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

Pediatric Network on Hemophilia Management (PedNet) Study Group

doi:10.1016/j.jtha.2024.12.020

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

Pediatric Network on Hemophilia Management (PedNet) Study Group

Department of Clinical Medicine - Department of Paediatrics

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	Journal of Thrombosis and Haemostasis
Volume	23
Issue	3
Pages (from-to)	921-927
Number of pages	7
ISSN	1538-7933
DOIs	https://doi.org/10.1016/j.jtha.2024.12.020
Publication status	Published - Mar 2025

Keywords

F9
hemophilia B
population-based
promotor

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10.1016/j.jtha.2024.12.020

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@article{60f2394289c54cc88dbfc56da2111703,

title = "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",

author = "Mutlu Kartal-Kaess and Fernando Pinto and Veerle Labarque and {de Kovel}, Marloes and Beatrice Nolan and Manuel Carcao and Roseline d'Oiron and Mikkelsen, {Torben Stamm} and Rolf Ljung and Andersson, {Nadine G.} and {Pediatric Network on Hemophilia Management (PedNet) Study Group}",

note = "Publisher Copyright: {\textcopyright} 2024 International Society on Thrombosis and Haemostasis",

year = "2025",

month = mar,

doi = "10.1016/j.jtha.2024.12.020",

language = "English",

volume = "23",

pages = "921--927",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7933",

publisher = "Elsevier B.V.",

number = "3",

}

Hemophilia B Leyden: characteristics and natural history in the International Pediatric Network of Hemophilia Management Registry. / Pediatric Network on Hemophilia Management (PedNet) Study Group.
In: Journal of Thrombosis and Haemostasis, Vol. 23, No. 3, 03.2025, p. 921-927.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Hemophilia B Leyden

T2 - characteristics and natural history in the International Pediatric Network of Hemophilia Management Registry

AU - Kartal-Kaess, Mutlu

AU - Pinto, Fernando

AU - Labarque, Veerle

AU - de Kovel, Marloes

AU - Nolan, Beatrice

AU - Carcao, Manuel

AU - d'Oiron, Roseline

AU - Mikkelsen, Torben Stamm

AU - Ljung, Rolf

AU - Andersson, Nadine G.

AU - Pediatric Network on Hemophilia Management (PedNet) Study Group

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

KW - F9

KW - hemophilia B

KW - population-based

KW - promotor

UR - http://www.scopus.com/inward/record.url?scp=85215837698&partnerID=8YFLogxK

U2 - 10.1016/j.jtha.2024.12.020

DO - 10.1016/j.jtha.2024.12.020

M3 - Journal article

C2 - 39742973

AN - SCOPUS:85215837698

SN - 1538-7933

VL - 23

SP - 921

EP - 927

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

IS - 3

ER -

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

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Keywords

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