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Thromb Haemost 2010; 104(04): 718-723
DOI: 10.1160/TH10-02-0085
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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

Mónica Martín-Salces
1   Haematology Department, Hospital Universitario La Paz, Madrid, Spain
,
Adoración Venceslá
2   Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
,
María Teresa Alvárez-Román
1   Haematology Department, Hospital Universitario La Paz, Madrid, Spain
,
Isabel Rivas
1   Haematology Department, Hospital Universitario La Paz, Madrid, Spain
,
Ihosvany Fernández
1   Haematology Department, Hospital Universitario La Paz, Madrid, Spain
,
Nora Butta
1   Haematology Department, Hospital Universitario La Paz, Madrid, Spain
,
Manel Baena
2   Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
,
Pablo Fuentes-Prior
3   Research Institute, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
,
Eduardo F. Tizzano
2   Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
,
Víctor Jiménez-Yuste
1   Haematology Department, Hospital Universitario La Paz, Madrid, Spain
› Author Affiliations Financial support:This work was supported by Real Fundación Victoria Eugenia, Fundació Catalana d’Hemofilia and SAF2007–64140 from Ministerio de Ciencia e Innovación, Spain.
Further Information

Publication History

Received: 02 February 2010

Accepted after major revision: 14 May 2010

Publication Date:
24 November 2017 (online)

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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.
    CrossrefPubMedGoogle Scholar
  • 2 Fay PJ, Jenkins PV. Mutating factor VIII: lessons from structure to function. Blood Rev 2005; 19: 15-27.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 8 Dhar P. et al. Management of pregnancy in a patient with severe haemophilia A. Br J Anaesth 2003; 91: 432-435.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 10 Seeler RA. et al. Severe haemophilia A in a female: a compound heterozygote with nonrandom X-inactivation. Haemophilia 1999; 5: 445-449.
    CrossrefPubMedGoogle Scholar
  • 11 Morita H. et al. The occurrence of homozygous hemophilia in the female. Acta Haematol 1971; 45: 112-119.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Andrejev NJ. et al. Haemophilia A in a patient with testicular feminization. Thromb Diath Haemorrh 1975; 33: 208-216.
    PubMedGoogle Scholar
  • 19 Pavlova A. et al. Molecular mechanisms underlying haemophilia A phenotype in seven females. J Thromb Haemost 2009; 7: 976-982.
    CrossrefPubMedGoogle Scholar
  • 20 Barrowcliffe TW. Monitoring haemophilia severity and treatment: new or old laboratory tests?. Haemophilia 2004; 10 (Suppl. 04) 109-114.
    CrossrefPubMedGoogle Scholar
  • 21 Sahud MA. Factor VIII inhibitors. Laboratory diagnosis of inhibitors. Semin Thromb Hemost 2000; 26: 195-203.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Dave BJ, Sanger WG. Role of cytogenetics and molecular cytogenetics in the diagnosis of genetic imbalances. Semin Pediatr Neurol 2007; 14: 2-6.
    CrossrefPubMedGoogle Scholar
  • 23 Shen BW. et al. The tertiary structure and domain organization of coagulation factor VIII. Blood 2008; 111: 1240-1247.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 25 Macedo-Ribeiro S. et al. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature 1999; 402: 434-439.
    CrossrefPubMedGoogle Scholar
  • 26 Pratt KP. et al. Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature 1999; 402: 439-442.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 28 Coppola A. et al. Prophylaxis in people with haemophilia. Thromb Haemost 2009; 101: 674-681.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 38 Acquila M. et al. A skewed lyonization phenomenon as cause of hemophilia A in a female patient. Blood 1995; 85: 599-600.
    PubMedGoogle Scholar
  • 39 Knobe KE. et al. Female haemophilia A: two unusual cases caused by skewed X inactivation. Haemophilia 2008; 14: 846-848.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar