Hemophilia B Leyden: Characteristics and natural history in the PedgNet Registry

Background: A unique form of Hemophilia B (HB) is HB Leyden. We evaluated the International PedNet Registry database to explore the natural history of HB Leyden, investigate genotype-phenotype associations and guide clinical decision-making.

Objectives: To assess the association between genetic variants, endogenous factor (FIX) levels over time, treatment and bleeding phenotype in children with HB Leyden.

Patients and methods: Data on genetic variants, FIX levels at diagnosis and over time, bleeding and treatment details, were extracted from the PedNet Registry in children with hemophilia born since 2000.

Results: Of 457 individuals with HB, 24 showed a HB Leyden genotype. The most frequent F9 variant was c.-35G>A affecting 14 individuals, followed by c.-35G>C (n=4), c.-49T>A (n=2), and c.-52C>T, c.-34A>G and c.-22delT (n=1 each). Major clinical differences in bleeding and treatment modality were observed comparing c.-35G>A to non-c.-35G>A genotypes: For all children with a c.-35G>A genotype, FIX levels increased before the age of 4 years , but did not normalize over time, irrespective of initial severity. In children with non-c.-35G>A genotypes, increase in FIX was less common (4/9) and occurred later.

Conclusions: HB Leyden is caused by the variant c.-35G>A in >50% of cases, in whom a FIX increase occurs at very young ages, associated with low bleeding rates. This contrasts to the phenotype of individuals with HB Leyden due to a non-c.-35G>A variant. Our study may thus help guide clinical decision-making in this rare HB entity.