 |
|
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of hemophilia B is established in individuals with low factor IX clotting activity. Molecular genetic testing of F9, the gene encoding factor IX, identifies disease-causing mutations in more than 99% of individuals with hemophilia B. Such testing is available clinically.
Management. Treatment of manifestations: referral to one of the approximately 140 federally funded hemophilia treatment centers (HTCs) for assessment, education, and genetic counseling; for those with severe disease, intravenous infusion of plasma-derived or recombinant factor IX concentrate within one hour of onset of bleeding. Training and home treatment with parental- followed by self-infusion are critical components of comprehensive care. Prevention of primary manifestations: For those with severe disease, prophylactic infusions of factor IX concentrate two to three times a week usually maintain factor IX clotting activity higher than 1% and prevent spontaneous bleeding. Prevention of secondary complications: reduction of chronic joint disease by prompt effective treatment of bleeding, including home therapy. Surveillance: For individuals with severe or moderately severe hemophilia B, annual assessments at an HTC are recommended; for individuals with mild hemophilia B, every two to three years; monitor carrier mothers for delayed bleeding post partum unless it is known that their baseline factor IX clotting activity is normal. Agents/circumstances to avoid: circumcision of at-risk males until hemophilia B is either excluded or treated with factor IX concentrate regardless of severity; intramuscular injections; activities with a high risk of trauma, particularly head injury; aspirin and all aspirin-containing products. Testing of relatives at risk: to clarify genetic status of females at risk before pregnancy or early in pregnancy, to facilitate management. Other: Vitamin K does not prevent or control bleeding in hemophilia B; no clinical trials for gene therapy in hemophilia B are currently in progress although several improved approaches are in pre-clinical testing.
Genetic counseling. Hemophilia B is inherited in an X-linked manner. The risk to sibs of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the F9 mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers. Affected males transmit the mutation to all of their daughters and none of their sons. Carrier testing for family members at risk and prenatal testing for pregnancies at increased risk are possible if the F9 disease-causing mutation has been identified in a family member or if informative intragenic, linked markers have been identified.
The diagnosis of hemophilia B cannot be made on clinical findings. A coagulation disorder is suspected in individuals with any of the following:
Hemarthrosis, especially with mild or no antecedent trauma
Deep-muscle hematomas
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
Prolonged bleeding or renewed bleeding following surgery or trauma *
Unexplained GI bleeding or hematuria *
Menorrhagia, especially at menarche *
Prolonged nosebleeds, especially recurrent and bilateral *
Excessive bruising, especially with firm, subcutaneous hematomas
* Any severity; otherwise, especially in more severely affected persons
Coagulation screening tests. Evaluation of an individual with a suspected bleeding disorder includes: platelet count and bleeding time or platelet function analysis (PFA closure times), activated partial thromboplastin time (APTTf), and prothrombin time (PT). Thrombin time and/or plasma concentration of fibrinogen can be useful for rare disorders.
In individuals with hemophilia B, the above screening tests are normal, with the following exceptions:
In severe and moderately severe hemophilia B, the APTT is prolonged.
In mild hemophilia B, the APTT may be normal.
Note: In many clinical laboratories, the APTT is not sensitive enough to diagnose a mild bleeding disorder.
Coagulation factor assays. Individuals with a history of a lifelong bleeding tendency should have specific coagulation factor assays performed, even if all the coagulation screening tests are in the normal range:
The normal range for factor IX clotting activity is approximately 50%-150% [Khachidze et al 2006].
Individuals with factor IX clotting activity higher than 30% usually have normal coagulation in vivo. However, some increased bleeding can occur with low to low-normal factor IX clotting activity in hemophilia B carrier females [Plug et al 2006].
In hemophilia B, the factor IX clotting activity is usually less than 30%.
Classification of hemophilia B based on in vitro clotting activity:
Severe hemophilia B: <1% factor IX
Moderately severe hemophilia B: 1%-5% factor IX
Mild hemophilia B: >5%-30% factor IX
Coagulation factor assays. Approximately 10% of carrier females have a factor IX clotting activity below 30%, regardless of the severity of hemophilia B in the family. Bleeding may also be more severe in those with low-normal factor VIII activity [Plug et al 2006].
Note: Normal factor IX clotting activity is found in most carriers and thus cannot be used to determine carrier status.
Gene. F9 is the only gene known to be associated with hemophilia B.
