A number sign (#) is used with this entry because of evidence that Loeys-Dietz syndrome-5 (LDS5) is caused by heterozygous mutation in the TGFB3 gene (190230) on chromosome 14q24.

Loeys-Dietz syndrome-5 (LDS5), also known as Rienhoff (pronounced REENhoff) syndrome, is characterized by syndromic presentation of aortic aneurysms involving the thoracic and/or abdominal aorta, with risk of dissection and rupture. Other systemic features include cleft palate, bifid uvula, mitral valve disease, skeletal overgrowth, cervical spine instability, and clubfoot deformity; however, not all clinical features occur in all patients. In contrast to other forms of LDS (see 609192), no striking aortic or arterial tortuosity is present in these patients, and there is no strong evidence for early aortic dissection (summary by Bertoli-Avella et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of Loeys-Dietz syndrome, see LDS1 (609192).

Rienhoff et al. (2013) described a 9-year-old European American girl, born to nonconsanguineous parents, whose birth weight was in the 5th centile with length and head circumference in the 50th centiles; in addition, she was noted to have contractures of the hands and feet, most severe in the third and fourth fingers of the right hand, and mild hypotonia. At 17 months of age, her weight was below the 1st centile with height in the 5th centile, and she could not crawl or roll, but could stand with support. She had bilateral pes planus, mild pectus excavatum, hyperextensibility of the large joints, and mild retrognathia. There was a small metopic ridge, and her eyes were prominent, with blue sclerae and hypertelorism, and she had a tubular nose. Her skin was of normal texture, tension, and wound healing. She had a bifid uvula with intact hard palate, normal arch, and normal voice quality. There were marked contractures of the proximal phalangeal joints of the right second and third digits and toes bilaterally, more severe on the right. Motor examination revealed decreased bulk in all appendicular and axial muscles, decreased strength, low tone, and diminished reflexes throughout; in addition, there was markedly reduced subcutaneous fat. A 3-year trial of losartan produced no change in muscle strength or mass. At 7 years of age, her weight was still below the 1st centile and height in the 5th centile, and the physical examination was unchanged. Muscle biopsy showed a normal checkerboard pattern with type 1 fiber predominance, but there was mild focal type 1 fiber disproportion consistent with disuse or decreased usage. Yearly echocardiograms showed no cardiac defect or dysfunction, and the aortic annulus and root and pulmonary artery dimensions were consistently within the normal range. Visual acuity remained normal.

Matyas et al. (2014) reported a 10.5-year-old girl who presented with tall stature, marfanoid features, and a recent history of 2 unexplained episodes of vagal syncope. Electrocardiogram revealed first-degree atrioventricular block with a borderline PR interval; echocardiography showed an aortic root diameter at the upper limit of normal, mild mitral valve prolapse, and mild aortic and mitral insufficiency. Other features included hypertelorism, long palpebral fissures, bifid uvula, cleft soft palate, low muscle mass and muscular hypotonia, reduced subcutaneous fat, generalized hyperextensibility of joints, pectus excavatum, and kyphoscoliosis. She had transient postnatal flexion of hands and feet but no arthrogryposis; ophthalmologic examination was normal, as was skin. Matyas et al. (2014) observed similarities to the patient reported by Rienhoff et al. (2013), including cleft soft palate with bifid uvula, but also noted that their patient differed in that she had overgrowth and generalized hyperextensibility, whereas the patient of Rienhoff et al. (2013) presented with growth retardation and had hyperextensible large joints but contracted small distal digits of the fingers and toes.

Bertoli-Avella et al. (2015) studied a large, 3-generation Dutch pedigree with 12 affected individuals, including 7 patients between 40 years and 68 years of age who presented with aneurysms and dissections that mainly involved the descending thoracic and abdominal aorta; 3 of those patients died from aortic dissection and rupture. Two family members exhibited aneurysmal disease beyond the aorta, with involvement of the right iliac artery in 1 and the left subclavian artery in the other. In addition, 4 family members had mitral valve abnormalities, ranging from mild prolapse to severe regurgitation requiring surgical intervention. Craniofacial abnormalities were subtle and included long face, high-arched palate, and retrognathia. Pectus deformity and scoliosis were frequently observed. Other recurrent findings included velvety skin, varices, and hiatal hernia. Several family members had autoimmune disorders, including HLA-B27 (see 142830)-positive spondyloarthritis, Graves disease, and celiac disease. Pathology reports from 2 family members described extensive elastic fiber fragmentation with 'pseudo-cyst formation' in the medial layer of the dissected aorta and 'aortic medial degeneration.'

