CASP8 – Autoimmune Lymphoproliferative Syndrome Type 2B

Autoimmune lymphoproliferative syndrome type 2B (ALPS2B) is a rare autosomal recessive immunodeficiency characterized by defective lymphocyte apoptosis, chronic lymphadenopathy, splenomegaly, and immune dysregulation. CASP8 encodes caspase-8, a key initiator of the extrinsic apoptotic pathway, and biallelic loss-of-function variants in CASP8 underlie ALPS2B by disrupting FAS-mediated cell death and immune homeostasis.

Genetic evidence supports a moderate association between CASP8 and ALPS2B. Five affected individuals from three unrelated families have been described: two pediatric patients with early-onset inflammatory bowel manifestations including failure to thrive (HP:0001508) (PMID:37038193), two adult siblings presenting with pulmonary arterial hypertension (HP:0002092) and multiorgan lymphocytic infiltration (PMID:25814141), and a toddler with dysentery and immune dysregulation (PMID:37038193). All carried homozygous or compound heterozygous CASP8 truncating variants.

The predominant variant spectrum comprises loss-of-function alleles, including the recurrent stop-gain mutation c.1096C>T (p.Gln366Ter) (PMID:25814141). Additional splice site and frameshift mutations have been reported in caspase-8 deficiency cohorts, consistent with a loss-of-function mechanism. Segregation analysis in the adult sibling pair confirmed one additional affected relative segregating the same homozygous variant (PMID:25814141).

Functional studies in patient-derived lymphocytes demonstrate markedly impaired caspase-8 activation and downstream apoptosis upon FAS or TNF receptor engagement, with persistence of autoreactive lymphocytes and heightened inflammatory cytokine production. These cellular assays corroborate the hypomorphic apoptotic phenotype and link CASP8 deficiency to immune dysregulation in ALPS2B.

No conflicting reports have been published to date disputing the CASP8–ALPS2B link. The combined genetic and experimental data meet the ClinGen criteria for a Moderate gene–disease association.

Key Take-home: Biallelic CASP8 loss-of-function variants cause autosomal recessive ALPS2B by abrogating caspase-8-mediated apoptosis, supporting genetic testing and early intervention in affected families.

References

• Journal of clinical immunology • 2015 • Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings. PMID:25814141
• Allergy, asthma, and clinical immunology • 2023 • A rare immunological disease, caspase 8 deficiency: case report and literature review. PMID:37038193

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