 134797) was found, Loeys et al. (2005) sequenced the TGFBR1 and TGFBR2 genes and found no mutations. At the extreme of clinical severity some individuals with LDS had phenotypes that overlapped considerably with the Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), also known as the marfanoid craniosynostosis syndrome. However, SGS is not associated with cleft palate, arterial tortuosity, or risk of aneurysm or dissection other than at the aortic root, and most affected individuals demonstrate no vascular pathology. Loeys et al. (2005) found no mutations in the TGFBR1 and TGFBR2 genes in 5 individuals with classic SGS. Nevertheless, given the extent of phenotypic overlap between SGS, MFS, and selected individuals with mutations in either TGFBR1 or TGFBR2, Loeys et al. (2005) concluded that the pathogenesis of SGS probably relates to alteration in TGF-beta (190180) signaling.