Clinical testing
Sequence analysis. Sequence analysis of F9 can identify a mutation in more than 99% of individuals with hemophilia B. Direct sequencing is the usual approach, although several screening strategies have been used [Mitchell et al 2005]. In some instances, it is appropriate to include F9 promoter mutations that cause hemophilia B Leyden, an uncommon variant that results from one of several mutations from base pairs -23 through +13 (see Genotype-Phenotype Correlations, Locus-Specific Database). In males, a presumptive diagnosis of a large or partial gene deletion occurs from failure to amplify one or more exon fragments.
Deletion/duplication analysis can detect and/or confirm exonic, multi-exonic, or complete F9 gene deletions in males with severe hemophilia B, or in carrier females.
Guidelines for laboratory practice for molecular analysis of F9 have been established in the UK [Mitchell et al 2005].
Note: Mutation scanning and sequence analysis cannot detect gene deletions and rearrangements in females.
| Test Method | Mutations Detected | Mutation Detection Frequency by Test Method 1 | Test Availability |
|---|---|---|---|
| Sequence analysis | F9 sequence variants 2 | 97% 3 | Clinical
 |
| Deletion analysis | F9 exonic and large gene deletions | 3% 4 |
1. Refers to affected males
2. Includes ~1% with hemophilia B Leyden with specific 5' base substitutions in an "androgen-responsive element" in which the bleeding tendency becomes milder after puberty
3. Somatic mosaicism is likely more common in hemophilia B than in hemophilia A and could lower the mutation detection frequency in males with hemophilia B [Leuer et al 2001].
4. In males, a deletion is presumed to be present when one or more exon fragments fail to amplify with PCR; detection of a deletion in a female carrier may require linkage analysis, breakpoint analysis, or other appropriate testing methods that detect gene dosage alterations.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Linkage analysis is used to track an unidentified F9 disease-causing allele in a family and to identify the origin of de novo mutations:
Tracking an unidentified F9 mutation. When a disease-causing mutation of the F9 gene is not identified in an affected family member by direct DNA testing, linkage analysis can be considered to obtain information for genetic counseling in families in which more than one family member has the unequivocal diagnosis of hemophilia B. Linkage studies are always based on accurate clinical diagnosis of hemophilia B in the affected family members and accurate understanding of the genetic relationships in the family. In addition, linkage analysis depends on the availability and willingness of family members to be tested and on the presence of informative heterozygous polymorphic markers. The markers used for hemophilia B linkage are intragenic and are informative with greater than 99% accuracy in approximately 95% of African American families, 85%-90% of Caucasian families, and 60% of Asian/Native American families with hemophilia B [Bajaj & Thompson 2006].
Identifying the origin of a de novo mutation. Among the nearly 50% of families with a simplex case of hemophilia B (i.e., occurrence in one family member only), the origin of a de novo mutation can often be identified by performing molecular genetic testing in conjunction with linkage analysis. The presence of the mutation on the affected individual's factor IX haplotype is tracked back through the parents and, if necessary, through maternal grandparents to identify the individual in whom the mutation originated.
Establishing the diagnosis of hemophilia B in a proband requires measurement of factor IX clotting activity.
Molecular genetic testing is performed on a proband to detect the family-specific mutation in F9 in order to obtain information for genetic counseling of at-risk family members.
For prognostication in individuals who represent a simplex case, identification of the specific F9 mutation can help predict the clinical phenotype and assess the risk of developing a factor IX inhibitor.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.
Note: Carriers are heterozygotes for an X-linked disorder and may develop clinical findings related to the disorder.
Prenatal diagnosis and preimplantation diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
No other phenotypes are associated with mutations in F9.
Hemophilia B in the untreated individual is characterized by prolonged oozing after injuries, tooth extractions, or surgery or renewed bleeding after initial bleeding has stopped [Kessler & Mariani 2006]. Muscle hematomas or intracranial bleeding can occur immediately or up to four to five days after the original injury. Intermittent oozing may last for days or weeks after tooth extraction. Prolonged or delayed bleeding or wound hematoma formation after surgery is common. After circumcision, males with hemophilia B of any severity may have prolonged oozing, or they may heal normally. In severe hemophilia B, spontaneous joint bleeding is the most frequent symptom.
Individuals with severe hemophilia B are usually diagnosed during the first year of life. On rare occasions, infants with severe hemophilia have extra- or intracranial bleeding following birth. In untreated toddlers, bleeding from minor mouth injuries and large "goose eggs" from minor head bumps are common; these are the most frequent presenting symptoms of severe hemophilia B. Intracranial bleeding may also result from head injuries. The untreated child almost always has subcutaneous hematomas; some have been referred for evaluation of possible non-accidental trauma.
