IL7R – Omenn syndrome

Omenn syndrome is a rare autosomal recessive combined immunodeficiency characterized by erythroderma, lymphadenopathy, splenomegaly and autoimmune features. Biallelic pathogenic variants in IL7R (HGNC:6024) have been identified in affected infants, establishing IL7R as a genetically heterogeneous cause of Omenn syndrome. This summary integrates clinical reports and functional studies to support diagnostic decision-making and future research.

Clinical case reports describe 2 unrelated probands with Omenn syndrome due to IL7R mutations (2 probands ([PMID:16492442]; [PMID:36919728])). The first, a consanguineous Middle Eastern infant presented with erythroderma, lymphadenopathy and autoimmune features due to homozygous c.353G>A (p.Cys118Tyr) in IL7R ([PMID:16492442]). The second, a 3-month-old female born to consanguineous parents, exhibited erythroderma, failure to thrive, hypothyroidism and splenomegaly; genetic testing revealed homozygous p.Arg206Gln ([PMID:36919728]). Both cases demonstrate autosomal recessive inheritance, absent family history of related immunodeficiency, and parental carrier status confirmed by segregation analysis.

Genetic evidence supports a limited but definitive link between IL7R LOF and Omenn syndrome: 2 probands with biallelic missense variants exhibiting conserved cysteine disruption in the extracellular domain and altered receptor function. No additional affected relatives were reported. The variant spectrum includes missense substitutions impacting receptor folding (c.353G>A (p.Cys118Tyr)) and ligand-binding (p.Arg206Gln).

Functional assessment of IL7R variants demonstrates impaired IL-7Rα expression and signaling. A nonsense mutation c.616C>T (p.Arg206Ter) in a Korean SCID patient led to absent receptor expression and profound T-cell lymphopenia ([PMID:15615257]), corroborating a loss-of-function mechanism. These data align with observed clinical T-B+NK+ immunophenotypes in Omenn syndrome.

No studies to date dispute the association of IL7R deficiency with Omenn syndrome. However, broader IL7R gain-of-function mutations in leukemia highlight the gene’s critical role in lymphocyte biology and underscore the need to distinguish LOF alleles in OS from activating alleles in malignancy.

In summary, autosomal recessive IL7R variants cause a LOF of IL-7Rα, leading to Omenn syndrome through impaired T-cell development and homeostasis. Early genetic diagnosis enables prompt hematopoietic stem cell transplantation, the only curative option. Key take-home: IL7R genetic testing should be included in newborn SCID screens when erythroderma and lymphadenopathy are present.

References

• The Journal of pediatrics • 2006 • Omenn syndrome in an infant with IL7RA gene mutation PMID:16492442
• Experimental and clinical transplantation • 2023 • Successful Hematopoietic Stem Cell Transplant in a Patient with Omenn Syndrome: A Case Report PMID:36919728
• International journal of hematology • 2004 • Characterization of a novel nonsense mutation in the interleukin-7 receptor alpha gene in a Korean patient with severe combined immunodeficiency PMID:15615257

Evidence Based Scoring (AI generated)