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.