As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and young adults with severe hemophilia B who are not treated have an average of two to five spontaneous bleeding episodes each month. Joints are the most common sites of spontaneous bleeding; other sites include the muscles, kidneys, gastrointestinal tract, brain, and nose. Without prophylactic treatment, individuals with hemophilia B have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.
Individuals with moderately severe hemophilia B seldom have spontaneous bleeding. However, without treatment they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years. Without treatment, the frequency of bleeding episodes varies from once a month to once a year. Signs and symptoms of bleeding are the same as for severe hemophilia B.
Individuals with mild hemophilia B do not have spontaneous bleeding. However, without treatment, abnormal bleeding occurs with surgery, tooth extractions, and major injuries. The frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia B are often not diagnosed until later in life when they undergo surgery or tooth extraction or experience major trauma.
Carrier females with a factor IX clotting activity level lower than 30% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activities between 30% and 60% [Plug et al 2006].
| Clinical Severity | Factor IX Clotting Activity 1 | Symptoms | Usual Age of Diagnosis |
|---|---|---|---|
| Severe | <1% | Frequent spontaneous bleeding; excessive and/or prolonged bleeding after minor injuries, surgery, or tooth extractions | 1st year of life |
| Moderately severe | 1%-5% | Spontaneous bleeding rare; excessive and/or prolonged bleeding after minor injuries, surgery, or tooth extractions | Before age 5-6 years |
| Mild | >5%-30% | No spontaneous bleeding; excessive and/or prolonged bleeding after major injuries, surgery, or tooth extractions | Often later in life |
1. Clinical severity does not always correlate with the in vitro assay result.
Complications of untreated bleeding. The leading cause of death related to bleeding is intracranial hemorrhage. The major cause of disability from bleeding is chronic joint disease [Luck et al 2004]. Currently available treatment with clotting factor concentrates is normalizing life expectancy and reducing chronic joint disease for children with hemophilia B. Prior to the availability of such treatment, the median life expectancy for individuals with severe hemophilia B was 11 years — the current life expectancy for affected individuals in several developing countries. Excluding death from HIV, life expectancy for those severely affected individuals receiving adequate treatment is 63 years [Darby et al 2007].
Other. Many affected individuals who received blood products from 1979 to 1985 contracted HIV. Approximately half of these individuals died of AIDS before the advent of effective HIV therapy.
Most affected individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of the hepatitis C virus. Viral inactivation and detection methods developed in the 1980s have essentially eliminated this complication. A recombinant factor IX concentrate that is free of human or animal plasma proteins and viral contaminants is available [Shapiro et al 2005, Kessler & Mariani 2006].
Approximately 3% of individuals with severe hemophilia B develop alloimmune inhibitors to factor IX. These individuals usually have partial or complete gene deletions or certain nonsense mutations (see Locus-Specific Database). At times, the onset of an alloimmune response has been associated with anaphylaxis to transfused factor IX [DiMichele 2007].
Large gene deletions, nonsense mutations, and most frameshift mutations cause severe disease. Missense mutations can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved (see Locus-Specific Database).
Uncommon variants within the carboxylase binding domain of the propeptide cause an increased sensitivity to warfarin anticoagulation in individuals without any baseline bleeding tendency [Bajaj & Thompson 2006] (see Management).
In hemophilia B Leyden, severity decreases after puberty; mild disease disappears and severe disease becomes mild, depending on the specific mutation.
All males with a disease-causing mutation are affected and will have hemophilia B of approximately the same severity as all other affected males in the family; however, other genetic and environmental effects may modify the clinical severity to some extent.
Approximately 10% of females with one F9 disease-causing mutation and one normal allele have a mild bleeding disorder.
Anticipation is not observed.
The birth prevalence of hemophilia B is approximately one in 20,000 live male births worldwide.
The birth prevalence is the same in all countries and all races, presumably because of the high spontaneous mutation rate of the F9 gene and its presence on the X chromosome.
Prevalence is approximately one in 25,000 in the US and other countries in which optimum treatment with clotting factor concentrates is available [Kessler & Mariani 2006].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
When an individual presents with bleeding or the history of being a "bleeder," the first task is to determine if he/she truly has abnormal bleeding. "Bleeding a lot" during or immediately after major trauma or after a tonsillectomy or for a few hours following tooth extraction may not be significant. On the other hand, prolonged or intermittent oozing that lasts several days following tooth extraction or mouth injury, renewed bleeding or increased pain and swelling several days after an injury, or development of a wound hematoma several days after surgery almost always indicates a coagulation problem. A careful history of bleeding episodes can help determine if the individual has a lifelong, inherited bleeding disorder or an acquired (often transient) bleeding disorder.
Physical examination provides few specific diagnostic clues. An older individual with severe or moderately severe hemophilia B may have joint deformities and muscle contractures. Large bruises and subcutaneous hematomas for which no trauma can be identified may be present, but individuals with a mild bleeding disorder have no outward signs except during an acute bleeding episode. Petechial hemorrhages indicate severe thrombocytopenia and are not a feature of hemophilia B.
A family history with a pattern of autosomal dominant, autosomal recessive, or X-linked inheritance provides clues to the diagnosis but is not definite. At least 10% of women who carry hemophilia B of any severity have low enough factor IX activity levels to have mild bleeding themselves, which in some families may erroneously suggest autosomal rather than X-linked inheritance.
Hemophilia B is only one of several lifelong bleeding disorders, and coagulation factor assays are the main tools for determining the specific diagnosis. Other bleeding disorders associated with a low factor IX clotting activity include the following:
Combined vitamin K-dependent factor deficiencies (prothrombin and factors VII, IX, and X and proteins C and S), usually caused by aγ-carboxylase deficiency [ Zhang & Ginsburg 2006]
Common acquired deficiencies of these factors in individuals with vitamin K disorders, including warfarin treatment or liver disease
Other bleeding disorders with normal factor IX levels include the following:
Hemophilia A is clinically indistinguishable from hemophilia B. Diagnosis is based on a factor VIII clotting activity level lower than 35% in the presence of a normal von Willebrand factor (vWF) level. Mutations in F8 are causative. Inheritance is X-linked.
von Willebrand disease type 1 or type 2 (type 1 and type 2 VWD) is characterized predominantly by mucous membrane bleeding. Eighty percent of individuals with VWD have a quantitative deficiency of von Willebrand factor (low vWF antigen, factor VIII activity, and ristocetin cofactor activity). Essentially all individuals with hemophilia B have a normal vWF level and a normal factor VIII activity. VWD types 2A and 2B are characterized by a qualitative deficiency of vWF, with a decrease of the high molecular weight multimers. vWF antigen and factor VIII clotting activity may be low-normal to mildly decreased. Functional vWF level is low in a ristocetin cofactor assay. Inheritance of VWD is autosomal dominant with the exception of some variants including 2N, which is autosomal recessive.
Severe (type 3) von Willebrand disease (type 3 VWD) is characterized by frequent episodes of mucous membrane bleeding and joint and muscle bleeding similar to that seen in individuals with hemophilia B. The vWF level is lower than 1% and the factor VIII clotting activity level is 2%-8%. Inheritance is autosomal recessive.
Factor XI deficiency [Thompson 2006] is inherited in an autosomal manner with heterozygotes showing a factor XI coagulant activity level of 25% to 75% of normal, while homozygotes have activity of less than 1% to 15%, depending on their genotype. Two mutations are common among individuals of Ashkenazi Jewish descent. Both compound heterozygotes and homozygotes may exhibit bleeding similar to that seen in mild or moderately severe hemophilia B. Specific factor assays establish the diagnosis.
Factor XII, prekallekrein, or high-molecular-weight kininogen deficiencies do not cause clinical bleeding, but can cause a long APTT.
Prothrombin (factor II), factor V, factor X, and factor VII deficiency are rare bleeding disorders inherited in an autosomal recessive manner. Affected individuals may display easy bruising and hematoma formation, epistaxis, menorrhagia, and bleeding after trauma and surgery. Hemarthroses are uncommon. Spontaneous intracranial bleeding can occur. Factor VII deficiency should be suspected if the PT is prolonged with a normal APTT. Individuals with factors II, V, or X deficiency usually have prolonged PT and APTT, but specific factor assays establish the diagnosis of these rare bleeding tendencies.
Fibrinogen disorders [Thompson 2006] include severe, mild, and asymptomatic variants:
Congenital afibrinogenemia is a rare disorder inherited in an autosomal recessive manner with manifestations similar to those observed in hemophilia B, except that bleeding from minor cuts is prolonged because of the lack of fibrinogen to support platelet aggregation.
