The value-based healthcare approach to haemophilia: Development of outcome measures for the evaluation of care of people with haemophilia.

INTRODUCTION: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations. AIM: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process. METHODS: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia. RESULTS: A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care. CONCLUSION: The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely.

IDEAL study: A real-world assessment of pattern of use and clinical outcomes with recombinant coagulation factor IX albumin fusion protein (rIX-FP) in patients with haemophilia B in Italy.

INTRODUCTION: Factor IX replacement therapy is used for treatment and prophylaxis of bleeding in haemophilia B. rIX-FP is an extended half-life albumin-fusion protein, which, in clinical studies, has demonstrated prolonged dosing intervals up to 21 days for routine prophylaxis, providing therapeutic benefit. AIMS: To describe dosing frequency and consumption (primary endpoint), efficacy and safety of rIX-FP treatment during routine clinical practice in Italy. METHODS: Patients with moderate/severe haemophilia B on prophylaxis with rIX-FP for ≥6 months, were enrolled in this observational study from October 2017 to February 2019 and followed-up for 2 years. Descriptive analysis included prospective and retrospective data (12 months prior to switching to rIX-FP). RESULTS: Data were collected from 59 male patients (median age 30.1 years) enrolled by 23 Italian centres. Of them, 50 were on prophylaxis during the entire observation period and completed the study. The infusion frequency changed from 2-3 times/week in 86.0% of patients with previous treatment, to less than once a week in 84.0% of patients treated with rIX-FP at the 2nd-year follow-up. The annual number of infusions decreased by about 70%, whereas the mean FIX activity trough level increased from 3.8% to 14.4% (mean > 10% in all the infusion regimens). Median Annualised Bleeding Rate of .0 was achieved across all prophylaxis regimens. Subjects with zero bleedings increased from 66.0% to 78.0% with rIX-FP. CONCLUSION: Treatment with rIX-FP reduced infusion frequency, while providing higher FIX trough levels with substantial benefit in terms of annualised bleeding rate and a good safety profile.

Assessment of joint bleeding and target joints in patients with severe or moderately severe hemophilia B (factor IX ≤2%) receiving prophylaxis with rIX-FP in the PROLONG-9FP clinical trial program.

OBJECTIVE: To assess the impact of prophylaxis with rIX-FP, a fusion protein linking recombinant factor IX (FIX) with human albumin, on joint outcomes. METHODS: Joint outcomes were assessed in pediatric (<12 years) and adult/adolescent (≥12 years) patients receiving rIX-FP prophylaxis every 7, 10, or 14 days; patients (>18 years) well-controlled on a 14-day regimen could switch to a 21-day regimen. Target joints were defined as ≥3 spontaneous bleeds into a single joint within a 6-month period. RESULTS: For adult/adolescent (n = 63) and pediatric (n = 27) patients, median (Q1, Q3) annualized joint bleeding rate was 0.39 (0.00, 2.31), 0.80 (0.00, 2.85), 0.20 (0.00, 2.58), and 0.00 (0.00, 1.78) when treated with 7-, 10-, 14-, or 21-day prophylaxis. 50.0%, 38.9%, 45.5%, and 63.6% of adult/adolescent patients had no joint bleeds when treated with 7-, 10-, 14-, or 21-day prophylaxis, respectively, and 40.7%, 37.5%, and 37.5% of pediatric patients had no joint bleeds when treated with 7-, 10-, or 14-day prophylaxis. Ten adult and two pediatric patients developed target joints; all resolved by the end of the study. CONCLUSION: Prophylaxis with rIX-FP produced low joint bleeding rates and provided excellent hemostatic efficacy in the treatment of joint bleeds. All target joints reported resolved with rIX-FP prophylaxis.

The effect of carriers' reproductive choices and pregnancy history on sporadic severe haemophilia: A 20-year retrospective study through a regional registry.

