GDF2 – GDF2-Related Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by mucocutaneous telangiectasias and arteriovenous malformations, most commonly due to ENG or ACVRL1 mutations. Variants in GDF2, encoding BMP9, have been identified in a subset of HHT cases, establishing a novel HHT5 subtype with overlapping clinical features. Initial exome sequencing in 191 unrelated probands revealed heterozygous missense GDF2 variants in three families presenting epistaxis and telangiectases ([PMID:23972370]).

A spectrum of GDF2 variants has been reported, including missense and frameshift alleles. A pediatric case harbored a homozygous c.1060_1062delinsAG (p.Tyr354ArgfsTer15) variant, presenting clubbing, hypoxemia, pulmonary AVMs and later epistaxis in one sibling, while heterozygous carriers showed mild epistaxis ([PMID:32669404]). Additional heterozygous missense variants have been documented in adult HHT and PAVM cohorts, underscoring variable expressivity and incomplete penetrance.

Segregation analysis in the Chinese family demonstrated variant co-segregation with HHT features in 4 affected relatives, including a great-uncle and a parent with mild epistaxis. Four unrelated probands with heterozygous GDF2 variants meeting Curaçao criteria further support autosomal dominant inheritance.

Functional assays reveal that pathogenic GDF2 alleles impair BMP9 proprotein processing and secretion, resulting in reduced circulating BMP9 and BMP10 levels. A bmp9-deficient zebrafish model recapitulated vascular malformations, and in vitro studies confirmed loss of BMP9 activity and endothelial signaling concordant with HHT pathophysiology ([PMID:23972370]).

No studies to date have refuted the GDF2–HHT association, and no conflicting phenotypes have been attributed solely to GDF2 variants outside the vascular spectrum. Limited pediatric cases suggest that homozygosity may exacerbate phenotypes but does not alter the dominant inheritance pattern in heterozygotes.

In conclusion, GDF2 variants cause an autosomal dominant HHT5 phenotype with variable penetrance. Genetic testing for GDF2 should be considered in HHT patients negative for ENG, ACVRL1, and SMAD4, particularly when PAVMs are prominent. Identification of GDF2 mutations informs clinical management through surveillance for AVMs and guides family counseling.

References

• American journal of human genetics • 2013 • BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. PMID:23972370
• Pediatrics • 2020 • Homozygous GDF2-Related Hereditary Hemorrhagic Telangiectasia in a Chinese Family. PMID:32669404

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