Hypofibrinogenemia can be inherited in either an autosomal dominant or autosomal recessive manner and is usually asymptomatic but may be combined with dysfibrinogenemia.
Dysfibrinogenemia is inherited in an autosomal dominant manner. Individuals with hypofibrinogenemia or dysfibrinogenemia have mild-to-moderate bleeding symptoms or may be asymptomatic; some individuals with dysfibrinogenemia are at risk for venous thrombosis. Diagnosis is based on kinetic and antigenic protein levels, although the thrombin time is usually prolonged and is a simple screening test.
Factor XIII deficiency [Thompson 2006] is a rare autosomal recessive disorder. Umbilical stump bleeding is common (>80% of individuals). Intracranial bleeding that occurs spontaneously or following minor trauma occurs in 30% of affected individuals. Subcutaneous hematomas, muscle hematomas, defective wound healing, and recurrent spontaneous abortion are also seen. Joint bleeding is rare. All the kinetic coagulation screening tests are normal; a specific test for clot solubility must be performed.
Platelet function disorders cause bleeding problems similar to those seen in individuals with thrombocytopenia. Affected individuals have skin and mucous membrane bleeding, recurring epistaxis, gastrointestinal bleeding, menorrhagia, and excessive bleeding during or immediately after trauma and surgery. Joint, muscle, and intracranial bleeding are rare.
Bernard-Soulier syndrome, inherited in an autosomal recessive manner, involves the vWF receptor, platelet GPIb.
Glanzmann's thrombasthenia, also autosomal recessive, involves the GPIIb-IIIa receptor necessary for platelet aggregation. Abnormal platelet function is usually associated with a prolonged bleeding time or prolonged closure times on platelet function analysis.
To establish the extent of disease in an individual diagnosed with hemophilia B, the following evaluations are recommended:
Identifying the individual's F9 mutation to aid in determining disease severity, the likelihood of inhibitor development, and the risk of anaphylaxis if an inhibitor does develop
A personal and family history of bleeding to help predict severity
A joint and muscle evaluation, particularly if the individual describes a past hemarthrosis or muscle hematoma
Screening for hepatitis A, B, and C and HIV, particularly if blood products or plasma-derived clotting factors have been used
Baseline CBC and platelet count, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding, or, in women, menorrhagia
Life expectancy for individuals with hemophilia B has greatly increased over the past four decades [Darby et al 2007; disability has decreased with the intravenous infusion of factor IX concentrates, home infusion programs, prophylactic treatment, and improved patient education.
Individuals with hemophilia B benefit from referral for assessment, education, and genetic counseling at one of the approximately 140 federally funded hemophilia treatment centers (HTCs) that can be located through the National Hemophilia Foundation. The treatment centers establish appropriate treatment plans and referrals or direct care for individuals with inherited bleeding disorders. They are also a resource for current information on new treatment modalities for hemophilia. An assessment at one of these centers usually includes extensive patient education, genetic counseling, and laboratory testing.
Intravenous infusion of factor IX concentrate. A recombinant factor IX concentrate that has no human- or animal-derived proteins is available [Kessler & Mariani 2006]. Virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV transmission since 1985, and of hepatitis B and C viruses since 1990.
Bleeding episodes are controlled rapidly after intravenous infusions of factor IX concentrate. Fast, effective treatment of bleeding episodes prevents pain, disability, and chronic joint disease. Ideally, the affected individual should receive clotting factor within an hour of noticing symptoms or trauma. Knowing the previous in vivo recovery of a patient with hemophilia B helps estimate the proper dose [Bjorkman et al 2007]:
Arranging efficient, effective treatment for infants and toddlers is especially challenging. Because frequent venipunctures may be necessary, it is important to identify staff members who are expert in performing venipunctures in small children.
It is recommended that the parents of children age two to five years with severe hemophilia B be trained to administer the infusions as soon as is feasible. Home treatment allows for prompt treatment after symptoms occur.
Obstetrical issues [Lee et al 2006]. It is recommended that the carrier status of a woman at risk be established prior to pregnancy or as early in a pregnancy as possible. In some carriers, postpartum hemorrhage has been a prominent feature, despite the absence of menorrhagia [Yang & Ragni 2004].
At birth or in the early neonatal period, intracranial hemorrhage is uncommon (<1%-2%), even in males with severe hemophilia who are delivered vaginally. Cesarean section is reserved for complicated deliveries.
