The importance of chilblains as a diagnostic clue for mild Aicardi–Goutières syndrome

Abstract

Aicardi-Goutières syndrome (AGS) is classically characterized by early-onset encephalopathy. However, in some cases, the presenting symptom of concern may actually be cutaneous rather than neurological, leading to the misdiagnosis of the condition. We report the case of three teenage siblings who presented with a lifetime history of chilblain lesions, only one of whom had notable neurologic deficits. Additional findings included acrocyanosis, Raynaud's phenomenon, low-pitch hoarse voice, headache, and arthritis. They were found to have two pathogenic sequence variants in the SAMHD1 gene: a c.602T>A substitution resulting in p.Ile201Asn protein change, previously reported as a pathogenic mutation, as well as a deletion c.719delT which has not been previously reported but results in a predicted pathogenic frame shift mutation. It is important to consider the diagnosis of AGS in patients and families with chilblain lesions in the presence of unexplained neurologic and rheumatic symptoms. © 2016 Wiley Periodicals, Inc.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS

“…The presence of vasculopathic skin lesions such as pernio (‘chilblain lesions’) or acral ischaemia presenting as Raynaud’s phenomenon, and/or ‘purple toes’ is suggestive of SAVI7 44 47 and AGS,33 52–55 the development of gangrene with prolonged ischaemic attacks is a feature of SAVI1 7 44 (table 3). Skin involvement is the most common symptom in patients with SAVI at presentation1 7 56–59 but some patients can present with severe lung disease and only minimal skin involvement 8 46 60 61…”

Diagnosis of Aicardi‐Goutières Syndrome in Adults: A Case Series

“…2 Chilblain lesions are reported in approximately 40% of patients and may be associated with mutations in any of the previously mentioned genes. 2,6 Although not reported in the original syndrome description 10 and possibly developing only late in adolescence, chilblains are an important clue for a retrospective diagnosis, 4 as in the present series. Therefore, when examining a patient with a previous diagnosis of cerebral palsy, it is important to inquire about previous encephalopathy episodes and the presence of chilblains.…”

“…3 Because the clinical course seems static from infancy and imaging findings are nonspecific, diagnosis can be challenging, and some patients may be misdiagnosed with cerebral palsy. 4 In this study, a series of 5 patients diagnosed with AGS in adulthood and the case of 1 asymptomatic homozygous carrier are described, and clinical findings relevant for diagnosis are reported, namely chilblain lesions and basal ganglia calcifications. 1…”

Musculoskeletal Disease in MDA5‐Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy

“…The prominent joint disease observed in the Singleton‐Merten syndrome phenotype indicates a particular association with mutations in IFIH1 compared to other type I interferonopathy genotypes . However, arthropathy has been noted in individual reports of patients with dysfunction of SAM domain and HD domain–containing protein 1 , 3′ repair exonuclease 1 , stimulator of IFN genes , retinoic acid–inducible gene 1 , and proteasome subunit β type 8 (results available upon request from the corresponding author), providing possible evidence of for a shared underlying pathology related to enhanced type I IFN signaling. If this is proven to be the case, the identification of such IFN‐associated phenotypes will be of increasing clinical relevance as anti‐IFN treatments become available .…”