D. E. Fransen Van De Putte

Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals.

Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation and/or multiple congenital anomalies (MR/MCA) has led to the identification of a number of new microdeletion and microduplication syndromes. Recently, a recurrent copy number variant (CNV) at chromosome 16p11.2 was reported to occur in up to 1% of autistic patients in three large autism studies. In the screening of 4284 patients with MR/MCA with various array platforms, we detected 22 individuals (14 index patients and 8 family members) with deletions in 16p11.2, which are genomically identical to those identified in the autism studies. Though some patients shared a facial resemblance and a tendency to overweight, there was no evidence for a recognizable phenotype. Autism was not the presenting feature in our series. The assembled evidence indicates that recurrent 16p11.2 deletions are associated with variable clinical outcome, most likely arising from haploinsufficiency of one or more genes. The phenotypical spectrum ranges from MR and/or MCA, autism, learning and speech problems, to a normal phenotype.

Co-morbidity in the ageing haemophilia patient: the down side of increased life expectancy

Summary.  Because of an increased life expectancy, (age‐related) co‐morbidity is becoming a common occurrence in haemophilia patients. In this review, haemophilia‐related and non‐haemophilia‐related medical problems, treatment recommendations and psychosocial consequences in ageing haemophilia patients are discussed. Haemophilic arthropathy is an important cause of pain and disability, and a frequent indication for surgery in haemophilia patients. In addition, many adult patients are infected with hepatitis C or HIV, the consequences and treatment of which can add to physical and mental discomfort. Moreover, inhibitors against factor VIII can also develop in adulthood, especially in patients with mild haemophilia. Hypertension is reported to occur more often in haemophilia patients than in the general population. Other internal problems, like renal abnormalities, overweight, diabetes mellitus and hypercholesterolemia are discussed. Haemophilia seems to protect against cardiovascular disease, although the incidence is increasing. Recommendations are given on dealing with tooth extractions, surgical interventions and sexuality problems in patients with haemophilia. In addition to haemophilia in itself, co‐morbidity has a major psychological impact, and an important effect on quality of life. It can also result in complex treatment regimens, in which coordination between health care workers is essential.

Unfavourable cardiovascular disease risk profiles in a cohort of Dutch and British haemophilia patients

Cardiovascular disease (CVD) mortality is reported to be decreased in haemophilia patients, but reports on the prevalence of CVD risk factors are conflicting. A cross-sectional assessment of CVD risk profiles was performed in a large cohort of haemophilia patients. Baseline data on CVD risk factors of 709 Dutch and UK haemophilia patients aged ≥30 years were analysed and compared with the general age-matched male population. CVD risk profiles were assessed using the QRISK®2-2011 and SCORE algorithms. Although QRISK® 2 was only validated in the UK, comparison with SCORE indicated similar properties of QRISK®2 in both Dutch and UK patients (correlation 0.86). Mean age was 49.8 years. Hypertension was more common in haemophilia patients than in the general population (49% vs. 40%), while the prevalences of obesity and hypercholesterolaemia were lower (15 vs. 20% and 44 vs. 68%, respectively), and those of diabetes and smoking were similar. The predicted 10-year QRISK®2 risk was significantly higher in haemophilia patients than in the general population (8.9 vs. 6.7%), indicating more unfavourable cardiovascular disease risk profiles. This increased risk became apparent after the age of 40 years. Our results indicate an increased prevalence of hypertension and overall more unfavourable CVD risk profiles in haemophilia patients compared with the general age-matched male population.

A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene

We present a young boy whose mild ataxia and abnormal eye movements repeatedly deteriorated with fever, making him unable to sit or walk during fever episodes. SNP-array analysis identified a 202 kb deletion in chromosome 13q33.1 containing the fibroblast growth factor (FGF)14 gene, which is associated with spinocerebellar ataxia (SCA) 27. This 13q deletion was also present in the probands mother and grandmother. The mother was unable to perform tandem gait walking and had abnormal eye movements but had never sought medical attention. The grandmother predominantly had a postural tremor. FGF14 regulates brain sodium channels, especially in the cerebellum. Sodium channels can be fever sensitive. This family demonstrates phenotypic variability of FGF14 deletions (SCA 27), fever sensitivity of ataxia and the added value of SNP-array analysis in making a diagnosis.

Morbidity and mortality in ageing HIV-infected haemophilia patients.

