Kartal-Kaess Mutlu, Pinto Fernando, Labarque Veerle, de Kovel Marloes, Nolan Beatrice, Carcao Manuel, d'Oiron Roseline, Mikkelsen Torben Stamm, Ljung Rolf, Andersson Nadine G
Division of Pediatric Hematology & Oncology, Department of Pediatrics, Inselspital, University Hospital, University of Bern, Bern, Switzerland.
Department of Haematology, Royal Hospital for Children, Glasgow, United Kingdom.
J Thromb Haemost. 2025 Mar;23(3):921-927. doi: 10.1016/j.jtha.2024.12.020. Epub 2024 Dec 30.
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.
To assess the association between genetic variants, endogenous factor (F)IX levels over time, treatment, and bleeding phenotype in children with HB Leyden.
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.
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.
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.
乙型血友病（HB）的一种独特形式是莱登型乙型血友病（HB Leyden）。我们评估了国际血友病管理注册儿科网络（PedNet）数据库，以探索HB Leyden的自然病史，研究基因型与表型的关联，并指导临床决策。
评估莱登型乙型血友病患儿的基因变异、内源性凝血因子（F）IX水平随时间的变化、治疗情况与出血表型之间的关联。
从国际PedNet中提取了2000年以后出生的血友病患儿的基因变异、诊断时及随访期间的FIX水平、出血情况和治疗细节等数据。
在457例HB患者中，24例表现出HB Leyden基因型。最常见的F9变异是c.-35G>A，有14例患者受其影响，其次是c.-35G>C（n = 4）、c.-49T>A（n = 2）以及c.-52C>T、c.-34A>G和c.-22delT（各n = 1）。比较c.-35G>A基因型与非c.-35G>A基因型时，观察到出血情况和治疗方式存在重大临床差异。对于所有c.-35G>A基因型的儿童，FIX水平在4岁前升高，但随时间推移未恢复正常，无论初始严重程度如何。非c.-35G>A基因型的儿童中，FIX升高的情况较少见（4/9）且出现较晚。
超过50%的HB Leyden病例是由c.-35G>A变异引起的，FIX在非常年幼时升高，出血率较低。这与因非c.-35G>A变异导致的HB Leyden个体的表型形成对比。因此，我们的研究可能有助于指导这一罕见的HB类型的临床决策。
