¹Lujayn Akbar, ¹Bashayer Alawam, ²Sulaiman M Al-Mayouf
¹King Fahad Hospital of the University, ²King Faisal Specialist Hospital and Research Center

Purpose Statement:

ISG15 deficiency is an ultra-rare disease that was recognized over a decade ago. Since then, only a few cases have been reported worldwide. It was described as a mixed syndrome of Mendelian susceptibility to mycobacterial disease and monogenic interferonopathy. Herein, we report a boy with ISG15 deficiency presenting with migratory arthritis. The patient’s background was suggestive of immune dysregulation including bronchial asthma, atopic dermatitis, mild recurrent skin lesions, recurrent admissions with pneumonia and hypoxia, and failure to thrive. Further, his family history was significant for consanguineous parents, a brother with a history of BCGitis and hypogammaglobulinemia, and a cousin with recurrent infections, severe skin lesions, and multiple food allergies. The patient was investigated for immune dysregulation, whole exome sequencing revealed homozygous mutations in ISG15 and COL9A3 genes. Family segregation showed homozygous mutation in the brother who had BCGitis and heterozygous mutation in the parents and sister who are asymptomatic. Further, brain MRI of the patient confirmed subcortical and globus pallidus calcification, which is described in individuals with ISG15 deficiency, secondary to enhanced INF-I. Positive serology of ANA and anti-smith antibodies were detected. Currently the patient is relatively well, apart from recurrent fevers and migratory arthritis flares. This report introduces a novel presentation of ISG15 deficiency with a combination of autoinflammation and autoimmunity, and highlights the contrasting functions of this gene contributing to its variable phenotypic expressivity.