Over 25 years of follow‐up is now available for HIV‐infected haemophilia patients. The aim of this study was to retrospectively asses the morbidity and mortality of HIV infection and the effects of HAART in these patients. Data on HIV infection, its treatment and all types of comorbidity were collected from medical records of all 60 HIV‐positive haemophilia patients who were treated at the Van Creveldkliniek since 1980 and compared with data from 152 HIV‐negative patients with severe haemophilia and the general age‐matched male population. AIDS developed in 27 patients (45%), while 31 patients died (52%). Death was solely or partially AIDS‐related in 71%. Development of AIDS and AIDS‐related deaths declined strongly after the introduction of HAART. Only one major ischaemic cardiovascular event occurred in our study population. Of the 27 patients who were still treated at our clinic in 2010, 25 (93%) were on HAART. They had more often hypertension and diabetes, but less often overweight and obesity and lower cholesterol levels than the general population. The occurrence of spontaneous intracranial bleeding was higher in HIV‐positive haemophilia patients on HAART than in HIV‐negative patients with severe haemophilia (16.6 vs. 1.2 per 1000 patient years). Since the introduction of HAART, the impact of HIV infection on morbidity and survival has decreased. The increased prevalences of hypertension and diabetes, however, warrant regular screening. HIV‐positive haemophilia patients on HAART appear to have an increased risk of spontaneous intracranial bleeding.

The burden of HCV treatment in patients with inherited bleeding disorders

Summary.  Many patients with inherited bleeding disorders are infected with hepatitis C virus (HCV). Antiviral treatment, consisting of pegylated interferon and ribavirin, has many side‐effects. The aim of the study was to prospectively assess the occurrence and course of side‐effects and changes in health‐related quality of life (HRQoL) during antiviral treatment in patients with inherited bleeding disorders and chronic HCV. Forty‐seven patients were followed during antiviral treatment. Side‐effects of treatment were recorded, and the Beck Depression Inventory and the RAND‐36 HRQoL questionnaire were administered at regular intervals. Frequently reported side‐effects were fatigue (100%), headache (94%), pruritus and skin rash (94%), concentration problems (89%), decreased appetite (89%), fever, irritability and hair loss (all 85%). Many side‐effects disappeared soon after end of treatment, but 4 weeks after cessation fatigue, concentration problems and sleeping problems were still present in more than 30% of patients. Dose reduction was necessary in 21 patients (45%), mostly because of decreasing weight or haemoglobin levels. Two patients stopped treatment prematurely because of side‐effects. Depression was present in 28 patients (60%). HRQoL decreased significantly during treatment in all RAND‐36 domains, and increased again within 4 weeks after treatment. Major side‐effects were similar in patients with successful (n = 31, 66%) and unsuccessful antiviral treatment. In patients with inherited bleeding disorders and chronic HCV, antiviral treatment has many, but mostly transient side‐effects and a significant impact on quality of life. Careful follow‐up and management of side‐effects will ensure optimal compliance and treatment results.

Occurrence, course and risk factors of depression during antiviral treatment for chronic hepatitis C in patients with inherited bleeding disorders: a prospective study

Summary.  Treatment of hepatitis C virus (HCV) consists of pegylated interferon (IFN)‐α and ribavirin for 24 or 48 weeks. An important side‐effect of IFN‐α is depression. The occurrence, course and risk factors of depression during antiviral treatment were studied prospectively in HCV patients with inherited bleeding disorders. The Beck Depression Inventory, indicating no, mild, moderate or severe depression, was administered to 47 patients before starting therapy, after 4, 12, 24 and 48 weeks of treatment, and 4 weeks after cessation of therapy. At baseline, five patients (11%) had mild depression. Depression worsened during treatment in three of these patients. In all five patients, (mild) depression persisted 4 weeks after treatment. Of the remaining 42 patients, 23 (55%) developed depression during treatment (14 mild, eight moderate and one severe), mostly (78%) during the first 12 weeks. Four weeks after cessation of treatment, three of 23 patients still had mild depression. The only independent risk factor for development of depression was a history of depression or other psychiatric problems (odds ratio 9.7). For patients with inherited bleeding disorders, depression is a significant, mostly transient, problem during HCV treatment. We recommend close monitoring of patients, especially those with previous psychiatric problems, to ensure adequate detection and treatment of depression during antiviral therapy.

Liver stiffness measurements to assess progression of fibrosis in HCV‐infected patients with inherited bleeding disorders

Summary.  Hepatitis C is a major co‐morbidity in patients with inherited bleeding disorders, leading to progressive liver fibrosis and eventually cirrhosis. Liver stiffness measurement (LSM) is a non‐invasive way of assessing the extent of liver fibrosis. This article describes our experience with serial LSM to assess prospectively progression of fibrosis in a cohort of patients with inherited bleeding disorders and chronic hepatitis C. A total of 84 patients underwent serial LSMs, with a median interval of 3.7 years. The change in LSM results over time was assessed. Overall, there was no significant difference between the median results of LSM 1 and LSM 2. The median result of LSM 2 was low (6.6 kPa), after a median duration of infection of 37 years. On the individual level, deterioration of LSM results of more than 2 kPa was seen in 13 patients (16%), 44 patients (52%) remained stable and 27 patients (32%) showed improvement of LSM results of more than 2 kPa. These results are comparable with those of paired liver biopsy studies. LSM appears to be a good alternative for liver biopsies in patients with hepatitis C and inherited bleeding disorders, although the interpretation of the unexpected improvement we found in some of our patients is not straightforward. LSMs will be repeated in our patient population in a few years to be able to better assess the value of serial LSM.

