Abstract
Background
Mutations in TGFB3 cause Loeys-Dietz syndrome-5 (LDS5), an autosomal dominantly inherited connective tissue disorder. LDS5 is characterized by aortic aneurysms and dissections associated with systemic features mainly involving the ocular and skeletal systems. Precise delineation of LDS5 phenotype is difficult because of the small number of identified cases.
Purpose
The purpose of this study was to further define LDS5 with an emphasis on cardiologic features by describing the genotype and phenotype in an international cohort of patients.
Methods
We performed a retrospective cross-sectional multicentre study. Genetic testing was performed as a part of standard medical care. Clinical data were collected by means of an anonymized questionnaire, which was sent to the referent physicians.
Results
Ten (7 novel) TGFB3 mutations were identified in 31 patients (16 index patients). The mean age at last evaluation was 32 years (range 4–60 years). Aortic root dilatation, varices, and mitral valve insufficiency were the most common cardiovascular findings, reported in 28%, 22%, and 21% of patients, respectively. Higher incidences (40%, 29%, and 25%) of these findings were observed in the index patients. Four patients (8%) underwent aortic surgery, all after age 40. Abdominal aortic aneurysms were reported in 2/26 (8%) patients. Extra aortic artery disease included iliac artery aneurysm (one index patient) and tortuosity of the internal carotid and vertebral arteries (one index patient and one relative). The most frequently reported systemic features were high-arched palate, arachnodactyly, pes planus, pectus deformity, and joint hypermobility. Interestingly, we identified an homozygous TGFB3 mutation in a patient who presented with aortic dilatation at age 17, splenic torsion, severe myopia, cleft palate, and other skeletal features. Her heterozygous parents, brother, and sister displayed signs of the disease, but to a milder degree. To the best of our knowledge, this is the first identification of homozygous TGFB3 mutation.
Conclusions
Our data are in line with previous research, showing that aortic root dilatation is the main cardiovascular feature of LDS5. No deaths related to cardiovascular events were reported in any of the presented families. The cardiovascular phenotype of LDS5 appears to be milder compared to other vascular connective tissue disorder, such as Marfan syndrome, although our findings suggest that homozygosity is associated with a more severe and early-onset phenotype.
A Newly Discovered Genetic Disorder Associated With Life-Threatening Aortic Disease in a 6-Year-Old Boy