If the mother is a symptomatic carrier (i.e., has a baseline factor IX clotting activity below ~30%), she may be at risk for excessive bleeding, particularly post partum, and may require therapy with factor IX concentrate [Yang & Ragni 2004].
Pediatric issues [Chalmers et al 2005]. Special considerations for care of infants and children with hemophilia B include the following:
Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure to prevent delayed oozing and poor wound healing.
Intramuscular injections should be avoided; immunizations should be administered subcutaneously.
Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children.
Inhibitors. Inhibitors greatly compromise the ability to manage bleeding episodes but are seen in only 1%-3% of patients with severe hemophilia B [Hay et al 2006]. Their onset can be associated with anaphylactic reactions to factor IX infusion and nephrotic syndrome [DiMichele 2007].
Children with severe hemophilia B are often given "primary" prophylactic infusions of factor IX concentrate two to three times a week to maintain factor IX clotting activity above 1%; these infusions prevent spontaneous bleeding and decrease the number of bleeding episodes. As shown for hemophilia A [Manco-Johnson et al 2007], prophylactic infusions almost completely eliminate spontaneous joint bleeding, decreasing chronic joint disease, although complications of venous access ports in young children can occur.
Prevention of chronic joint disease is a major concern. Controversy still exists as to whether all individuals with severe hemophilia B benefit from primary prophylaxis and, especially, whether the benefits of primary prophylaxis justify the risk of an indwelling venous catheter in a young individual.
"Secondary" prophylaxis is often used for several weeks, even in adults, if recurrent bleeding in a "target" joint or synovitis occurs.
Persons with hemophilia followed by HTCs (see Resources) have lower mortality than those who are not [Soucie et al 2000]. It is recommended that young children with severe or moderately severe hemophilia B have assessments at an HTC (accompanied by the parents) every six to 12 months to review and evaluate signs and symptoms of possible bleeding episode and to adjust treatment as needed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, and a discussion of any other problems related to the individual's hemophilia and family and community support.
Screening for alloimmune inhibitors is usually done in those with severe hemophilia B after treatment with factor IX concentrates has been initiated either for bleeding or prophylaxis; additional screening is usually performed up to a few years of age when the genotype is a large partial or complete gene deletion or a nonsense mutation at p.Arg29X (c.85C>T) (see Normal allelic variants and Normal gene product for reference sequences). Testing for inhibitors should also be performed in any hemophilic patient whenever a suboptimal clinical response to treatment is suspected, regardless of severity; with hemophilia B, the onset may be heralded by an allergic reaction to infused factor IX concentrate.
Older children and adults with severe or moderately severe hemophilia B benefit from contact with an HTC (see Resources) and periodic assessments to review bleeding episodes and treatment plans, evaluate joints and muscles, screen for an inhibitor, perform viral testing if indicated, provide education, and discuss other issues relevant to the individual's hemophilia.
Individuals with mild hemophilia B can benefit by maintaining a relationship with an HTC and having regular assessments every two to three years.
Avoid the following:
Activities that involve a high risk of trauma, particularly head injury
Aspirin and all aspirin-containing products
Cautious use of other medications and herbal remedies that affect platelet function is indicated.
Identification of at-risk relatives. A thorough family history may identify other male relatives who are at risk but have not been tested (particularly in families with mild hemophilia B).
Note: (1) The cord blood for factor IX clotting activity assay should be drawn into a syringe containing one-tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. (2) Factor IX clotting activity in cord blood in a normal-term newborn is lower than in adults (mean: ~30%; range: 15%-50%); thus, the diagnosis of hemophilia B can be established in an infant with activity lower than 1%, but is equivocal in an infant with moderately low (15%-20%) activity.
Determination of genetic status of females at risk. Approximately 10% of carriers have factor IX clotting activity lower than 30% and may have abnormal bleeding themselves. In a recent Dutch survey of hemophilia carriers, bleeding symptoms correlated with baseline factor clotting activity; there was suggestion of a very mild increase in bleeding even in those with 40% to 60% factor IX clotting activity [Plug et al 2006]. Therefore, all daughters and mothers of an affected male and other at-risk females should have a baseline factor IX clotting activity assay to determine if they are at increased risk for bleedingf unless they are known on the basis of molecular genetic testing to be non-carriers.