Beneficial effect of successful HCV treatment in patients with inherited bleeding disorders, assessed by liver stiffness measurements

Summary.  Hepatitis C infection is a major comorbidity in patients with inherited bleeding disorders. Successful antiviral treatment leads to a reduction in liver fibrosis, as shown by liver biopsies. Liver stiffness measurement (LSM) is a non‐invasive method of assessing liver fibrosis. The aim of this cohort study was to evaluate the long‐term effect of successful antiviral treatment, using LSM, in HCV‐infected patients with inherited bleeding disorders. The LSM were performed in 2005 (LSM 1) and 2009 (LSM 2) in 39 patients who were successfully treated for HCV. The change in liver fibrosis between LSM 1 and 2 was assessed. The median duration of HCV infection was 28.8 years. A total of 22 patients (56%) underwent successful antiviral treatment before LSM 1 (group 1), and 17 patients between LSM 1 and LSM 2 (group 2). The median time since antiviral treatment was 8.8 years in group 1 and 2.5 years in group 2. In group 1, the median results of LSM 1 and 2 were similar (6.0 vs. 5.6 kPa, P‐value 0.36), so overall, patients remained stable. In three patients in this group, all treated more than 15 years ago, an increase of liver stiffness was shown. Group 2 showed a significant improvement in median LSM results (10.3 vs. 6.1 kPa, P‐value <0.01), with decrease of liver stiffness in 82%. Even after a long HCV infection duration, successful antiviral treatment led to a significant improvement of fibrosis, measured by LSM, mainly in the first few years after completing treatment.

Does haemophilia protect against ischaemic cardiovascular disease

pressive effect; both actions could lead to an eradication of the acquired haemostatic disorder. The actual incidence of AVWS is certainly underestimated [2–4], because most patients do not bleed until they are exposed to a major trauma or to major invasive procedures and surgery. Six categories of underlying disorders have been reported to occur in patients with AVWS: lymphoproliferative and myeloproliferative disorders; solid tumours; immunological and cardiovascular disorders; miscellaneous conditions. Lymphoproliferative and myeloproliferative disorders are most frequently associated with AVWS (48–63% of cases, according to literature and registry data) [4–6]. However, in a recent retrospective study, Tiede et al. found a relatively high association with cardiovascular disorders (46%) in comparison with monoclonal gammopathies, including multiple myeloma and Waldenstrom’s disease (31%) [3]. Different pathogenetic mechanisms have been described: the production of specific and non-specific autoantibodies against VWF, inhibiting functional sites or increasing its clearance from the circulation; the absorption of VWF onto malignant cell clones or platelets; the degradation of high molecular weight multimers of VWF under conditions of high shear stress; and increased proteolysis of VWF [2,4,7]. The selective adsorption of the VWF multimers onto malignant cells is usually associated with lymphoproliferative diseases(myeloma, Waldenstrom’s macroglobulinemia, non-Hodgkin’s lymphoma, hairy cell leukaemia), adrenal cell carcinoma and myeloproliferative disorders (essential thrombocythemia) [8]. However, it should be outlined that in many cases, none of these mechanisms appears to be specifically linked to an associated disease, and several mechanisms may be simultaneously responsible for the VWF acquired deficiency [8]. The diagnosis of AVWS is based on the same laboratory tests used for inherited VWD: FVIII:C, VWF:Ag, VWF:RCo, VWF:CB, RIPA, VWF:RCo/Ag ratio and multimer analysis. Test for autoantibodies should be performed, but unlike other acquired hemostatic defects (such as acquired haemophilia), the presence of anti-VWF antibodies is demonstrated only in some patients [2,7,8]. In our case, we did not perform the assay for the search of a VWF inhibitor, because when the patient came to our attention, we did not suspect an acquired hemostatic defect; in fact, 2 years earlier, a diagnosis of VWD was made in the absence of histological evidence of MALT lymphoma. Retrospectively, we can speculate that in 2003, there could already have been a clone of lymphoma cells that was still clinically undetectable. Therefore, the diagnosis of AVWS was made ‘a posteriori’, taking into account the age of the patient at the onset of symptoms, her negative personal and family haemorrhagic history, the site of bleedings, and the concomitant disappearance of the coagulopathy at the lymphoma remission [2]. To our knowledge, only another association between MALT lymphoma and AVWS has so far been reported in the literature [9]. In conclusion, we would like to highlight two aspects that emerge from the present case. In the presence of a severe-moderate bleeding disorder occurring in adulthood, without a previous haemorrhagic history, it is mandatory to investigate for an acquired disorder, possibly secondary to an underlying disease (cancer, autoimmune diseases, etc.) and for any primary disease. Moreover, the resolution of the coagulopathy may be obtained following treatment and remission of the primary disease. Due to the rarity of this syndrome and for a better management of these patients, we highlight the need to collect new cases in prospective registries.