Severe Hemophilia A in a Patient with Sexual Differentiation Disorder: A Case Report

Abstract Hemophilia A is an inherited X-linked disease where the VIII Factor (FVIII) production is altered, causing hemorrhagic diathesis. It can be classified into mild, moderate or severe, depending on the levels of circulating FVIII. It is suffered by males with an incidence of 1 in 5000 live births. Women are carriers, and they transmit the mutation in 90% of the cases, whereas 10% are de novo mutations. Females are usually asymptomatic, showing normal or intermediate FVIII factor, although it is estimated that 1 in 100.000 carriers will show severe bleeding manifestations due to FVIII severe deficit. For this to occur, some of the following physiopathologic mechanisms should be present: 1) heterozygous compound mutations affecting both alleles of the FVIII; 2) Homozygous mutations; 3) Extreme lionization of all the normal X chromosomes; 4) Numerical or structural alterations of the X chromosomes, as in Turner´s syndrome; 5) Genetical mutation in a patient with XY genotype and female phenotype. The objective of this report is to describe the case of a girl with severe Hempohilia A and XY cariotype. Case report: A 2-year-old female patient presented to consultation, with no remarkable previous perinatal history nor family history of hematologic diseases, referred due to spontaneous hematomas and bleeding events of difficult medical management with a 4 ISTH score. Coagulation studies were performed, showing a FVIII level of less than 1%, with the rest of the blood parameters being normal. Coagulation studies of the mother showed FVIII levels of 30%, Von Willebrand antigen of 59% and ristocetin cofactor of 43%. The genetic analysis of both the child and mother informed a type I inversion of the 22 intron. A karyotype analysis of the patient is done. She is phenotypically a female, but she has a 46XY genotype. At present she is being studied to rule out if the sexual differentiation disorder is due to the lack of SRY gen (Swyer´s syndrome) or to insensitivity to androgens (Morris´syndrome). From the moment of the diagnosis, the patient started prophylaxis with recombinant FVIII factor, not showing complications. Discussion The severe manifestations of the X linked diseases are infrequent in females. Approximately 30% of the carriers of hemophilia have an activity of the FVIII of less than 40%, with the consequent risk of bleeding. The most common cause for this is the selective inactivation of the normal X chromosome, that usually occurs in a balanced and randomized fashion. The diagnosis of hemophilia is made based on the FVIII activity dosage, and is confirmed with the molecular study of the mutations of the gene. In asymptomatic carriers, the status of homozygous or heterozygous mutation must be determined. Similarly, it is important to know what is the patient´s karyotype, because although its frequency is low, the disease can be the result of a sexual differentiation disorder, as it is the case presented here, or a chromosomopathy. In both cases is important to follow up the patient interdisciplinary with endocrinology, to treat the hormonal disorders related to each situation. Conclusion It is of paramount importance to obtain a complete clinical and molecular diagnosis, to perform a correct treatment and follow up, and also offer an adequate genetic counseling. Disclosures No relevant conflicts of interest to declare.