Hemophilia B Leyden: characteristics and natural history in the International Pediatric Network of Hemophilia Management Registry.

BACKGROUND

A unique form of hemophilia B (HB) is HB Leyden. We evaluated the international Pediatric Network on Hemophilia Management Registry (PedNet) 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 (F)IX levels over time, treatment, and bleeding phenotype in children with HB Leyden.

METHODS

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

RESULTS

Of 457 individuals with HB, 24 showed an 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 when comparing c.-35G>A with 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, an increase in FIX was less common (4/9) and occurred later.

CONCLUSION

HB Leyden is caused by the variant c.-35G>A in >50% of cases in whom a FIX increase occurs at very young ages, which is associated with low bleeding rates. This contrasts with 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.