Singleton-Merten Syndrome 1

A number sign (#) is used with this entry because of evidence that Singleton-Merten syndrome-1 (SGMRT1) is caused by heterozygous mutation in the IFIH1 gene (606951) on chromosome 2q24.

Description

Singleton-Merten syndrome (SGMRT) is an uncommon autosomal dominant disorder characterized by abnormalities of blood vessels, teeth, and bone. Calcifications of the aorta and aortic and mitral valves occur in childhood or puberty and can lead to early death. Dental findings include delayed primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, and severe root and alveolar bone resorption associated with dysregulated mineralization, leading to tooth loss. Osseous features consist of osteoporosis, either generalized or limited to distal extremities, distal limb osteolysis, widened medullary cavities, and easy tearing of tendons from bone. Less common features are mild facial dysmorphism (high anterior hair line, broad forehead, smooth philtrum, thin upper vermilion border), generalized muscle weakness, psoriasis, early-onset glaucoma, and recurrent infections. The disorder manifests with variable inter- and intrafamilial phenotypes (summary by Rutsch et al., 2015).

Genetic Heterogeneity of Singleton-Merten Syndrome

An atypical form of Singleton-Merten syndrome (SGMRT2; 616298) is caused by mutation in the DDX58 gene (609631) on chromosome 9p21.

Clinical Features

Singleton and Merten (1973) and Gay and Kuhn (1976) reported a total of 4 unrelated patients, male and female, with dental dysplasia, progressive calcification of the thoracic aorta, calcific aortic stenosis, osteoporosis, and expansion of the marrow cavities in hand bones like that observed in anemia. In 2 of the 4 patients, there was also generalized muscle weakness and atrophy beginning in the first or second year of life following a febrile illness. Onset was between 4 and 24 months and death between 4 and 18 years. The 2 patients of Gay and Kuhn had a chronic psoriasiform skin eruption. The father of one of their patients was said to have poor teeth and a 'leaky aortic valve,' so the disorder may be dominant.

Feigenbaum et al. (1988) described a family with multiple affected members with variable expression and vertical transmission. Males were affected, and male-to-male transmission occurred. There was early loss of secondary dentition, and dental x-rays showed a type of dentin dysplasia with poor root development that was not like any other reported type.

Feigenbaum et al. (2013) provided follow-up on the family previously reported by Feigenbaum et al. (1988) and reviewed the clinical details of 8 other previously reported cases from 6 families (Singleton and Merten, 1973; Gay and Kuhn, 1976; Rutsch et al., 2005; Valverde et al., 2010). Feigenbaum et al. (2013) noted significant variability in phenotype, even within families. Core manifestations included marked aortic calcification, dental anomalies, osteopenia and acroosteolysis, and, to a lesser extent, glaucoma, psoriasis, muscle weakness, and joint laxity. A particular facies was also observed, consisting of high anterior hairline, broad forehead, smooth philtrum, and thin upper vermilion border.

Inheritance

The transmission pattern of Singleton-Merten syndrome in the family described by Feigenbaum et al. (1988) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected individuals from 3 unrelated families with Singleton-Merten syndrome, previously reported by Feigenbaum et al. (1988), Rutsch et al. (2005), and Valverde et al. (2010), respectively, Rutsch et al. (2015) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the IFIH1 gene (R822Q; 606951.0009). The variant was not found in any unaffected family members; analysis of 17 additional family members from the largest family (Feigenbaum et al., 1988) showed that all but 1 individual with dental anomalies carried the mutation, and 1 individual with only psoriasis carried the mutation, whereas 3 others with only psoriasis did not. Functional analysis demonstrated that R822Q is a gain-of-function substitution that triggers production of type 1 interferon (see 147660), resulting in a heightened inflammatory state.