Bertoli-Avella et al. (2015) summarized the clinical features in 10 families segregating heterozygous mutations in the TGFB3 gene, in which affected individuals exhibited syndromic aortic aneurysmal disease that showed significant overlap with Loeys-Dietz syndrome (LDS), although striking intrafamilial and interfamilial clinical variability was observed. No early arterial dissection, or dissection at small aortic dimension, was observed. Other cardiovascular features included persistent foramen ovale and atrial or ventricular septal defects. No striking aortic or arterial tortuosity was observed. Typical LDS findings, such as hypertelorism, bifid uvula and cleft palate, cervical spine instability, and clubfoot deformity, were also seen. Other recurrent features included dolichocephaly, high-arched palate, retrognathia, tall stature, joint hypermobility, arachnodactyly, pectus deformity, and inguinal hernia. No evidence for ectopia lentis was found in the medical records. The youngest patient in this cohort was a 3-year-old Japanese girl who had a 19.5-mm aortic root aneurysm and atrial and ventricular septal defects, as well as other features of LDS, including hypertelorism, bifid uvula, and osteoarthritis. Microscopic examination of dissected aortic wall from 1 patient showed elastic fiber fragmentation with increased collagen and proteoglycan deposition, reminiscent of findings in both Marfan syndrome (154700) and LDS. In pathology reports from 2 other families, only mild elastic fiber fragmentation was noted.

The transmission pattern of LDS4 in the large Dutch family (family 1) reported by Bertoli-Avella et al. (2015) was consistent with autosomal dominant inheritance.

In a large Dutch pedigree with syndromic aortic aneurysm, negative for mutation in 15 known thoracic aortic aneurysm/dissection (TAAD)-associated genes, Bertoli-Avella et al. (2015) performed linkage analysis and identified 2 large genomic regions on chromosomes 14 and 15 that were shared by all affected patients; the region on chromosome 14 included the candidate gene TGFB3 at 14q24.

In a 9-year-old girl with low muscle mass, growth retardation, and distal arthrogryposis, who also exhibited features of Marfan, Loeys-Dietz, and Beals (121050) syndromes but did not meet the established diagnostic criteria for those syndromes, Rienhoff et al. (2013) analyzed 6 genes known to be associated with those disorders, including TGFB2 (190220), TGFBR1 (190181), TGFBR2 (190182), SMAD3 (603109), FBN1 (134797), and FBN2 (612570), but found no mutations. Exome sequencing revealed 2 heterozygous de novo changes: 1 was a nonsense mutation in the CDH2 gene (114020); however, Rienhoff et al. (2013) noted that dermal fibroblasts from the patient showed CHD2 levels that were not statistically different from 6 age-matched controls, and that Garcia-Castro et al. (2000) had shown that mice heterozygous for a null mutation in Cdh2 were phenotypically normal at 2 years and muscle mass was not affected. The other variant was a de novo missense mutation in the TGFB3 gene (C409Y; 190230.0003), encoding a nonfunctional TGFB3 ligand. Rienhoff et al. (2013) concluded that the TGFB3 mutation most likely accounted for the clinical findings.

In a 10.5-year-old girl with low muscle mass, marfanoid features, and bifid uvula, who was negative for mutation in FBN1, TGFBR1, TGFBR2, TGFB2, and SMAD3, Matyas et al. (2014) identified heterozygosity for a de novo missense mutation in the TGFB3 gene (R300Q; 190230.0004).

In a large Dutch pedigree with syndromic aortic aneurysm mapping to chromosome 14 or 15, Bertoli-Avella et al. (2015) sequenced the candidate gene TGFB3 at chromosome 14q24 and identified heterozygosity for a splice site mutation (190230.0005). The mutation, which segregated with disease in the family, was not found in variant databases. Analysis of TGFB3 in an additional 470 probands with syndromic or nonsyndromic TAAD, the majority of whom had been screened for mutation in all known TAAD genes, revealed TGFB3 mutations in 10 probands, including 4 different missense mutations, 2 single-base deletions, and 1 nonsense mutation (see, e.g., 190230.0006-190230.0008).