Comprehensive Pediatric Care of Rare Bleeding Disorders

Muriel Giansily-Blaizot; Jean-François Schved


Pediatr Health. 2010;4(2):209-217. 

In This Article

Genotype: Is Molecular Diagnosis Useful in Common Practice?

As discussed previously, each RBD has an autosomal recessive pattern of inheritance, except for the FXI deficiency, which can mimic a dominant trait since bleeding also occurs in heterozygous individuals. The molecular diagnosis of all RBDs, apart from the FV plus FVIII and VKDC combined deficiencies, is based on the identification of the mutation located within the gene encoding the respective missing factor. The FV plus FVIII deficiency is caused by mutations in two different genes encoding proteins involved in the transportation of both FV and FVIII, namely the leguminous mannose-binding lectin gene (LMAN 1) and the multiple coagulation factor deficiency gene 2 (MCFD 2).[16] VKDC deficiency is caused by mutations located in the genes encoding proteins involved in vitamin K metabolism, namely vitamin K epoxide reductase unit 1 (VKORC1) and γ-glutamyl carboxylase (GGCX).[19,20] Databases available online now provide lists of causative mutations for almost every RBD ( Table 1 ).

The considerable interindividual heterogeneity in bleeding phenotypes is the result of a combination of parameters, including the molecular heterogeneity of the RBD but also other factors, both genetic and environmental. Indeed, no clear genotype–phenotype relationship has emerged between the clinical expression of the deficiency, plasma activity levels of the corresponding missing factor and the respective mutations, whichever RBD is considered. Furthermore, the severity of bleeding can be highly variable, even among patients bearing the same genotype. Therefore, one could consider that the main interest of molecular diagnosis is in the scientific community. Exhaustive genotyping increases the amount of available data on each RBD, which in turn helps to characterize the mutational spectrum, highlighting recurrent mutations within specific geographical areas, and this improves our chances of discovering genotype–phenotype correlations. However, that is partly true, especially for pauci- or asymptomatic patients, but it must be kept in mind that early molecular diagnosis can be useful for severely affected children. When a child manifests severe bleedings of any kind (ICHs, gastrointestinal bleedings or recurrent hemarthroses), they must be considered at risk for further life-threatening bleedings and therefore, prophylactic replacement therapies must be initiated. It is more complicated when a severe RBD is diagnosed in the early days of life owing to 'mild' bleeding features. In those cases, the option of long-term prophylaxis could be supported by molecular biology. Indeed, null mutations, when combined in the homozygous or compound heterozygous state, have been demonstrated, particularly in FVII deficiency, to be associated with a high risk of developing cerebral bleeding within the first few days or weeks of life (reviewed in [21]). The deleterious mutations involved include nonsense mutations, splice-site mutations located in the invariant AG or GT dinucleotides, complete or partial gene deletions and frame-shift or missense mutations occurring on critical residues. In these cases, early identification of the underlying null mutation could be of great interest to individuals in whom a RBD manifests early in life, as this will improve their risk assessment.[22] Therefore, international molecular diagnosis networks should be developed, as DNA samples can easily be transferred to a reference center or research team.

Elsewhere, molecular diagnosis is essential for genetic counseling and prenatal diagnosis. Prenatal diagnosis in the event of a subsequent pregnancy is generally only proposed to families with an affected child who suffers from very severe manifestations, for example, intracerebral hemorrhage or recurrent hemarthroses. Prenatal diagnosis is sometimes considered when both parents are heterozygous carriers of a null mutation where there is a high risk of having a severely affected child.[23] The prenatal diagnosis of several RBDs has already been performed.[24,25]


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