It is recommended that the carrier status of a woman at risk be established prior to pregnancy or as early in a pregnancy as possible.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
A preparation in which recombinant factor IX is fused to a portion of the immunoglobulin Fc protein shows prolonged survival and efficacy in animal models [Peters & Bitonti 2007]; clinical trials are planned but have not yet been initiated.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Clinical trials for gene therapy in hemophilia B have been discontinued because of complications and failure to achieve significant factor IX expression in humans with hemophilia B. The hemophilia community remains hopeful, but many obstacles must be overcome before new trials will begin [Pierce et al 2007].
Vitamin K does not prevent or control bleeding caused by hemophilia B. The prothrombin complex concentrates should be used cautiously (if at all) because of the risk of thrombosis.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Hemophilia B is inherited in an X-linked manner.
Parents of a male proband
The father of an affected male will not have the disease nor will he be a carrier of the mutation.
Women who have an affected son and one other affected relative in the maternal line are obligate carriers.
If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she has germline mosaicism.
Approximately 50% of affected males have no family history of hemophilia B. If an affected male represents a simplex case (an affected male with no family history of hemophilia), several possibilities regarding his mother's carrier status and the carrier risks of extended family members need to be considered:
The mother is not a carrier and the affected male has a de novo disease-causing mutation
The mother is a carrier of a de novo disease-causing mutation that occurred in one of the following ways:
As a "germline mutation" (i.e., in the egg or sperm at the time of her conception, and thus present in every cell of her body and detectable in her DNA)
As a somatic mutation (i.e., a change that occurred very early in embryogenesis, resulting in somatic mosaicism, in which the mutation is present in some but not all cells and may be detectable in leukocyte DNA in ≤11% of families) [Ketterling et al 1999]
As "germline mosaicism" (in which some germ cells have the mutation and some do not, and the mutation is not detectable in DNA from her leukocytes)
The mother is a carrier and has inherited the disease-causing mutation either from her mother who has a de novo disease-causing mutation or from her asymptomatic father who is mosaic for the mutation.
The mother is a carrier of a mutation arising in a previous generation that has been passed on through the family without manifesting symptoms in female carriers.
Direct DNA testing combined with linkage analysis can often determine the point of origin of a de novo mutation [Sommer et al 2001]. Determining the point of origin of a de novo mutation is important for determining which branches of the family are at risk for hemophilia B.
Sibs of a male proband
The risk to the sibs depends on the mother's carrier status. If the proband's mother is a carrier, each male sib has a 50% chance of having hemophilia B and each female sib has a 50% chance of being a carrier.
Germline mosaicism is possible, albeit uncommon. Thus, if an affected male represents a simplex case and if his mother has normal factor IX clotting activity and no evidence of her son's F9 disease-causing mutation in DNA from her leukocytes, she is still at a theoretically increased (but low) risk of having additional affected children.
All sibs should have factor IX clotting activity assayed unless mutation analysis confirms that they have not inherited the F9 mutation present in their family.
Offspring of a male proband
All daughters will be carriers for hemophilia B of the same severity as their father's hemophilia.
No sons will inherit the mutant allele, have hemophilia B, or pass it on to their offspring.
Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).
Carrier testing by molecular genetic testing is clinically available for most at-risk females if the mutation has been identified in the family.
Large-deletion mutations are not detectable by sequence analysis in females.
When carrier testing is performed on an at-risk relative without the previous identification of the F9 mutation in the family, a negative result does not necessarily exclude a potential carrier.
Factor IX clotting activity is not a reliable test for determining carrier status; it can only be suggestive, if low.
See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
See Ludlam et al 2005 for published guidelines for a UK framework for genetic services and Thomas et al 2007 for findings of a qualitative study in Australia on how cultural and religious issues influenced parental attitudes about genetic testing.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future diagnostic purposes. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Molecular genetic testing. Prenatal testing is available for pregnancies of women who are carriers if the mutation has been identified in a family member or if linkage has been established in the family. The usual procedure is to determine fetal sex by performing chromosome analysis of fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15-18 weeks' gestation. If the karyotype is 46,XY, DNA extracted from fetal cells can be analyzed for the known F9 disease-causing mutation or for the informative markers.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Percutaneous umbilical blood sampling (PUBS). If the disease-causing F9 mutation is not known and if linkage is not informative, prenatal diagnosis is possible using a fetal blood sample obtained by PUBS at approximately 18-21 weeks' gestation for assay of factor IX clotting activity. (Factor IX clotting activity in a 20-week fetus averages 10% [range 6%-14%]; thus, the diagnosis of hemophilia B can be established if factor IX clotting activity is less than 1%, but is equivocal when activity is moderately low.)
