New Phenotypes Associated With Pathogenic RNASEH2B and SAMHD1 Variants

Abstract

Pathogenic variants in nine genes (AGS1-9) were mainly reported in patients with Aicardi–Goutières syndrome (AGS), which is a genetic disorder of the innate immune response associated with improper induction of Type I interferon (IFN). These variants led to a broad range of clinical manifestations ranging from congenital type of AGS displaying congenital microcephaly, severe developmental delay, spasticity, basal ganglia calcification, white matter abnormalities and early lethality up to infantile or juvenile onset with a broader phenotypic spectrum of AGS with severe to mild disease, including a form of spastic paraparesis. More recently, these variants have been reported to be associated with rare extra-neurologic presentations. In this report, we present two patients with homozygous pathogenic variants in RNASEH2B (p.Ala177Thr) and SAMHD1 (p.Arg442Ter). The first patient showed persistent arthropathy livedo reticularis, intermittent fever and hepatosplenomegaly, whereas the second had late onset of muscle spasms, impaired calcium/phosphorus homeostasis, severe and progressive intracranial calcification and chilblains. The two patients had average intelligence. We believe to be the first time; an idiopathic hypoparathryroidism is associated with pathogenic variant of SAMHD1. As such, this extends the phenotypes linked to SAMHD1 (likely) pathogenic variants. We also summarize the extra-neurologic manifestations associated with AGS genes-related disorders. Thus, by facilitating early diagnosis, counselling and health surveillance of these patients are improved.