GNA11 – Congenital Hemangioma

Congenital hemangiomas are rare, benign vascular tumors fully formed at birth and typically GLUT1-negative. Although usually solitary, they can present in multifocal or segmental patterns and be complicated by transient hematologic abnormalities such as anemia and thrombocytopenia. Somatic activating mutations in GNA11 have been identified as the molecular driver underlying these vascular lesions, supporting a unifying diagnosis across clinical variants.

Clinical Validity and Genetic Evidence

The overall gene–disease association is classified as Moderate. Two unrelated infants harboring somatic GNA11 p.Gln209Pro mutations presented with congenital hemangiomas and consistent histopathology (2 probands; PMID:27438697; PMID:32255239). No familial segregation has been reported, reflecting postzygotic mosaicism rather than germline inheritance.

Variant Spectrum and Inheritance

All reported mutations are somatic, mosaic, gain-of-function missense variants at codon 209. A recurrent hotspot, c.626A>C (p.Gln209Pro), was identified in two independent cases ([PMID:27438697]; [PMID:32255239]). No loss-of-function or non-coding variants have been implicated in congenital hemangioma. Inheritance is Somatic mosaic with no transmitted alleles.

Functional Evidence

Activating Q209 mutations in GNA11 constitutively activate Gα₁₁ signaling, as established in uveal melanoma models, leading to downstream MAPK and PI3K pathway activation. Although direct functional assays in hemangioma-derived cells are lacking, the recurrent hotspot and concordant signaling defects in other GNAQ/GNA11–driven neoplasms support a causative mechanism.

Conflicting Evidence

No studies to date have refuted the role of somatic GNA11 Q209 variants in congenital hemangioma. GNAQ mutations can also underlie some vascular tumors, but the presence of GNA11 p.Gln209Pro in hemangiomatosis cases underscores locus specificity.

Conclusion

Somatic mosaic GNA11 p.Gln209Pro mutations are a consistent genetic driver of congenital hemangioma, accounting for both solitary and multifocal presentations with hematologic complications. Diagnostic testing for postzygotic GNA11 variants can confirm the diagnosis and refine prognostic expectations in affected infants.

Key Take-home: Identification of somatic GNA11 p.Gln209Pro variants provides a molecular diagnosis for congenital hemangioma and informs clinical management.

References

• JAMA dermatology • 2016 • Symptomatic Congenital Hemangioma and Congenital Hemangiomatosis Associated With a Somatic Activating Mutation in GNA11. PMID:27438697
• Pediatric dermatology • 2020 • Segmental congenital hemangiomas: Three cases of a rare entity. PMID:32255239

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