HAVCR2 – Subcutaneous Panniculitis-like T-cell Lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare peripheral T-cell lymphoma characterized by panniculitic skin lesions and frequent hemophagocytic lymphohistiocytosis (HLH). Germline biallelic mutations in HAVCR2, encoding the immune checkpoint receptor TIM-3, have emerged as a key genetic predisposition for SPTCL. Initial whole-exome sequencing in 13 sporadic Asian SPTCL cases identified HAVCR2 mutations in 11/13 probands, predominantly homozygous c.245A>G (p.Tyr82Cys), with one compound heterozygote carrying p.Tyr82Cys and p.Thr101Ile (PMID:30792187).

A nationwide Korean cohort of 49 SPTCL patients confirmed HAVCR2 mutations in 25/49 (51.0%), all p.Tyr82Cys, correlating with younger age, HLH or HLH-like systemic illness, and shorter relapse-free survival (PMID:34535012). Founder effect analysis shows p.Tyr82Cys enrichment in East Asian and Polynesian ancestries, whereas p.Ile97Met predominates in Europeans. Case reports, including a pediatric patient with mesenteric SPTCL and HLH developing two clonally unrelated episodes carrying germline HAVCR2 variants, underscore recurrent risk and clinical heterogeneity (PMID:32285995).

Inheritance is autosomal recessive; biallelic loss-of-function TIM-3 variants abrogate cell-surface expression and inhibitory signaling. Segregation data remain limited with no large multiplex families reported, suggesting a low segregation count beyond sporadic occurrence. Carrier frequencies in gnomAD (<0.7%) contrast starkly with high case enrichment, supporting pathogenicity of rare homozygous/compound mutations.

Functional studies demonstrate that p.Tyr82Cys and p.Ile97Met TIM-3 variants cause protein misfolding, retention in the endoplasmic reticulum, loss of membrane expression, and hypersecretion of inflammatory cytokines (TNF-α, IL-1β), driving HLH and SPTCL pathogenesis (PMID:30374066). Ruxolitinib therapy targeting JAK-STAT inflammatory pathways induces rapid remission in refractory SPTCL-HLH cases, indicating immunomodulation rather than cytotoxicity as an effective strategy.

Collectively, over 60 unrelated SPTCL probands with biallelic HAVCR2 mutations across diverse populations, combined with concordant mechanistic evidence of TIM-3 loss-of-function, support a Strong gene–disease association. No substantial conflicting data have been reported. Further studies on population screening and genotype–phenotype correlations may refine prognostic stratification.

Key Take-home: Germline HAVCR2 biallelic loss-of-function mutations underpin a distinct, immunologically driven subtype of SPTCL with HLH propensity, warranting genetic testing and targeted immunomodulatory therapy for optimal clinical management.

References

• Blood Advances • 2019 • Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma PMID:30792187
• Blood Advances • 2021 • Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations PMID:34535012
• Nature Genetics • 2018 • Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome PMID:30374066
• Pediatric Blood & Cancer • 2020 • TIM-3 deficiency presenting with two clonally unrelated episodes of mesenteric and subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis PMID:32285995

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