Clinical and genetic findings in five female patients with haemophilia A: Identification of a novel missense mutation, p.Phe2127Ser

Summary

Severe manifestations of X-linked recessive disorders such as haemophilia A (HA) are rare in females. Here we describe the clinical and genetic findings in five female HA patients from two different Spanish families. Three sisters born to consanguineous parents presented moderate bleeding due to a known mutation (p.Ser1791Pro) detected in a homozygous state. In the second family, two sisters with Morris syndrome (46,XY) and mild/moderate illness were hemizygous for a novel missense mutation, p.Phe2127Ser. The mutation is predicted to impair binding to the factor VIII (FVIII) carrier protein, von Willebrand factor, and thus increased clearance of FVIII from plasma. Clinical and molecular characterisation of these patients is essential to optimise follow-up, genetic counselling and treatment of the disease.

Keywords

Haemophilia A - females - F8 gene - mutations - von Willebrand factor

• References

• 1 Graw J. et al. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet 2005; 6: 488-501.
• 2 Fay PJ, Jenkins PV. Mutating factor VIII: lessons from structure to function. Blood Rev 2005; 19: 15-27.
• 3 Vencesla A. et al. Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients – Structural analysis of 20 missense mutations suggests new intermolecular binding sites. Blood 2008; 111: 3468-3478.
• 4 Cai XH. et al. Female hemophilia A heterozygous for a de novo frameshift and a novel missense mutation of factor VIII. J Thromb Haemost 2006; 4: 1969-1974.
• 5 Vencesla A. et al. Severe haemophilia A in a female resulting from an inherited gross deletion and a de novo codon deletion in the F8 gene. Haemophilia 2008; 14: 1094-1098.
• 6 David D. et al. Female haemophiliac homozygous for the factor VIII intron 22 inversion mutation, with transcriptional inactivation of one of the factor VIII alleles. Haemophilia 2003; 9: 125-130.
• 7 Martin-Salces M. et al. Haemoperitoneum in a female patient with haemophilia A caused by a ruptured ovarian follicle. Haemophilia 2007; 13: 770-771.
• 8 Dhar P. et al. Management of pregnancy in a patient with severe haemophilia A. Br J Anaesth 2003; 91: 432-435.
• 9 Windsor S. et al. Severe haemophilia A in a female resulting from two de novo factor VIII mutations. Br J Haematol 1995; 90: 906-909.
• 10 Seeler RA. et al. Severe haemophilia A in a female: a compound heterozygote with nonrandom X-inactivation. Haemophilia 1999; 5: 445-449.
• 11 Morita H. et al. The occurrence of homozygous hemophilia in the female. Acta Haematol 1971; 45: 112-119.
• 12 Favier R. et al. Unbalanced X-chromosome inactivation with a novel FVIII gene mutation resulting in severe hemophilia A in a female. Blood 2000; 96: 4373-4375.
• 13 Bennett CM. et al. Female monozygotic twins discordant for hemophilia A due to nonrandom X-chromosome inactivation. Am J Hematol 2008; 83: 778-780.
• 14 Valleix S. et al. Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A. Blood 2002; 100: 3034-3036.
• 15 Chuansumrit A. et al. Inversion of intron 22 of the factor VIII gene in a girl with severe hemophilia A and Turner’s syndrome. Thromb Haemost 1999; 82: 1379.
• 16 Panarello C. et al. Concomitant Turner syndrome and hemophilia A in a female with an idic(X)(p11) heterozygous at locus DXS52. Cytogenet Cell Genet 1992; 59: 241-242.
• 17 Loreth RM. et al. Haemophilia A in a female caused by coincidence of a Swyer syndrome and a missense mutation in factor VIII gene. Thromb Haemost 2006; 95: 747-748.
• 18 Andrejev NJ. et al. Haemophilia A in a patient with testicular feminization. Thromb Diath Haemorrh 1975; 33: 208-216.
• 19 Pavlova A. et al. Molecular mechanisms underlying haemophilia A phenotype in seven females. J Thromb Haemost 2009; 7: 976-982.
• 20 Barrowcliffe TW. Monitoring haemophilia severity and treatment: new or old laboratory tests?. Haemophilia 2004; 10 (Suppl. 04) 109-114.
• 21 Sahud MA. Factor VIII inhibitors. Laboratory diagnosis of inhibitors. Semin Thromb Hemost 2000; 26: 195-203.
• 22 Dave BJ, Sanger WG. Role of cytogenetics and molecular cytogenetics in the diagnosis of genetic imbalances. Semin Pediatr Neurol 2007; 14: 2-6.
• 23 Shen BW. et al. The tertiary structure and domain organization of coagulation factor VIII. Blood 2008; 111: 1240-1247.
• 24 Ngo JCK. et al. Crystal structure of human factor VIII: Implications for the formation of the factor IXa-factor VIIIa complex. Structure 2008; 16: 597-606.
• 25 Macedo-Ribeiro S. et al. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature 1999; 402: 434-439.
• 26 Pratt KP. et al. Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature 1999; 402: 439-442.
• 27 Mazurier C. et al. Evidence for a von Willebrand factor defect in factor VIII binding in three members of a family previously misdiagnosed mild haemophilia A and haemophilia A carriers: consequences for therapy and genetic counselling. Br J Haematol 1990; 76: 372-379.
• 28 Coppola A. et al. Prophylaxis in people with haemophilia. Thromb Haemost 2009; 101: 674-681.
• 29 Fernandez-Lopez O. et al. The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations. Haematologica 2005; 90: 707-710.
• 30 Jayandharan G. et al. Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions. Haemophilia 2005; 11: 481-491.
• 31 Jacquemin M. et al. A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Wille-brand factor. Blood 2000; 96: 958-965.
• 32 Liu M-L. et al. Hemophilic factor VIII C1– and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure. Blood 2000; 96: 979-987.
• 33 Habart D. et al. Thirty-four novel mutations detected in factor VIII gene by multiplex CSGE: modeling of 13 novel amino acid substitutions. J Thromb Haemost 2003; 1: 773-781.
• 34 Citron M. et al. High throughput mutation screening of the factor VIII gene (F8C) in hemophilia A: 37 novel mutations and genotype-phenotype correlation. Human Mutation 2002; 20: 267-274.
• 35 Waseem NH. et al. Start of UK confidential haemophilia A database: Analysis of 142 patients by solid phase fluorescent chemical cleavage of mismatch. Thromb Haemost 1999; 81: 900-905.
• 36 Cutler JA. et al. The identification and classification of 41 novel mutations in the factor VIII gene (F8C). Hum Mutat 2002; 19: 274-278.
• 37 Bogdanova N. et al. Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. Hum Mutat 2005; 26: 249-254.
• 38 Acquila M. et al. A skewed lyonization phenomenon as cause of hemophilia A in a female patient. Blood 1995; 85: 599-600.
• 39 Knobe KE. et al. Female haemophilia A: two unusual cases caused by skewed X inactivation. Haemophilia 2008; 14: 846-848.
• 40 Wang X. et al. Haemophilia A in two unrelated females due to F8 gene inversions combined with skewed inactivation of X chromosome. Thromb Haemost 2009; 101: 775-778.
• 41 Pieneman WC. et al. Screening for mutations in haemophilia A patients by multiplex PCR-SSCP, Southern blotting and RNA analysis: the detection of a genetic abnormality in the factor VIII gene in 30 out of 35 patients. Br J Haematol 1995; 90: 442-449.