Skewed lyonization of X chromosome causing severe Haemophilia A in a female carrierA case study

Introduction Haemophilia A is a bleeding disorder characterized by FVIII deficiency. It presents with symptoms such as easy bruising, haemorrhage following trauma or surgery. Severe cases may lead to haematomas and haemarthrosis. Haemophilia A is a X linked recessive disorder typically affecting hemizygous male and females who are homozygous for mutant F8 gene on the long arm of X chromosome (Xq28).Case history A 20 year female presented with history of gum bleeding, deep haematomas and haemarthrosis of large joints including bilateral elbow and knee joints . She had been referred to our hospital for further evaluation. She is second born child of nonconsanguineous marriage. Family history revealed two younger brothers with prolonged bleeding and one brother had expired at age of 3 years due to prolonged bleeding ( haemophilia) .Her elder sisters son has been diagnosed with haemophilia at the age of one year. Her maternal uncle died following circumcision (definite cause not known).Results While complete blood counts, bleeding time, Prothrmobin time and thrombin time were found to be within our normal reference range, Activated partial thromboplastin time was found to be elevated and hence further mixing studies were done which showed the following results.APTT- Pt 81.1 secs Normal range 25.1-36.7 secsMixing studies= APTT (Pt) 12 Control 31.5 secs APTT with factor VIII deficient plasma 79.0 secs APTT with factor IX deficient plasma 38.7secsFactor assay FVIII 1 (0.7) Fibrinogen 291.7mg VWFRCo 104.6 VWAg 103 Udl On evaluating the parents, mother was found to have mild factor VIII deficiency. Platelet aggregometry showed normal results in patient and both parents.Conclusion Investigation was suggestive of severe haemophilia A in our young female patient. It is an extremely rare condition, but there are studies to support it and suggest that X linked recessive inheritance may be seen in females under rare circumstances such as skewed inactivation (lyonization) of X chromosomes leading to predominate expression of the mutated alleles as the result of a preferential inactivation of the X chromosomes with wild type F8 gene.