INTRODUCTION: Haemophilias are X-linked inherited bleeding disorders, due to de novo F8/F9 gene variants in 30-50% of cases. The identification of causative variant in index cases (IC) is crucial for genetic counselling in related women. Over the last 20 years the Emilia-Romagna Regional Haemophilia Registry documented high proportions of sporadic severe haemophilia. AIM: To clarify if carriers' reproductive choices influence the sporadic/familial ratio of severe haemophilia. METHODS: Genetic counselling and genotyping in 221 relatives of severe IC were retrospectively reviewed, retrieving reproductive choices and pregnancy history of childbearing-age carriers from familial and sporadic pedigrees and according to the IC degree of relationship (mothers, daughters, II/other). RESULTS: Carriers' identification rates were lower in sporadic women and in other-degree relatives. Among childbearing age women (n = 140), carriers were 37/48 (77%) and 57/92 (62%) of familial and sporadic relatives, respectively. Forty-five/57 sporadic carriers experienced 67 pregnancies, while 21/37 familial carriers had 39 pregnancies (four voluntary terminations), with a significantly higher number of affected sons in the former (40/67 vs. 12/35, P = .025). Prenatal diagnosis was chosen by 40% and 47% of sporadic and familial aware carriers, respectively. Sporadic mothers often avoided further pregnancies (17/38, 45%) after a firstborn affected child, while familial mothers tended to face pregnancies without prenatal approaches (6/10, 60%). CONCLUSION: In this cohort sporadic offspring account for more than 70% of severe haemophilia cases. This increasing proportion is likely to reflect the influence in reproductive choices of awareness of carriers' status, particularly in sporadic mothers, and of prenatal diagnosis options.

Predictors of inhibitor eradication by primary immune tolerance induction in severe haemophilia A with high responding inhibitors.

BACKGROUND: Immune tolerance induction (ITI) is the only proven strategy to eradicate factor VIII inhibitors in patients with haemophilia A (HA). AIM: To identify patients and treatment options with the highest chance of inhibitor eradication by primary ITI. PATIENTS AND METHODS: In the frame of the Italian ITI Registry, carried out from 1995 to 2015 (last follow-up 2018), 137 primary ITI courses in severe HA patients (90/137 with poor prognosis) were analysed for predictors of outcome (complete/partial response or failure). Sixty-six of them (48%) were prospectively evaluated. RESULTS: ITI was successful in 91/137 patients (66.4%) and 70 (51.1%) achieved complete response within 11 months (median). Historical peak titres ≤200 BU/ml (P = .033), inhibitor titres ≤5 BU/ml at ITI start (P = .001), peak titres ≤100 BU/ml during ITI (P < .001) and missense mutations and small insertions/deletions of FVIII gene (P = .027) predicted complete inhibitor eradication. A score that considers the cumulative number of these variables predicted complete response with positive predictive values up to .81 at ITI start and .91 during ITI, respectively. Patients who had no bleeding (OR, 3.45, 95% CI: 1.4-8.6) nor other adverse events (OR 2.6, 95%CI: 1.3-5.3) during ITI had higher chances of complete response. During the 120-month follow-up (median), 2/70 patients who had achieved complete response relapsed (2.9%). CONCLUSIONS: This Registry, with a centralized review of outcomes, homogeneous data collection (half of which prospective) and long-term follow-up, provides insights for optimizing ITI, with a rationale for further studies in the currently evolving scenario of inhibitor management in HA patients.

ABO Blood Group and Inhibitor Risk in Severe Hemophilia A Patients: A Study from the Italian Association of Hemophilia Centers.

Considering the profound influence exerted by the ABO blood group system on hemostasis, mainly through the von Willebrand factor and factor VIII (FVIII) complex, we have conducted a study evaluating the possible role of blood type on the risk of inhibitor development in hemophilia A. A total of 287 consecutive Caucasian patients with severe hemophilia A (202 without FVIII inhibitors and 85 with FVIII inhibitors) followed at seven Italian Hemophilia Treatment Centers belonging to the Italian Association of Hemophilia Centers (AICE) were included in the study. A higher prevalence of O blood group was detected in patients without inhibitors as compared in inhibitor patients (55 vs. 30.6%; p < 0.001). Among the other variables analyzed (age, F8 mutation, type and intensity of treatment and treatment regimen), F8 mutation class (high-risk vs. low-risk), and treatment regimen (on-demand vs. prophylaxis) were significantly correlated with inhibitor development. However, on a multivariate analysis, only the effects of F8 mutation and ABO blood type were independent of other covariates, being that non-O blood type is associated with a 2.89-fold increased risk of inhibitor development. In conclusion, our study supports the protective effect of O blood type on inhibitor risk in severely affected hemophilia A patients.

Safety and efficacy of nonacog alfa for the treatment of haemophilia B in children younger than 6 years of age in a routine clinical care setting: the EUREKIX registry study.