Requests for prenatal testing for conditions such as hemophilia B that do not affect intellect and for which treatment is available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| F9 | Xq27.1-q27.2 | Coagulation factor IX | Hemobase: Hemophilia B mutation registry Haemophilia B mutation database F9 @ LOVD |
F9 |
Normal allelic variants: The normal F9 gene (reference sequence NM_000133.2) is 34 kb in length and has eight exons. Normal variants are uncommon in the F9 gene, but several have been identified [Mitchell et al 2005, Bajaj & Thompson 2006, Khachidze et al 2006].
Normal allelic variants (and their dbSNP identifier) that are useful for linkage analysis include an MseI site 5' (rs378815) and an HhaI site (rs3117459) 3' to the gene in all populations, a 50-bp intron 1 insert and an exon 6 MnlI site (rs6048) in blacks and whites, a 5' BamHI (rs4149657) and an intron 4 MspI (rs408567) site in blacks, and an intron 1 transition in Asians and Native Americans. The MnlI site is the only known exonic polymorphism and codes for Thr at codon 148* or, less frequently, Ala, and is in strong linkage disequilibrium with a TaqI site (rs398101) in intron 4; however, they are not polymorphic in East Asians or Native Americans. See Locus-Specific Database, Bajaj & Thompson 2006, Khachidze et al 2006.
* Assuming the initiating Met is the first of three within the first seven codons of the signal peptide, this would be residue 194 in the translated protein.
Pathologic allelic variants: Severe hemophilia B is caused by gross gene alterations, frameshift or splice junction changes, or nonsense or missense mutations. Mild or moderately severe hemophilia B is predominantly associated with missense changes (see Locus-Specific Database). Occasionally, individuals with severe hemophilia B have exonic, multi-exonic, or complete F9 gene deletions. Mild to moderately severe hemophilia is most often caused by missense mutations. Approximately half of the missense mutations are recurrent, and some clearly represent founder effects (see Locus-Specific Database).
Normal gene product: The factor IX gene product (reference sequence NP_000124.1) includes several distinct domains [Bajaj & Thompson 2006]. The first and second domains are a signal peptide and a propeptide (respectively) that are cleaved to yield the mature protein, which is secreted as a single-chain peptide with 415 amino acid residues. Post-translational modifications include glycosylation, sulfation, phosphorylation,β-hydroxylation, and γ-carboxylation. A γ-carboxylase binds to the propeptide before cleavage and, in a vitamin K-dependent step, converts the first 12 glutamic acid residues (near the amino-terminus) to γ-carboxyglutamic residues or Gla. This Gla domain then binds calcium ions and adopts a conformation capable of binding to a phospholipid surface where the clotting cascade occurs. Adjacent to the Gla domain are two domains homologous with epidermal growth factor. The next domains are a connecting sequence that includes the activation peptide, and finally the catalytic domain. The latter is typical of serine proteases. Crystal structures are consistent with other data that show the catalytic domain elevated above a lipid surface. Factor IX is homologous with clotting factors VII and X and protein C.
Factor IX is synthesized in hepatocytes and circulates as a zymogen at 90 nmol/L (5µg/mL). During coagulation in vivo, it is activated by factor VIIa-tissue factor in a reaction in which the activation peptide is cleaved. Activated factor IX is the intrinsic factor X activator, requiring its cofactor, activated factor VIII, a lipid surface, and calcium. Sites of interaction of the active enzyme and cofactor are being identified [Bajaj & Thompson 2006]. Factor X activation is a critical early step that can regulate the overall rate of thrombin generation in coagulation.
Abnormal gene product: Different genotypes are associated with either absolute or relative lack of factor IX protein. Several missense mutations are associated with dysfunctional protein (see Locus-Specific Database).
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Cheryl L Brower, RN, MSPH (2008-present)
Frank K Fujimura, PhD, FACMG; GMP Genetics, Inc, Waltham (2000-2003)
Maribel J Johnson, RN, MA (2000-2008)
Arthur R Thompson, MD, PhD (2000-present)
8 April 2008 (me) Comprehensive update posted to live Web site
17 August 2005 (me) Comprehensive update posted to live Web site
11 May 2004 (cd) Revision: molecular genetic testing table
8 May 2003 (me) Comprehensive update posted to live Web site
2 October 2000 (me) Review posted to live Web site
August 2000 (at) Original submission
