A number sign (#) is used with this entry because of evidence that Loeys-Dietz syndrome-6 (LDS6) is caused by heterozygous mutation in the SMAD2 gene (601366) on chromosome 18q21.

Loeys-Dietz syndrome-6 (LDS6) is characterized by aortic/arterial aneurysm and dissection in association with connective tissue findings. Most patients have thoracic aortic aneurysm involving the ascending aorta and/or aortic root, but cerebral and iliac arteries can be affected, and abdominal aortic aneurysm has been observed. Arterial tortuosity involving cerebral vessels, the aorta, and/or iliac arteries has also been reported (Granadillo et al., 2018; Cannaerts et al., 2019).

For a general phenotypic description and discussion of genetic heterogeneity of LDS, see LDS1 (609192).

Micha et al. (2015) reported 4 patients from 3 unrelated families with aneurysms of the aorta, carotid, and cerebral arteries as well as dysmorphic features and skeletal and skin anomalies who had mutations in the SMAD2 gene. In family 1, the proband was a 51-year-old woman who experienced transient ischemic attacks at age 47 and was found to have aneurysms of the vertebral, left internal carotid, and left intracavernous carotid arteries, with evidence of dissection. Caliber changes of the left and right internal carotid arteries and the left vertebral artery were visible on CT angiography, but she had no aortic abnormalities. Other features included long fingers with positive wrist and thumb sign, and bilateral pes planus. She experienced spontaneous pneumothorax at age 50. Her mother had an abdominal aortic aneurysm repaired at age 55 years, and CT of the thorax at age 62 revealed a large aneurysm of the descending aorta and an infrarenal aneurysm as well as tortuosity of the aorta. A maternal uncle died at the age of 50 due to dissection of the abdominal aorta. In family 2, the proband was diagnosed at age 17 with possible Marfan syndrome (MFS; 154700); she had inguinal hernia, pes planus, genu valgum, mild scoliosis, long thin fingers, and high-arched palate. By age 23, aortic root dilation was present and dural ectasia was also observed. In family 3, 2 sisters had ascending aortic aneurysms, at age 46 and 59 years, respectively. Both had striae and long toes; other features included downslanting palpebral fissures, high-arched palate, and abdominal wall hernia. Their mother died suddenly at age 56 of unknown cause, and their paternal grandfather died at age 76 of aortic aneurysm. The patients in families 2 and 3 also experienced joint pain with significant osteoarthritis, requiring replacement of some joints.

Zhang et al. (2017) reported a 51-year-old Chinese man with an abdominal aortic aneurysm requiring surgical repair and mutation in SMAD2. He had previously undergone replacement of the ascending aorta with valve reimplantation at age 46 for a thoracic aneurysm. Other features included long face, high-arched palate, and intervertebral disc degeneration. His father had died at age 40 due to thoracic aortic aneurysm rupture.

Using GeneMatcher, Granadillo et al. (2018) ascertained a 42-year-old woman with aneurysm and mutation in the SMAD2 gene. She presented initially with a cardiac murmur associated with bicuspid aortic valve. Cardiac MRI at age 33 years revealed an aortic root aneurysm that was surgically repaired. In addition, brain MRI showed arterial dilation and tortuosity (dolichoectasia) with mildly ectatic cavernous internal carotid arteries bilaterally. Other features included sparse hair, midface hypoplasia, prominent and hyperextensible ears, and high-arched palate. She had multiple retained deciduous teeth, with only a few adult teeth. Skeletal features included short stature, joint laxity, genu valgus, and brachydactyly.

Cannaerts et al. (2019) reported 9 patients from 5 unrelated families with aortic/arterial aneurysm and dissection, connective tissue findings reminiscent of MFS and/or LDS, and mutation in the SMAD2 gene. They reviewed the findings from 6 previously reported patients with SMAD2-associated LDS (Micha et al., 2015; Zhang et al., 2017), noting that 10 of the 15 reported patients had thoracic aortic aneurysm. In addition, involvement of cerebral vessels was reported in 3 patients, abdominal aorta in 1, and iliac arteries in 1. None of the proven SMAD2 mutation carriers had aortic dissection, but it was present in relatives in several families, and carotid and coronary artery dissection occurred in 1 patient each. Arterial tortuosity was reported in 4 patients, involving the cerebral vessels, aorta, and iliac arteries. Valve abnormalities, including prolapse and insufficiency of the aortic, tricuspid, or mitral valve, were observed in 5 of the 15 variant carriers. Recurrent skeletal anomalies included tall stature (6/13), scoliosis (5/12), long slender fingers (6/14), pectus deformity (3/12), and pes planus (3/10). Osteoarthritis (8/10) and hernias (7/12), including diaphragmatic, inguinal, and umbilical, were common. Other frequent features included hypertelorism (4/15), high palate or broad uvula (8/15), easy bruising (5/9), and striae (3/9). Other findings included varices (4/12) and migraine (5/10), and transient ischaemic attack was reported in 1 patient.

The transmission pattern of Loeys-Dietz syndrome in the families reported by Micha et al. (2015) was consistent with autosomal dominant inheritance.

In a cohort of 365 patients with arterial aneurysm and/or dissection, who were 60 years of age or younger and negative for mutation in the FBN1 (134797), TGFBR1 (190181), TGFBR2 (190182), ACTA2 (102620), or MYH11 (160745) genes, Micha et al. (2015) sequenced the SMAD2 gene and identified 2 probands with heterozygous missense mutations that were not found in public variant databases: L449S (601366.0003) in family 1 and G457R (601366.0004) in family 2. Analysis of exome data from 211 additional families with thoracic aortic aneurysm identified another SMAD2 missense variant (Q388R; 601366.0005) in 2 affected sisters (family 3).

By whole-exome sequencing in a 51-year-old Chinese man with thoracic and abdominal aortic aneurysms, Zhang et al. (2017) identified heterozygosity for a missense mutation in the SMAD2 gene (A278V; 601366.0006). His mother did not carry the mutation, suggesting that it was inherited from his father, who died at age 40 due to thoracic aortic aneurysm rupture. The mutation was not found in public variant databases.

In a 42-year-old woman with aneurysm of the aortic root and dilation and tortuosity of cerebral arteries, Granadillo et al. (2018) identified heterozygosity for a 1-bp duplication in the SMAD2 gene (601366.0010) that was not found in public variant databases.

Cannaerts et al. (2019) identified heterozygous SMAD2 mutations in 9 patients from 5 unrelated families with thoracic aortic aneurysm and/or arterial tortuosity and connective tissue and skeletal anomalies (see, e.g., 601366.0010 and 601366.0011).