INTRODUCTION: European regulatory authorities request postmarketing safety and efficacy data for factor IX (FIX) products. AIM: Collect additional clinical data from routine nonacog alfa use in children aged <6 years with haemophilia B. METHODS: The EUREKIX registry included retrospective and prospective data collection phases. Safety was assessed via adverse drug reactions (ADRs)/adverse events (AEs) and events of special interest (ESIs) as the primary objective; efficacy was evaluated via annualised bleeding rates (ABRs). RESULTS: The retrospective phase comprised 37 subjects. Of these, 25 had severe haemophilia B. One subject experienced 2 ADRs; another experienced 4 ESIs of hypersensitivity. Median ABR in subjects receiving a predominantly on-demand regimen (prophylaxis <50% of time; n = 11) was 2.0; median ABR was 3.8 in those receiving predominantly prophylactic treatment (prophylaxis ≥50% of time; n = 24). Joint bleeding was infrequent (median ABR, 0.4; n = 35). The prospective phase included 26 subjects, with 17 continuing from the retrospective phase. A total of 20 subjects had severe haemophilia B. Three subjects experienced 7 treatment-related AEs; 3 experienced 4 ESIs. Median ABR was 4.5 and 1.1 in subjects who received predominantly on-demand (n = 5) or prophylactic treatment (n = 19), respectively; the overall median ABR for joint bleeding events was 0.0. CONCLUSIONS: Overall, nonacog alfa treatment effectively controlled bleeding events, with no new safety signals identified. These data support the safety and efficacy of nonacog alfa in routine clinical settings in children aged <6 years.

Immune tolerance induction with moroctocog-alpha (Refacto/Refacto AF) in a population of Italian haemophilia A patients with high-titre inhibitors: Data from REF.IT Registry.

BACKGROUND: The appearance of inhibitors is the most serious complication in haemophilia A (HA) patients. The primary objective is their eradication. Up to date, immune tolerance induction (ITI) was the only therapeutic option to achieve this. AIM: To assess the efficacy of moroctocog-alpha as an ITI regimen in a population of HA patients with high-titre inhibitors. METHODS: The REF.IT Registry is a retrospective-prospective study that collected data on all patients with HA and high-titre inhibitors treated with moroctocog-alpha as an ITI regimen at twelve Italian Haemophilia Centres. RESULTS: We enrolled 27 patients, 85.2% were children. All patients were high responders, 88.9% had severe HA. We found 69.3% of them had one or more risk factors for poor ITI prognosis, 14.8% were ITI rescue. Overall 59.3% achieved a complete/partial success (complete in 51.9%). ITI failed in 11 patients, 63.6% of them with poor-prognosis risk factors. Inhibitors appeared after a mean of 27 exposure days. Mean historical peak was 78.8 BU/mL. The primary ITIs started on average 20.2 months after the diagnosis. A partial or complete success after a mean of 15 months of treatment was achieved in 56.6% of the children while the same result was obtained by 75.0% adults after 22 months from ITI onset. Patients who were treated with high-dose moroctocog-alpha (200 UI/kg/day) were 63.0%. CONCLUSION: Our Registry showed that the use of moroctocog-alpha in the setting of ITI was effective and safe also in a population of patients with high-titre inhibitors, presenting one or more risk factors for poor ITI prognosis.

Consensus statements on vaccination in patients with haemophilia-Results from the Italian haemophilia and vaccinations (HEVA) project.

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence- and consensus-based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement.

Inhibitors in Hemophilia B.

Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication.

Pain assessment and management in haemophilia: A survey among Italian patients and specialist physicians.

INTRODUCTION: Persons with haemophilia (PWH) experience recurrent joint bleeding which leads from early synovitis to irreversible joint damage. Pain strongly affects patients' quality of life, as PWH suffer from acute pain associated with haemarthroses and chronic pain due to arthritic and degenerative complications. AIM: To investigate pain issues among PWH and their treaters in Italy. METHODS: Persons with haemophilia and specialist physicians responded to a survey focused on pain characteristics, assessment, and management by phone call and online, respectively. RESULTS: One hundred and nineteen patients (76% severe haemophilia, 61% ≥18 years) and 44 physicians were involved. Pain was reported by 61% of PWH; among those who did not experience pain, 70% were children on prophylaxis. Patients described pain as chronic (71%), acute (69%) or postoperative (8%), and rated it as severe in 65% of cases. Clinicians reported lower percentages of patients with pain (46%), classified as chronic (58%), acute (33%) or postoperative (21%), half using specific scales. Pain was systematically investigated by treaters according to 36% of patients. Paracetamol was largely the most prescribed first-line pain therapy (89%), as well the most employed analgesic by PWH (51%), who also used non-steroidal anti-inflammatory drugs (24%), cyclo-oxygenase-2 inhibitors (21%) or opioids (26%). To manage pain, 61% of clinicians stated to collaborate with other specialists. Physiotherapy was often suggested but less frequently used by PWH. CONCLUSIONS: Pain is under-recognized and unsatisfactorily addressed by haemophilia treatment centre (HTC) clinicians, with discrepant management compared to PWH responses. Education in systematic pain assessment and multidisciplinary treatment and development of management guidelines are highly needed.

