Siblings with Rare Hemophilia a Genetic Mutation and Normal Factor VIII Levels

Abstract BACKGROUND Hemophilia A is an X-linked inherited disorder which affects 1 in 5,000 males and is caused by mutations in the factor VIII (FVIII) gene. Hemophilia is typically diagnosed by measurement of FVIII procoagulant (FVIII:C) activity. Molecular genetic testing of the FVIII gene identifies pathogenic variants in as many as 98% of individuals with hemophilia A. The specific genetic test performed varies and must take into account the severity of hemophilia and the gene affected. Hemophilia A families with severe disease may have genetic analysis for intron 22 and intron 1 mutation performed followed by DNA sequencing if intron analysis is uninformative. Families with mild to moderate disease often need upfront gene sequencing for diagnosis. OBJECTIVE To describe a case series of siblings with FVIII gene mutation having normal Factor VIII activity levels, with grandfather found to have similar gene mutation DESIGN/METHOD: Case Series RESULTS Case 1 An 8 year old boy with presumed Von Willebrand disease (VWD) was seen in our clinic for evaluation for bleeding disorders. Testing prior to being seen in clinic showed Factor VIII level of 37%, Von Willebrand factor activity of 53% and Von Willebrand factor antigen of 103%. He had post-operative hemorrhage after tonsillectomy and adenoidectomy at 3 years of age, as well as frequent epistaxis. Family history was significant for sibling with epistaxis, a maternal grandfather with VWD and sister with menorrhagia. Subsequently, his maternal grandfather was found to have mild hemophilia A based on genetic testing which brought into question the child's diagnosis of mild Type 1 VWD. Repeat testing showed Factor VIII 64%, Von Willebrand factor antigen 126% and Ristocetin cofactor activity 93%. Genetic testing revealed he was hemizygous for the pathogenic variant, c.1621A>T (p.Thr541Ser), in the FVIII gene. He is doing well with normal Factor VIII levels, without significant bleeding episodes and remains on DDAVP as needed. Case 2 A 7 year old boy with presumed history of type 1 VWD was seen in our clinic for evaluation for a bleeding disorder. He had a history of cephalohematoma after skull fracture, as well as frequent epistaxis. Testing prior to being seen in our clinic showed Von Willebrand factor antigen of 87%, Von Willebrand factor activity of 69%, and Factor VIII activity of 32%. Family history was as reported for his sibling (Case 1). In our clinic, he had genetic testing performed that was not consistent with VWD Type 2N (Normandy phenotype). Repeat labs in our clinic showed Von Willebrand factor antigen of 100%, Von Willebrand factor activity of 92%, and Factor VIII activity of 50%. He was treated with Von Willebrand factor replacement prior to planned foot surgery as well as DDAVP. Subsequent to identification of a FVIII gene mutation in his maternal grandfather and brother, testing revealed he was hemizygous for the same mutation detailed in Case 1. He is doing well with normal Factor VIII levels, no significant bleeding and remains on DDAVP as needed for bleeding. CONCLUSION The c.1621A>T (p.Thr541Ser) variant which occurs in exon 11 of the FVIII gene, has been is known to cause mild hemophilia A. The Thr541Ser substitution is rare and is present in ~0.009% of the NHLBI exome sequencing project. This is a unique case series of siblings with a rare mutation having normal Factor VIII levels and grandfather with similar mutation who was eventually also diagnosed with mild hemophilia A. The underlying gene mutation is an important but not sole determinant of residual FVIII:C in hemophilia A patients. As our understanding of pathophysiologic process of causative genetic event and baseline FVIII:C in patients is limited, this case series highlights the current diagnostic challenges in the mild Hemophilia A population and the importance of appropriate diagnostic techniques to avoid delayed diagnosis. Correct identification of mutations also provides the opportunity to define molecular consequences and identify residues important for factor VIII activity. Disclosures Carpenter: Bayer: Honoraria; Kedrion Biopharmaceuticals: Consultancy; Nationwide Children's Hospital: Speakers Bureau; Kane County State's Attorney: Consultancy; 4th Judicial District Attorney's Office- Colorado: Consultancy; Kedrion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Consultancy; CSL Behring: Speakers Bureau; National Hemophilia Foundation (Impact Education): Speakers Bureau; Genentech Incorporated: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk Pharmaceuticals, Inc: Consultancy; Novo Nordisk: Consultancy.