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

Introduction: A unique and rare 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 correlations and guide clinical decision-making. The primary obejctive was to assess the association between genetic variants, endogenous factor (F) IX levels over time, treatment and bleeding phenotype in children with HB Leyden.

Method: Data on genetic variants, FIX levels at diagnosis and over time, onset and type of bleeding, and treatment modality were extracted from the PedNet Registry including 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 showed a rise, but not normalization over time, irrespective of initial severity, before the age of four years. In children with non-c.-35G>A genotypes, a rise 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, associated with a low bleeding rate. 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.

 

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Conflict of Interest:

M.K.K . reports consulting/ advisory role: Bayer, SOBI, Takeda; research funding: NovoNordisk; travel, accommodations, expenses: Bayer, NovoNordisk, SOBI, Takeda. M.d.K.has nothing to declare during the last 3 years related to the present work. M.C. reportshaving received research support from Bayer, Bioverativ/Sanofi, Novartis, Novo Nordisk, Pfizer, Roche and Shire/Takeda. Having received honoraria for speaking/participating in advisory boards from Bayer, Bioverativ/Sanofi, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche and Shire/Takeda. F.P.:has received financial support from Roche for participating in advisory boards and for travel/accommodation in scientific meetings R.L. has nothing to declare during the last 3 years related to the present work. V.L. has been as a speaker and/or advisor for Bayer, Novartis, NovoNordisk, Octapharma, Roche, Sobi, and Takeda, and has received financial support for travel, accommodations, and expenses from Jazz Pharmaceuticals, Roche, caf-dcf and Sobi. B.N . reports having received research support from Sanofi and Sobi and honoraria for speaking/participating in advisory boards from Sobi. R.O. reports having received payment or honoraria from Biomarin, CSL Behring, NovoNordisk, Pfizer, Roche, Sanofi, Sobi, Takeda; financial support for travel, accommodations, and expenses from NovoNordisk, Pfizer, Roche, Sanofi, Sobi, Takeda; T.S.M. has nothing to declare during the last 3 years related to the present work. N.G.A. has been as a speaker and/or advisor for Sobi and Octapharma.

Publication History

Article published online:
13 February 2025