Hemophilia A (HA, due to FVIII deficiency) and hemophilia B (HB, due to FIX deficiency) are the most frequent con genital coagulation diseases (incidence 1:5000 and 1:30,000 in newborn males, respectively). They are transmitted as a recessive X-chromosome-related character and manifest clinically in males. In rare cases, hemophilia may occur in the female: (1) by selective inactivation of the non-mutated X chromosome; (2) in females born from a hemophilic father and a carrier mother; (3) in cases of Turner syndrome (X0) in which the hemophilic gene is mutated. Vice versa, the carrier female is asymptomatic. The characteristics of hemophilia have been known since ancient times. The Talmud, sacred text of Judaism, prescribed to exempt from circumcision boys who had lost a little brother to hemorrhage during the operation; in the eleventh century, the rule was extended to boys born from the same mother but different father, demonstrating the knowledge of the diagenetic transmission of the disease. Hemophilia was made famous by the descendants of Queen Victoria, some of whom were hemophiliacs—sadly known the story of the little Nikolas, son of the last Tsar of Russia, “cured” by Rasputin; famous the story of one of his sisters (escaped the massacre of the Romanovs) who toured the courts of Europe. Only DNA analysis of the remains of members of the Romanov family, found many years after her death, made it possible to establish that she was a braggart.

The diagnosis of hemophilia is suspected based on symptoms (or familiarity) and coagulation tests (normal pro thrombin time [PT] and elongation of activated partial thromboplastin time [aPTT]) and confirmed by analysis of factor VIII and IX activity in plasma. Based on the activity of the deficient factor, hemophilia is classified as A or B and clinically as mild (activity between 5% and 25%), moderate (activity between 1% and 5%), and severe (activity <1 % ). The severe forms of hemophilia, which constitute more than half of the known cases, manifest themselves with hemorrhages that in 10% of the patients appear already in the peri natal period, putting the patient’s survival at risk. The availability of prenatal diagnosis, in the cases in which there is familiarity and the pregnant woman is a carrier, helps to plan the delivery and to face the perinatal complications in the couples that choose to continue the pregnancy after a prenatal diagnosis of hemophilia.

The molecular analysis, in the case of hemophilia, is of little help to the patient (since the diagnosis is made based on traditional coagulation tests) but can identify the carriers (asymptomatic) in the family (mother, sisters, etc.). In fact, in front of a new hemophilic patient, there are two possibilities:

• There are other affected members in the family (Fig. 1), and, in this case, the mutation in the patient has been inherited from the mother (who is an obligate carrier), and the patient’s sisters have a 50% risk of being carriers; in this case, it is helpful to identify the mutation in the patient and assess its presence in the sisters to establish whether they are carriers.

• The patient does not show familiarity (Fig. 2). In this case, the mutation may have been inherited from the mother who is a carrier (and therefore, the sisters are at risk), or the mutation may have arisen de novo in the patient, so that the mother is not a carrier and the sisters are not at risk of being carriers (and it is not necessary to test them for the mutation).

Fig1. Hemophilia: familiarity. (Copyright EDISES 2021. Reproduced with permission)

Fig2. Hemophilia: unfamiliarity. (Copyright EDISES 2021. Reproduced with permission)

The hemophilia A gene includes 26 exons, while the F9 gene that encodes for factor IX includes 8 exons. Both forms of hemophilia are due to a myriad of different mutations, because the X chromosome, where the two genes are located, is much more susceptible to de novo mutations than the other chromosomes. This means that molecular analysis for HB in a new patient must be based on scanning all gene coding regions by sequencing (as shown in the two examples in Fig. 3 showing nonsense and a missense mutation, respectively). For HA, there is a difference between the different forms. One-half of severe HA cases are due to a complex rearrangement involving intron 22, called intron inversion (InvIVS-22), which can be analyzed by long-distance polymerase chain reaction (PCR). Approximately 5% of cases of severe HA have a similar mutation in intron 1 (intron 1 inversion), and the remaining 45–50% of cases, as well as all cases of mild to moderate HA, are due to different mutations involving the entire gene and, therefore, require sequencing analysis.

Fig3. Scanning of the coding regions of the gene by sequencing: (a) nonsense mutation and (b) missense mutation

However, even using sequencing of the entire gene coding region, there is a small percentage (varying from case to case) of hemophilic patients in whom the mutation is not identified. A proportion of these patients may have extensive gene deletions, which may escape sequencing analysis and require quantitative PCR analysis. Even after rearrangement analysis, there is a residual number of hemophilic patients who do not show mutations: about 2% for HB and about 5% for HA. Presumably, these patients have mutations in non- coding areas, even far from the gene.

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المزيد

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Monogenic Causes of Diabetes : Glucokinase MODY

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