Abstract
OBJECTIVES: Homozygous loss-of-function mutations in SAMHD1 classically cause Aicardi-Goutières syndrome type 5 (AGS5), characterized by neuroinflammation and intracranial calcifications. Increasing evidence suggests a broader clinical spectrum. We aimed to describe the phenotypic heterogeneity associated with a single homozygous SAMHD1 variant in paediatric patients and to highlight diagnostic and therapeutic implications. METHODS: We retrospectively reviewed three paediatric patients evaluated at a tertiary centre who carried the same homozygous SAMHD1 missense variant (c.625G>A; p. Gly209Ser). Clinical features, laboratory findings, imaging results, genetic analyses, treatments and longitudinal responses were extracted from medical records. Whole-exome sequencing confirmed the pathogenic variant in all patients. RESULTS: Despite sharing an identical homozygous SAMHD1 mutation, the patients exhibited markedly divergent phenotypes: a chronic myopathy-dominant presentation without central nervous system involvement, a classical interferonopathy with panniculitis and intracranial calcifications and a lupus-like connective tissue disease phenotype with calcinosis and vasculopathy. Neuroimaging findings ranged from normal to classical AGS features. All patients received Janus kinase (JAK) inhibitors, predominantly tofacitinib, resulting in partial to sustained clinical improvement. Disease flares consistently occurred during treatment interruptions, emphasizing the importance of continuous therapy. CONCLUSIONS: Homozygous SAMHD1 deficiency demonstrates striking phenotypic heterogeneity in childhood, extending beyond classical AGS. SAMHD1 mutations should be considered in children with unexplained systemic inflammation, even in the absence of typical neuroimaging findings. Clinical responses to JAK inhibition across diverse phenotypes support a shared interferon-driven pathogenesis and highlight the value of early genetic diagnosis to guide targeted therapy.