A Case of Non-Resolving Hemophilia B Leyden in a 40 year Old Male (Factor IX promoter +13 A to G)

Abstract number: P1848

Stakiw¹ JL, James¹ PD, Leggo¹ J, Walker² I, Lillicrap¹ D

¹¹Queen's University, Kingston, Canada ¹¹Queen's University, Kingston, Canada ²²McMaster University, Hamilton, Canada

Hemophilia B (inherited factor IX deficiency) is a bleeding disorder caused by mutations in the FIX gene on the X chromosome. A subset of Hemophilia B patients with mutations in the promoter region of the factor IX gene spanning nucleotides -21 to +13, (also known as the Leyden specific region) exhibit a spontaneous resolution of the phenotype following puberty, characterized by increasing factor IX levels in the post-pubertal period and normalizing by age 40. The recovery mechanism in Hemophilia B Leyden is postulated to be based on the action of the androgen receptor and testosterone. In this report, we describe an adult male diagnosed with Hemophilia B as a young child. His baseline FIX level was 0.08 IU/mL in childhood, 0.17 IU/mL at age 16 and 0.14 IU/mL at age 37. He continues to exhibit hemorrhagic symptoms as an adult. Genotypic analysis revealed a point mutation in the Leyden specific region at nucleotide +13 (A to G). This mutation has been reported in the Hemophilia B mutation database (http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html) 13 times and patients with this change have all been reported to spontaneously resolve. The remainder of the coding region of his FIX gene is intact, as are both the specific Androgen Responsive Element and the D binding protein site. FIX levels did not rise in adulthood as would have been predicted by his mutation. This patient had normal physical maturation and secondary sex characteristics, fathered 2 children, and his adult testosterone level was normal. This is the first reported case of Hemophilia B Leyden, with a mutation in the classic Leyden-specific region, not spontaneously resolving following puberty. This has important implications both in our present understanding of the mechanism of post-pubertal resolution in cases of Hemophilia B Leyden and for the future counseling of patients with similar mutations.