Combined Hereditary Disorders of Haemophilia B Leyden (-6 G → A) and Type 1 von Willebrand Disease

Summary

Multiple coagulation disorders are unusual. We report here a combination of haemophilia B Leyden with type 1 von Willebrand disease (vWD) affecting different members of the same family. Haemophilia B Leyden was due to a -6 G → A mutation within the promoter of the factor IX gene and was responsible for a mild haemophilia in the father of the proband. The proband and her sister (age 4 and 6) exhibited a twofold lower level of factor IX activity (0.4 IU/ml) than the paternal grandmother (0.95 IU/ml). The differences in FIX levels in the three carriers of the same -6 G → A mutation suggest the implication of an age-related mechanism responsible for the increase in factor IX plasma level. Haemophilia B Leyden patient and carriers suffered also from a mild von Willebrand disease. The diagnosis of this associated type 1 vWD was performed by assaying plasma von Willebrand factor together with multimer electrophoretic studies and DDAVP test. The inheritance of this vWD was investigated by haplotype analysis of the vWF gene. Individuals affected by such an association are actually asymptomatic, but per- and post-operative bleeding risk remains to be evaluated.

• References

• 1 Veltkamp JJ, Remmelts HG, Van Der Vlerk D, Loeliger EA. Another genetic variant of haemophilia B: haemophilia B Leyden. Scand J Haematol 1970; 7: 82-90
• 2 Giannelli F, Green PM, High KA, Sommer S, Poon MC, Ludwig M, Schwaab R, Reitsma PH, Goossens M, Yoshioka A, Brownlee GG. Haemophilia B: database of point mutations and short additions and deletions - Fourth Edition, 1993. Nucl Acids Res 1993; 21: 3075-3087
• 3 Royle G, Van Der Water NS, Berry E, Ockelford PA, Browett PJ. Haemophilia B Leyden arising de novo by point mutation in the putative factor IX promoter region. Br J Haematol 1991; 77: 191-194
• 4 Reitsma PH, Bertina RM, Ploos van Amstel JK, Riemens A, Briet E. The putative factor IX gene promoter in haemophilia B Leyden. Blood 1988; 72: 1074-1076
• 5 Ghanem N, Costes B, Martin J, Vidaud M, Rothschild C, Foyer-Gazengel C, Goossens M. Twenty four novel hemophilia B mutations revealed by rapid scanning of the whole factor IX gene in a french population sample. EurJ Hum Genet 1993; 1: 144-155
• 6 Vidaud D, Tartary M, Costa JM, Bahnak BR, Gispert-Sanchez S, Fressinaud E, Gazengel C, Meyer D, Goossens M, Lavergne JM, Vidaud M. Nucleotide substitutions at the -6 position in the promoter region of the factor IX gene result in different severity of hemophilia B Leyden: consequences for genetic counseling. Hum Genet 1993; 91: 241-244
• 7 Hirosawa S, Fahner JB, Salier JP, Wu CT, Lovrien EW, Kurachi K. Structural and functional basis of the developmental regulation of human coagulation factor IX gene: factor IX Leyden. Proc Natl Acad Sci 1990; 87: 4421-4425
• 8 Crossley M, Winship PR, Austen DEG, Riza CR, Brownlee GG. A less severe form of haemophilia B Leyden. Nucl Acids Res 1990; 18: 4633
• 9 Stowell KM, Figueiredo MS, Brownlee GG, Jones P, Bolton-Maggs PHB. Haemophilia B Liverpool: a new British family with haemophilia B Leyden associated with a -6 G to A mutation in the factor IX promoter. Br J Haematol 1993; 85: 188-190
• 10 Briet E, Bertina RM, Van Tilburg NH, Veltkamp JJ. Hemophilia B Leyden. A sex-linked hereditary disorder that improves after puberty. N Engl J Med 1982; 306: 788-790
• 11 Crossley M, Ludwig M, Stowell KM, De Vos P, Olek K, Brownlee GG. Recovery from hemophilia B Leyden: an androgen-responsive element in the factor IX promoter. Science 1992; 257: 377-379
