Severe and moderate haemophilia A and B in US females

Abstract

Haemophilia A and B are rare X-lined hemorrhagic disorders that typically affect men. Women are usually asymptomatic carriers, but may be symptomatic and, rarely, also express severe (factor VIII (FVIII) or factor IX (FIX) <0.01 U mL(-1)) or moderately severe (FVIII/FIX 0.01-0.05 U mL(-1)) phenotypes. However, data on clinical manifestations, genotype and the psychosocial ramifications of illness in severely affected females remain anecdotal. A national multi-centre retrospective study was conducted to collect a comprehensive data set on affected US girls and women, and to compare clinical observations to previously published information on haemophilic males of comparable severity and mildly affected haemophilic females. Twenty-two severe/moderate haemophilia A/B subjects were characterized with respect to clinical manifestations and disease complications; genetic determinants of phenotypic severity; and health-related quality of life (HR-QoL). Clinical data were compared as previously indicated. Female patients were older than male patients at diagnosis, but similarly experienced joint haemorrhage, disease- and treatment-related complications and access to treatment. Gynaecological and obstetrical bleeding was unexpectedly infrequent. F8 or F9 mutations, accompanied by extremely skewed X-chromosome inactivation pattern (XIP), were primary determinants of severity. HR-QoL was diminished by arthropathy and viral infection. Using systematic case verification of participants in a national surveillance registry, this study elucidated the genetics, clinical phenotype and quality of life issues in female patients with severe/moderate haemophilia. An ongoing international case-controlled study will further evaluate these observations. Novel mechanistic questions are raised about the relationship between XIP and both age and tissue-specific FVIII and FIX expression.

The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in theRPGRGene

“…Extremely skewed X inactivation has been shown in specific mutations in some nonretinal X-linked disease genes, 39,40 and has been in favor of the nonmutated allele. Secondary X inactivation skewing may manifest through a selective (dis)advantage for cells with the mutation-containing X-chromosome, 41 which may be hereditary. 42 The relative family-based, rather than mutation-based, aggregation of affected heterozygotes in this cohort, along with cases of intrafamilial variability, points to a highly likely role of genetic and/or environmental modifiers, as well as potentially skewed X inactivation.…”

The Role of X-Chromosome Inactivation in Retinal Development and Disease

“…For example, in Lesch-Nyhan Syndrome and Menkes disease, cells with a normal active X chromosome have a growth advantage over cells with a mutant active X (Migeon 2007; Desai et al 2011). In contrast, some female carriers of Duchenne Muscular Dystrophy and Hemophilia A demonstrate preferential inactivation of the wild-type allele and can manifest disease (Pegoraro et al 1994; Di Michele et al 2014). This pattern appears to be heritable in some cases (Renault et al 2007; Esquilin et al 2012), indicating that either the disease locus or another genetic modifier is biasing XCI in these families.…”

Haemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation

“…Skewed X chromosome inactivation was already shown to play a role in the development of disease symptoms in female carriers of several X-linked recessive disorders. These include in particular metabolic diseases and disorders of the nervous, haematopoietic and musculoskeletal systems (Boonyawat et al, 2013;Di Michele et al, 2014;Giliberto et al, 2014;Pavlova et al, 2009;Pinto et al, 2010). Prior to this report, BRCC3 was not implicated in morbidity in females.…”

“…The phenotype includes mild descending aorta coarctation, hypertension (observed as measured on upper but not the lower extremities), ventricular arrhythmia and low factor VIII levels (mean 22%), but she has no evidence of moyamoya or other angiopathies in angiographic imaging. As skewed paternal X chromosome inactivation combined with F8 or F9 defects is the most frequent cause of symptomatic haemophilia in females (Di Michele et al, 2014;Pavlova et al, 2009) we hypothesized that the clinical discrepancy between patient's sister and mother might be due to skewed X chromosome inactivation leading to differential expression of SHAM syndrome genes (F8, BRCC3).…”