Caspase-8 deficiency-a rare cause of immune dysregulation – First case report from India

Abstract

A 3½-year-old boy presented with generalized lymphadenopathy since 1 year of age. After 5 months of age, he had multiple infections and two episodes of pneumonia. At 2½ years, he developed chronic diarrhea. Colonoscopy showed ileal ulcers and inflammatory pan colitis with skip areas and histopathologic examination showed mild chronic ileitis, villous shortening, and diffused active colitis. Next-generation sequencing revealed a previously reported homozygous missense mutation Caspase-8. Unlike autoimmune lymphoproliferative syndrome, Caspase-8 deficiency states have immunodeficiency, autoimmunity, and early-onset inflammatory bowel disease in addition to lymphoproliferation. Early diagnosis aided by molecular confirmation is essential as haploidentical hematopoietic stem cell transplant is curative.

Infections in Disorders of Immune Regulation

“…Caspase-8 also regulates necroptosis and pyroptosis, which are inflammatory lytic cell death pathways [ 17 ]. Therefore, apart from lymphoproliferation, CEDS is associated with profound immunodeficiency and manifests as recurrent infections, inflammation, and autoimmunity [ 14 , 15 , 16 , 18 ].…”

“…Very-early-onset inflammatory bowel disease with fistulating perineal disease presenting with chronic diarrhea and mimicking cow milk protein has been described. Other autoimmune manifestations like hemolytic anemia and interstitial lung disease have also been described [ 14 , 15 , 16 , 18 , 19 ]. Recurrent mucocutaneous herpetic infection was reported as a cardinal infection in patients with CEDS [ 19 ].…”

“…Recurrent mucocutaneous herpetic infection was reported as a cardinal infection in patients with CEDS [ 19 ]. Recurrent sinopulmonary bacterial infections and viral infections like herpes, EBV, and molluscum contagiosum are also described [ 15 , 16 , 18 , 19 , 20 ] ( Table 2 ). Fatal Nocardia meningoencephalitis has also been reported in a patient [ 16 ].…”

“…Serum immunoglobulin levels could be in the normal range or low, but the specific antibody response is insufficient. Despite normal T cell counts, pediatric patients had reverse CD4+ /CD8+ ratios [ 16 , 18 , 19 ]. These patients are managed with IVIg replacement therapy and acyclovir prophylaxis [ 16 , 19 ].…”

“…These patients are managed with IVIg replacement therapy and acyclovir prophylaxis [ 16 , 19 ]. One patient was transplanted and seemed well on follow-up [ 18 ].…”