Background/Purpose: IFN-mediated diseases are mendelian innate immunodysregulatory disorders that present early in life with fevers, sterile organ inflammation, and a high type-I IFN-response gene signature in peripheral blood cells. To date, monumental discoveries of novel genetic variants with various phenotypic features have been recognized. We sought to describe novel genotype and phenotype findings in Saudi children with a final diagnosis of autoinflammatory interferonopathy and compare our data to previous studies.

Methods: This is a descriptive retrospective cohort study of pediatric patients with final genetically confirmed type I interferonopathies. Medical records were reviewed for demographic, family history, clinical and genetic data.

Results: Total of 17 patients (11 female) were included in the study. Eight patients (47%) presented within the first six months. Median age of disease onset was nine months (IQR: 3-36), and the median age of diagnosis was four years (IQR: 2-9). The rates of consanguinity and family history of affected members were high (88% and 47%, respectively). Whole exome sequencing was performed in 13 patients, two had a Leukoencephalopathy genetic panel and two target gene tests. six patients with Aicardi-Goutières syndrome (RNASEH2A, RNASEH2C, IFIH1), two patients with STING-associated vasculopathy with onset in infancy (TMEM173), 1 patient with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (PSMB8), one patient with DNASE2. seven patients had rare interferonopathy conditions (3=ISG15, 2=ZNFX1, 1=SOCS1, 1=STAT1). Of 17 patients, 11 (64%) had novel genetic variants. The most frequent features were fever (76%), neurology (70%), mucocutaneous (59%), gastrointestinal (53%), and pulmonary (47%). Hypogammaglobinemia and recurrent infections were seen in (47%) and (23%) respectively. Thirteen patients (76%) had elevated inflammatory markers. More than half patients treated aggressively; corticosteroids (59%), Jak inhibitor (35%), IVIG (29%), and various immunosuppressive agents in (23%) patients. Most of the patients had partial response to treatment. The majority had features of disease damage: growth failure (70%) followed by developmental delay (159%) and zero death.

Conclusion: This Saudi monogenic interferonopathies cohort represents the largest single center study from the Arab population. Our findings support the previous reports; early-onset fever, neurology and respiratory features should raise the suspicion of interferonopathies. However, there is eminent evidence of novel phenotypic variability. Our data expands the spectrum of clinical finding in relation to novel genetic variants.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/monogenic-interferon-mediated-diseases-novel-phenotype-and-genotype-characteristics-from-saudi-population/