• 12 Tavori S, Brenner B, Tatarsky I. The effect of combined factor XI deficiency with von Willebrand factor abnormalities on haemorrhagic diathesis. Thromb Haemost 1990; 63: 36-38
• 13 Chediak J, Lambert E, Johnson El, Telfer MC. Combined severe factor XI deficiency and von Willebrand’s disease. Am J Clin Pathol 1980; 74: 108-114
• 14 Sano M, Saito H, Shimamoto Y, Sugiura I, Ohtsubo H, Kohda H, Yamaguchi M. Combined hereditary factor XI (plasma thromboplastin antecedent) deficiency, von Willebrand’s disease, and xeroderma pigmentosum in a Japanese family. Am J Hematol 1993; 44: 129-133
• 15 Sanger F, Nicklen S, Coulson A. DNA sequencing with chain-termination inhibitors. Proc Natl Acad Sci Usa 1977; 74: 5463-5467
• 16 Mazurier C, Samor B, Goudemand M. Improved characterization of plasma von Willebrand factor heterogeneity when using 2.5% agarose gel electrophoresis. Thromb Haemost 1986; 55: 61-67
• 17 Mercier B, Gaucher C, Mazurier C. Characterization of 98 alleles in 105 unrelated individuals in the F8vWF gene. Nucl Acids Res 1991; 19: 4800
• 18 Gaucher C, Mercier B, Mazurier C. von Willebrand disease family studies: comparison of three methods of analysis of the von Willebrand factor gene polymorphism related to a variable number tandem repeat sequence in intron 40. Br J Haematol 1992; 82: 73-80
• 19 Blombäck M, Eneroth P, Andersson O, Anvret M. On laboratory problems in diagnosis of mild von Willebrand’s disease. Am J Hematol 1992; 40: 117-120
• 20 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-525
• 21 Eikenboom JC, Reitsma PH, Peerlinck KMJ, Briet E. Recessive inheritance of von Willebrand’s disease type 1. Lancet 1993; 341: 982-986
• 22 Kurachi S, Furukawa M, Salier JP, Wu CT, Wilson EJ, French FS, Kurachi K. Regulatory mechanism of factor IX gene: protein binding at the Leyden-specific region. Biochem 1994; 33: 1580-1591
• 23 Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P. Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice. Blood 1995; 86: 2198-2205
• 24 Song CS, Rao TR, Demyan WF, Mancini MA, Chatterjee B, Roy AK. Androgen receptor messenger ribonucleic acid (mRNA) in the rat liver: changes in mRNA levels during maturation, aging, and calorie restrcition. Endocrinology 1991; 128: 349-356
• 25 Picketts DJ, Lillicrap DP, Mueller CR. Synergy between transcription factors DBP and C/EBP compensates for a haemophilia B Leyden factor IX mutation. Nat Genet 1993; 3: 75-79
• 26 Crossley M, Brownlee GG. Disruption of a C/EBP binding site in a factor IX promoter is associated with haemophilia B. Nature 1990; 345: 444-446
• 27 Reijnen MJ, Maasdam D, Bertina RM, Reitsma PH. Haemophilia B Leyden: the effect of mutations at position + 13 on the liver-specific transcription of the factor IX gene. Blood Coag Fibrinolysis 1994; 5: 341-348
• 28 Mueller CR, Maire P, Schibler U. DBP, a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranslationally. Cell 1990; 61: 279-290
• 29 Salier JP, Kurachi S, Kurachi K. Hemophilie B Leyden: les corrections naturelles d’un deficit temporaire de transcription. Med Sci 1994; 10: 186-194
• 30 Poon MC, Anand S, Fraser BM, Hoar BI, Sinclair DGD. Hemophilia B carrier determination based on family-specific mutation detection by DNA single-strand conformation analysis. J Lab Clin Med 1993; 122: 5-63
• 31 Coyle TE, Spicer T, Michalovic D, Poiesz BJ. Moderate hemophilia B: identification by polymerase chain reaction, sequencing, and oligomer restriction. Am J Hematol 1994; 46: 234-240
• 32 Ginsburg D, Bowie EJ. Molecular genetics of von Willebrand disease. Blood 1992; 79: 2507-2519