Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1β inhibition

None of the patients had a family history of consanguinity. Because of the complex nature of their disease, whole-exome sequencing (WES) was performed in all patients and identified 3 distinct monoallelic, heterozygous, possibly pathogenic de novo variants in CDC42. Immunophenotypic changes in monocytes and natural killer cells (Fig 1, A and B) were also noted. Because of the complex nature of the disease, WES was performed and identified a heterozygous and possibly pathogenic de novo variant in CDC42 c.563G>A (p.C188Y; Fig 1). At 8 months, he was found to have retinal detachment, phthisis of his right eye and papilledema of the left eye, both of which were presumed to be secondary to his inflammatory disease and increased intracranial pressure. Because of the patient's phenotypic similarities to patients with NOMID, he was started on prednisone and anakinra at age 8 months, with resolution of systemic inflammation and cytopenias. Patient 1 Patient 2 Patient 3 Patient 4 CDC42 variant c.563G>A (p.C188Y) c.563G>A (p.C188Y) c.556C>T (p.R186C) c.576A>C (stop lost [p.*192C*24]) Dose of anakinra (d) Before anakinra 1 mg/kg 2.5 mg/kg Before anakinra 6 mg/kg 5 mg/kg Before anakinra 3 mg/kg 8.5 mg/kg Canakinumab, 8 mg/kg/mo Before anakinra 3 mg/kg 4.5 mg/kg Clinical presentation Facial dysmorphism Mild frontal bossing, mild hypertelorism, depressed nasal bridge Frontal bossing, macrocephaly, thin sparse hair, depressed nasal bridge None Mild frontal bossing Weight (percentile)