Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome

Chan, Vivian; Yip, B.; Chim, Chor Sang; Chan, T. K.

doi:10.1002/(sici)1096-8652(199805)58:1<72::aid-ajh13>3.0.co;2-7

Cited by 10 publications

(6 citation statements)

References 18 publications

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“…Nonrandom X inactivation was reported in occasional females with clinical manifestations of various X-linked diseases, such as Fabry disease [Ropers et al, 1977;Redonnet-Vernhet et al, 1996], Duchenne muscular dystrophy [Richards et al, 1990;Lupski et al, 1991;Azofeifa et al, 1995], hemophilia B [Schroder et al, 1997;Chan et al, 1998], and Wiscott-Aldrich syndrome [Parolini et al, 1998]. These females were chromosomally normal as was the case in the woman we described and presumably had a mutant copy of the gene for these disorders on an X chromosome that was active in most of their cells.…”

Section: Discussionsupporting

confidence: 53%

B�rjeson-Forssman-Lehmann syndrome in a woman with skewed X-chromosome inactivation

et al. 1999

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Börjeson-Forssman-Lehmann (BFL) syndrome is an X-linked recessive disorder characterized by minor facial anomalies, obesity, epilepsy, and severe mental retardation. The phenotype of male patients is usually severe, whereas that of carriers is less severe, suggesting X-linked incompletely recessive inheritance. A recent linkage study mapped the BFL syndrome gene to Xq26-q27. The etiology of the condition in female patients with full manifestations is not known, although nonrandom X-chromosome inactivation has been considered. We recently developed an assay for X-inactivation studies based on the methylation-specific polymerase chain reaction (PCR) technique. Using the methylation-specific PCR assay, a woman with typical findings of this syndrome was shown to have an extremely skewed X-inactivation pattern. This finding suggests that the full manifestations of the BFL syndrome in carriers may be caused by skewed X inactivation with a high proportion of cells in which the X chromosome with a normal gene be inactivated, leaving the X chromosome with a mutant gene active.

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Section: Discussionsupporting

confidence: 53%

B�rjeson-Forssman-Lehmann syndrome in a woman with skewed X-chromosome inactivation

et al. 1999

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“…Missense changes involving the Cysteine–Alanine–Glycine residues either of the other serine proteases of the coagulation system or of F11 have been described. 28–38 Therefore, we speculated that p.Ala561Asp, when present in homozygosity or in trans , could influence plasmatic levels and/or bleeding tendency. In the present study, bleeding episodes were not recorded in the proband P10, who showed p.Phe301Leu combined with the c.595+3 A>G, whereas bleeding complications were reported when this missense mutation is combined with p.Trp519* (P11 and P12), as previously described.…”

Section: Discussionmentioning

confidence: 99%

Factor XI gene variants in factor XI-deficient patients of Southern Italy: identification of a novel mutation and genotype–phenotype relationship

et al. 2017

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Congenital Factor XI (FXI) deficiency shows a high variability in clinical phenotype. To date, many allele variants have been shown to cause this bleeding disorder. However, the genotype–phenotype relationship is difficult to establish. This report provides insights into this bleeding disorder. Sixteen unrelated Italian index cases with congenital FXI deficiency and their relatives were investigated. After the identification of the deficiency, we obtained DNA from each subject and analyzed the FXI gene using direct sequencing. We identified 5 and 11 individuals with severe and moderate deficiency of FXI activity, respectively. Most patients (8/16) carried mutations in the Apple 2 domain and 4 patients showed c.403G>T (p.Glu135*; type II mutation). Four novel compound heterozygosities were identified. Bleeding symptoms were present in two severely deficient subjects carrying the combinations c.901T>C (p.Phe301Leu)/c.1556G>A (p.Trp519*) and c.943G>A (p.Glu315)/c.1556G>A (p.Trp519*), respectively. Bleeding episodes were also observed in the presence of a moderate deficiency in two individuals heterozygous for c.449C>T (p.Thr150Met) and c.1253G>T (p.Gly418Val), respectively. One novel mutation, c.1682C>A (p.Ala561Asp), was identified as potentially deleterious in an asymptomatic individual. We confirm an unclear prediction of phenotype from mutational data. The FXI levels should be coupled with FXI analysis for a more comprehensive prediction of the bleeding phenotype in FXI deficiency.

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“…Since factor IX is smaller than albumin, it distributes in both the extra vascular and intra vascular compartments [2]. Characterization of a young female with mild hemophilia B is a novel missense mutation (codon 351, GCT (Ala) → CCT (Pro) of the FIX gene [8]. Menorrhagia therefore, a life threatening hidden disorder can be unusually due to severe and unexpected inherited bleeding disorder with a very high mortality rate if unchecked needs precise screening of coagulation disorder.…”

Section: Discussionmentioning

confidence: 99%

Hereditary bleeding disorder, factor ix deficiency in females: a case series

Mishra

2009

Cases J

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IntroductionHemophilia is uncommon in females and there is little knowledge about the clinical manifestation.Case presentationWe report here an unusual case of three hemophilic females diagnosed as factor IX deficient. Normal reports of ultrasonography (USG) and relevant endocrine investigations conducted in two adult females ruled out any usual gynecological and endocrinal causes of bleeding. Complete coagulation profiles were conducted and diagnosed these female bleeders to be hemophiliacs suffering from factor IX deficiency.ConclusionFemales presenting with menorrhagia and bleeding from other sites without any discernable cause require proper evaluation for congenital coagulation disorders. In the present case series, females are diagnosed factor IX deficient (Hemophilia B).

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Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome

Cited by 10 publications

References 18 publications

B�rjeson-Forssman-Lehmann syndrome in a woman with skewed X-chromosome inactivation

B�rjeson-Forssman-Lehmann syndrome in a woman with skewed X-chromosome inactivation

Factor XI gene variants in factor XI-deficient patients of Southern Italy: identification of a novel mutation and genotype–phenotype relationship

Hereditary bleeding disorder, factor ix deficiency in females: a case series

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