MedGen

Hemophilia A is characterized by deficiency in factor VIII clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor VIII clotting activity. Individuals with severe hemophilia A are usually diagnosed during the first two years of life following oral or soft tissue bleeding either with procedures or due to a known family history of hemophilia. Without prophylactic treatment, individuals may average up to two to five spontaneous bleeding episodes each month including spontaneous joint bleeds or deep-muscle hematomas, and prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions. Individuals with moderate hemophilia A seldom have spontaneous bleeding, although it varies between individuals; however, they do have prolonged or delayed bleeding after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies, usually from once a month to once a year. Individuals with mild hemophilia A do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding episodes varies widely, typically from once a year to once every ten years. Individuals with mild hemophilia A are often not diagnosed until later in life. Approximately 30% of heterozygous females have factor VIII clotting activity below 40% and are at risk for bleeding (even if males in the family are only mildly affected). After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity. In addition, 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency. [from GeneReviews]

Von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age. Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type. Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding. Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include: Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding; Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances; Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding; Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A. Type 3 VWD (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding. [from GeneReviews]

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population. [from GeneReviews]

Von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age. Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type. Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding. Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include: Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding; Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances; Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding; Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A. Type 3 VWD (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding. [from GeneReviews]

Combined deficiency of factor V and factor VIII (F5F8D1) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of factor V (612309) or factor VIII (300840), respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (summary by Zhang and Ginsburg, 2004). Genetic Heterogeneity of Combined Deficiency of Factor V and Factor VIII Another form of combined deficiency of factor V and factor VIII (F5F8D2; 613625) is caused by mutation in the MCFD2 gene (607788) on chromosome 2p21. [from OMIM]

Combined deficiency of factor V and factor VIII type 2 (F5F8D2) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of FV (612309) or FVIII (300841), respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D2 is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (summary by Zhang and Ginsburg, 2004). For a general phenotypic description and a discussion of genetic heterogeneity of F5F8D, see 227300. [from OMIM]

Reduced activity of coagulation factor VIII. Factor VIII (fVIII) is a cofactor in the intrinsic clotting cascade that is activated to fVIIIa in the presence of minute quantities of thrombin. fVIIIa acts as a receptor, for factors IXa and X. [from HPO]