Familial multiple coagulation factor deficiency (FMCFD) is a rare bleeding disorder, characterized by deficiency of more than one coagulation factor in the same individual. They occur either due to a coincidental inheritance of both the deficiencies1-4 or due to a common molecular event for instance, a deletion involving parts of both the genes specifically in cases where the two genes are not far apart.5 They can also occur in association with the commonest bleeding disorder, von Willebrand disease.6 We report an uncommon case of a combined deficiency of factor VIII (FVIII) and factor IX (FIX) in an Indian family most probably due to a rare phenomenon of de novo factor VIII gene (F8) mutation in a haemophilia B family. The index case (III4) presented with a history of recurrent epistaxis since childhood. He bled profusely during dental extraction and had to be transfused with fresh frozen plasma. The laboratory investigations revealed a prolonged activated partial thromboplastin time (APTT) (Patient: 55.1 seconds, Control: 27.2 seconds) and reduced FVIII and FIX levels that is, FVIII:C: 8 IU/dL and FIX:C: 4.5 IU/dL. Von Willebrand factor (VWF) antigen, factor XI and factor XII levels were normal. Screening for factor VIII and IX inhibitors was negative. Thus, a diagnosis of combined factor VIII and factor IX deficiency was made. DNA was extracted from peripheral blood leucocytes using standard procedure and all 26 exons in F8 and 8 exons in F9 and their flanking intronic regions were sequenced using Big Dye Terminator cycle sequencing kit in ABI 3130XL genetic analyser (Applied Biosystems, Foster City, CA, USA). The index case (III4) showed the presence of two previously reported missense mutations, that is, c.1018G>A (p. Glu340Lys) in exon 8 of F8 and c.316G>A (p.Gly106Ser) in exon 4 of F9. In corresponding international databases, c.1018G>A mutation has been associated with mild HA phenotype in six cases (http://www. factorviii-db.org) whereas c.316G>A mutation has been associated with 1 severe, 2 moderate and 62 mild HB phenotype (http://www. factorix.org/). Subsequently, all the available family members were subjected to both phenotypic and genotypic analysis. The results are shown in Table 1 and Figure 1. As shown in Figure 1, this family shows different haplotypes in different family lineages. Several explanations are possible for this unique laboratory finding in the family. The F9 haplotype analysis as well as the presence of a common F9 mutation in all the family members is suggestive that the family originally is a haemophilia B family. In generation 3 at the level of III4, a de novo F8 mutation might have occurred at the level of grandfather I1 or daughter’s II3 germ cell resulting in a combined deficiency of both F8 and F9 in III4. The other possibility is that the mother of the index case (II3) is homozygous for the F9 mutation and heterozygous for the F8 mutation i.e. one of the X chromosomes carries both the F8 and F9 mutation while the other X chromosome carries only the F9 mutation. However, based on the bleeding history taken from the family, neither she nor the maternal grandparents were bleeders. F8 and F9 haplotype analysis7-9 revealed a difference in the haplotypes of branch ‘III3’ and ‘III6’ from those associated with branch ‘III4’. Recombination is a fairly common event in the telomeric region of the X chromosome with fragile site at Xq27 which is near to F8 and F9 loci.10 Hence, the possibility of a crossover or recombination between F8 and F9 cannot be ruled out which might have taken place in the germ cells of II3 manifesting in III4. The incidence of haemophilia A and B as per the Western literature is 1 in 10 000 and 50 000 live births respectively. About 40% of haemophilia patients have no family history and in most of these cases the mutation arises during male spermatogenesis in the maternal grandfather, leaving only a small fraction of cases with a true “de novo” origin. In India, there is no systematic data on the prevalence but considering the population and male to female birth ratio more than 100 000 severe haemophilia patients are anticipated out of which only around

A de novo factor VIII mutation in a haemophilia B family leading to combined deficiency of factor VIII and IX.

Background: Familial multiple coagulation factor deficiencies (FMCFDs) are a group of inherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management of bleeding/thrombotic episodes vary among patients. The aim of this study was to identify the underlying genetic defect in patients with FMCFDs. Methods: Activity levels were collected from the largest cohort of laboratory-diagnosed FMCFD patients described so far. Genetic analysis was performed using next-generation sequencing. Results: In total, 52 FMCFDs resulted from coincidental co-inheritance of single-factor deficiencies. All coagulation factors (except factor XII (FXII)) were involved in different combinations. Factor VII (FVII) deficiency showed the highest prevalence. The second group summarized 21 patients with FMCFDs due to a single-gene defect resulting in combined FV/FVIII deficiency or vitamin K–dependent coagulation factor deficiency. In the third group, nine patients with a combined deficiency of FVII and FX caused by the partial deletion of chromosome 13 were identified. The majority of patients exhibited bleeding symptoms while thrombotic events were uncommon. Conclusions: FMCFDs are heritable abnormalities of hemostasis with a very low population frequency rendering them orphan diseases. A combination of comprehensive screening of residual activities and molecular genetic analysis could avoid under- and misdiagnosis.

Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients-A Single-Center Experience in Genetic Diagnosis.

We report 2 patients with coinheritance of the X-linked bleeding disorders hemophilia A and hemophilia B. We describe the family pedigrees, clinical features, and genotyping. The case report addresses the key clinical questions of how to manage patients with both hemophilia A and B and how to counsel families regarding recurrence risk. The patients with coinherited hemophilia A and B require a combination of factor VIII and factor IX replacement to achieve hemostasis. We calculated the estimated genomic meiotic recombination frequency between F8 and F9 to be 38%. The findings in these cases are consistent with this calculation. These findings provide critical information for management of families with coinherited hemophilia A and B.

/pdf/the-odds-and-implications-of-coinheritance-of-hemophilia-a-3z3onxc39g.pdf

The odds and implications of coinheritance of hemophilia A and B

Congenital combined bleeding disorders (CBDs) are extremely rare disorders which mainly occur in regions with a high rate of consanguineous marriage. These disorders can present with a variety of symptoms ranging from mucocutaneous bleeding to life-threatening episodes. This study aims to evaluate the prevalence and clinical course of Iranian patients with congenital CBDs. This study is conducted on 450 patients with CBDs who were referred to the Iranian Comprehensive Hemophilia Care Center (ICHCC) between 2010 and 2020. All these patients were diagnosed through evaluation of past medical history and coagulation laboratory investigation. Out of 450 patients, 33 were entered in this study. Having excluded cases with factor (F) V and FVIII deficiency, as well as those with hereditary combined Vitamin K dependent clotting factor deficiency (VKCFD), We found the most common CBDs to be FV-FVII deficiency (n: 6, 18.1%), together with FVII and FX deficiency (n: 6, 18.1%). The most common reason for referral of these patients to ICHCC was postoperative bleeding (14.3%). The mean of The International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) and condensed MCMDM-1VWD bleeding assessment tool were 9.6 ± 4.79 and 9.1 ± 4.87, respectively (P < 0.005). In 10 females of reproductive age, the mean of Pictorial Bleeding Assessment Chart (PBAC) score was 649.3 ± 554. Among all patients, 23 (69.7%) received on-demand replacement therapy, whereas 5 patients (15.1%) received prophylaxis. In Iran, the coinheritance of bleeding disorders is surprisingly higher than expected. Moreover, patients with congenital CBDs may experience serious bleeding manifestations.

https://journals.sagepub.com/doi/pdf/10.1177/1076029621996813

Congenital Combined Bleeding Disorders, a Comprehensive Study of a Large Number of Iranian Patients.

Haemophilia A (FVIII deficiency) and haemophilia B (FIX deficiency) are X-linked inherited bleeding disorders. It is a very rare event to identify both haemophilias in the same patient. So far, only two families with such combination are reported in the literature worldwide supported by genetic background. Patients and methods: Evaluation of clinical data, determination of FVIII and FIX levels and genetic analysis of F8 and F9 genes by direct sequencing. Results: We report on a patient having severe haemophilia B (FIX:C T, p.R75X), whereas F8 gene analysis revealed a point mutation in exon 4 (c.545A>C, p.D182A). The mother of the patient was heterozygous for F8 mutation, but not for F9 mutation suggesting a de novo F9 mutation. Accidentally, further family from Germany with mild Haemophilia A was identified to have the same F8 mutation. F8 Haplotype analysis revealed that the p.D182A mutation most likely represents a founder mutation with common ancestors of the German and the Lithuanian family. Conclusions: Our results confirm the rare event of Haemophilia A and haemophilia B in the same patient originating from two distinct genetic defects in F8 and F9 genes.

Combined coagulation factor VIII and factor IX deficiency (CDF8F9) in a patient from Lithuania.

Lithuanian Hemophilia Register (LHR) was constructed in 1994 under the supervision of Dr. R. Jurgutis in Klaipeda Seamen’s Hospital (Klaipeda, Lithuania). The aims of the register were: 1. to gather data from lithuanian patients suffering from inherited bleeding disorders including hemophilia A (HA), hemophilia B (HB), von Willebrand disease (VWD), rare coagulation factor deficiencies, e.g. FVII deficiency, FX deficiency 2. controlling of infectious diseases (HBV, HCV and HIV) in hemophiliacs, 3. controlling of bleeding and concentrates consumption, 4. identification of molecular defects in corresponding genes, 5. comparison of phenotype-genotype correlation, 6. providing carrier and prenatal diagnosis in affected families [1, 2].

https://link.springer.com/content/pdf/10.1007%2F3-540-27022-1_3.pdf

Lithuanian Hemophilia Register: Update 2003

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Combined coagulation factor VIII and factor IX deficiency (CDF8F9) in a patient from Lithuania.

Lithuanian Hemophilia Register: Update 2003