Singleton-merten syndrome

Singleton-Merten syndrome (SMS) is a rare, autosomal dominant, multi-system congenital immune disorder characterized by early and severe aortic and valvular calcification, dental and skeletal abnormalities, psoriasis, glaucoma and other diverse clinical findings. SMS belongs to the type 1 interferonopathies.

Type1 interferonopathies are a group of rare, genetically and phenotypically heterogeneous diseases caused by a malfunction of the innate immune system (Crow YJ 2011). With the exception of multifactorial SLE, these are very rare diseases. Pathogenetically, type 1 interferonopathies are based on disorders in the metabolism and immunological recognition of intracellular nucleic acids.

Singleton-Merten syndrome 1 is caused by heterozygous activating mutations in the IFIH1 gene encoding the pattern recognition receptor MDA5, which recognizes viral dsRNA and activates antiviral type I interferon (IFN) signaling. In Singleton-Merten syndrome 1, IFIH1 mutations lead to a gain of function that causes overactivation of type I interferon (IFN) signaling and leads to auto-inflammation (Rutsch F et al. 2015; Jang MA et al. 2015).

Singleton-Merten syndrome 2 is caused by mutations in the RIGI gene. The RIGI gene (RIGI stands for RNA sensor RIG-I; RIG is the acronym for: Retinoic Acid-Inducible Gene I Protein) is a protein-coding gene located on chromosome 9p21.1.

Clinically, the syndrome is characterized by progressive calcification of large vessels, periodontitis with root resorption and osteoporosis.

Cutaneous involvement is defined as localized or generalized psoriasis and is present in the majority of patients.

In addition, glaucoma and an increased susceptibility to infections may occur

JAK inhibition is a valuable therapeutic option for patients with SGMRT1 (Broser P et al. 2022).

Broser P et al (2022) reported the case of a nine-year-old child who initially presented with slowly progressive deterioration of gross motor development and muscle weakness. At the age of five, he developed osteoporosis, acro-osteolysis, alveolar bone loss and severe psoriasis. Whole exome sequencing revealed a pathogenic de novo IFIH1 mutation and confirmed the diagnosis of SGMRT1. Consistent with constitutive type I interferon activation, the patient's blood cells exhibited a strong IFN signature as evidenced by marked upregulation of IFN-stimulated genes. The patient was treated with the Janus kinase (JAK) inhibitor ruxolitinib, which inhibits signaling at the IFN-α/β receptor. Within a few days of treatment, the psoriatic skin lesions regressed completely and the IFN signature normalized. Therapeutic efficacy was sustained, and muscle weakness, osteopenia and growth also improved over time.

1. Broser P et al. (2022) Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report. Pediatr Rheumatol Online J 20:24.

2. Rutsch F et al. (2015) A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet 96:275-282
3. Jang MA et al. (2015) Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet 96:266-274

4. Lu C et al. (2017) RIG-I-Like Receptor Signaling in Singleton-Merten Syndrome. Front Genet 8:118.

5. Sumpter R Jr et al. (2005) Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 79:2689-2699.

6. Villamayor L et al. (2023) Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation. Front Immunol14:1105309.

7. Yoneyama M et al. (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730-737.