In a male patient of German origin with Loeys-Dietz syndrome (LDS2; 610168), Singh et al. (2006) identified a c.1489C-T transition in exon 6 of the TGFBR2 gene that resulted in premature termination of the protein at arg497 (R497X). Height was 195 cm, while family members were of rather short stature. Dilated ascending aorta without dissection was replaced at a size of 8.0 cm. Involvement of the skeletal system included pectus excavatum, scoliosis, and arachnodactyly with positive thumb and wrist signs. Ocular symptoms were absent. The patient was lost to follow-up.
Tooley et al. (2017) reported a 3-generation pedigree with LDS2 segregating the R497X mutation. The proband was a 48-year-old man who had been referred for genetic testing because his maternal cousin had undergone surgery for a dilated aortic root and was found to carry the R497X mutation, prompting cascade testing. The proband had a right inguinal hernia repair at age 14 years, resection of Meckel diverticulum at age 16, and gastric adenocarcinoma at 42 years of age, treated with subtotal gastrectomy and chemotherapy. A dilated aortic root of 43 mm was present at the sinus of Valsalva. His oldest son had hypertelorism, downslanting palpebral fissures, and bifid uvula. Echocardiogram showed a dilated aortic root of 40 mm. The second affected son was diagnosed antenatally with hypoplastic left heart syndrome (HLHS) on ultrasound scan at 20 weeks' gestation. At 12 years of age he had subtle nasal speech but no other features to suggest LDS. At 14 years of age he had developed downslanting palpebral fissures, hypertelorism, and arachnodactyly; these were not appreciated before. The neoascending aorta was found to be 50 mm at that time. The last affected child was 8 months old and had been diagnosed with Loeys-Dietz syndrome, with aortic root measurement at the upper limit of normal. The proband and his 2 older affected sons were being treated with irbesartan. The proband's mother and maternal aunt, ages 73 and 68 years, respectively, were both mutation carriers and were asymptomatic at the time of the proband's diagnosis.