Singleton-Merten Syndrome 2

A number sign (#) is used with this entry because of evidence that Singleton-Merten syndrome-2 (SGMRT2) is caused by heterozygous mutation in the DDX58 gene (609631) on chromosome 9p21.

Description

Singleton-Merten syndrome-2 is characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies (summary by Jang et al., 2015).

For a general phenotypic description and discussion of genetic heterogeneity of Singleton-Merten syndrome, see SGMRT1 (182250).

Clinical Features

Jang et al. (2015) studied a large 4-generation Korean family with aortic calcification, glaucoma, and skeletal abnormalities. The 56-year-old proband was diagnosed with bilateral glaucoma at 6 years of age and was blind by age 17. In early adulthood, she had arthritis of the hands with metacarpophalangeal contractures; x-rays showed calcific tendinitis and mild calcified ligaments of the interphalangeal and metacarpophalangeal joints, as well as mild erosive changes in the terminal tufts of the distal phalanges. CT scan showed severe calcification of the aorta and coronary arteries as well as mild aortic valve stenosis. The patient also had dry skin with scabbing; skin biopsy showed papillomatosis and hyperkeratosis. Her son was diagnosed with bilateral glaucoma at 3 years of age. He had atopic dermatitis in early childhood that developed into psoriatic skin lesions, and skin biopsy confirmed psoriasiform hyperplasia. At 21 years of age, he was found to have calcification of the aorta, aortic valve, and coronary arteries. One year later, he had acute severe mitral regurgitation due to chordae rupture with subsequent pulmonary edema, and underwent mitral valvuloplasty and aortic valve decalcification. Skeletal survey showed hypoplastic and cone-shaped distal phalanges due to terminal tuft erosion. The proband's 35-year-old niece and her 2 daughters had glaucoma. The niece also had calcification of the proximal ascending aorta and coronary arteries, with mild calcification of the aortic valve, but no stenosis. The proband's 33-year-old nephew did not have glaucoma, but exhibited calcification of the aorta and the subclavian and iliac arteries; his son and daughter both had glaucoma, and x-rays of the hands and feet in all 3 showed erosive changes of the terminal tufts. No one in the family had dental anomalies, dysmorphic facial features, muscle weakness, or hypotonia.

Molecular Genetics

In a large 4-generation Korean family with glaucoma, aortic calcification, and skeletal anomalies, Jang et al. (2015) performed exome sequencing and identified heterozygosity for a missense mutation in the DDX58 gene (E373A; 609631.0001) that segregated with disease. Analysis of the DDX58 gene in 100 unrelated patients with glaucoma revealed a missense mutation (C268F; 609631.0002) in a 20-year-old Korean woman and her affected mother and maternal grandmother. In this family, features consisted of glaucoma, phalangeal osteoarthropathy with flexion contractures, and acroosteolysis of the distal phalanges. Small aortic calcifications in the arch and abdominal aorta were believed to be age-related in the 61-year-old grandmother; none of the 3 had dental anomalies, facial dysmorphism, muscle weakness, or hypotonia. Jang et al. (2015) designated the phenotype in the 2 families 'atypical Singleton-Merten syndrome' manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies.