Hemophilia B Leyden: characteristics and natural history in the International Pediatric Network of Hemophilia Management Registry
- PMID: 39742973
- DOI: 10.1016/j.jtha.2024.12.020
Hemophilia B Leyden: characteristics and natural history in the International Pediatric Network of Hemophilia Management Registry
Abstract
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.
Keywords: F9; hemophilia B; population-based; promotor.
Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of competing interests M.K.K. reports consulting/advisory role: Bayer, Sobi, and Takeda; research funding: Novo Nordisk; travel, accommodations, and expenses: Bayer, Novo Nordisk, Sobi, and Takeda. M.d.K. has nothing to declare during the last 3 years related to the present work. M.C. reports having received research support from Bayer, Bioverativ/Sanofi, Novartis, Novo Nordisk, Pfizer, Roche, and Shire/Takeda; 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 a speaker and/or advisor for Bayer, Novartis, Novo Nordisk, 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, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and Takeda; financial support for travel, accommodations, and expenses from Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and Takeda. T.S.M. has nothing to declare during the last 3 years related to the present work. N.G.A. has been a speaker and/or advisor for Sobi and Octapharma.
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