Rate and appropriateness of polypharmacy in older patients with hemophilia compared with age-matched controls.

BACKGROUND: In older people, multiple chronic ailments lead to the intake of multiple medications (polypharmacy) that carry a number of negative consequences (adverse events, prescription and intake errors, poor adherence, higher mortality). Because ageing patients with haemophilia (PWHs) may be particularly at risk due to their pre-existing multiple comorbidities (arthropathy, liver disease), we chose to analyse the pattern of chronic drug intake in a cohort of PWHs aged 60 years or more. PATIENTS AND METHODS: S + PHERA is a multicentre observational study, with the broad goal to evaluate prospectively the health status and medication intake in 102 older patients with severe haemophilia A or B compared with 204 age- and residence-matched controls chosen randomly from the same general practices of PWHs. The rate of potential drug-drug interactions (PDDI) was evaluated as a proxy of prescription appropriateness. RESULTS: After excluding replacement therapies and antiviral drugs, PWHs took in average less daily drugs than controls (2.4 ± 2.5 vs 3.0 ± 2.4) and had a lower rate of polypharmacy. Moreover, their prevalence of PDDI was lower (16.7% vs 27%). CONCLUSIONS: The rate of polypharmacy and the appropriateness of medications other than those for haemophilia and related comorbidities are acceptable in Italian PWHs, and better than those in their age peers without haemophilia, perhaps owing to drug tailoring and deprescribing by the specialized haemophilia centres at the time of regular visits. However, the PWHs investigated herewith were relatively young and the rate of polypharmacy and related PDDIs may become more prominent and crucial when older ages are reached, suggesting the need of continuous surveillance on prescribed drugs and the risk of drug-drug interactions.

Blood Group O Protects against Inhibitor Development in Severe Hemophilia A Patients.

Increasing evidence supports the link between ABO(H) blood group determinants and hemostasis. In particular, the ABO-related different glycosylation patterns of von Willebrand factor strongly influence its clearance and functional levels, and this may contribute to the inter-individual variations in the half-life of infused Factor VIII (FVIII) in hemophilia A (HA) patients. We investigated the role of ABO blood groups in regulating FVIII immunogenicity by evaluating their distribution in patients with severe (FVIII < 1 IU/dL) HA according to inhibitor development and other known relevant factors. In a cohort of Italian severe HA patients (n = 209), the ABO blood group distribution was similar to that in the healthy general population. However, the distribution of inhibitors, developed in 56 patients overall (26.8%), was significantly different in the four ABO phenotypes (O, 18.2%; A, 31.9%; B, 39.1%, AB, 25%; p = 0.033); this difference seemed more pronounced when only high-titer inhibitors (overall, 21.1%) were considered (O, 11.4%; A, 27.7%; B, 34.8%; p = 0.011). Relative risks in O versus non-O blood group were 0.55 (95% CI: 0.33-0.92) and 0.40 (95% CI: 0.21-0.77) for any and high-titer inhibitors, respectively. In a multivariate logistic regression, O blood group was shown to lower (approximately twofold) inhibitor risk, similarly with plasma-derived FVIII, whereas high-risk F8 mutations were associated with increased risk. However, the estimated effect of O blood type on inhibitor development was free from any significant correlation to other covariates, including presence of high-risk F8 mutations and type of replacement FVIII used. In this retrospective cohort of severe hemophiliacs, blood group O appears to protect against inhibitor development, with independent effects from other covariates. Larger prospective studies are needed to confirm this finding and to delve deeper into its pathophysiologic mechanisms.

Assessment of Hemophilic Arthropathy by Ultrasound: Where Do We Stand?

Joint hemorrhages represent the most common type of bleeding episode in persons with hemophilia, and recurrent hemarthrosis triggers chronic arthropathy, which is the most frequent chronic complication in these patients. In recent years, in the frame of a comprehensive care approach, a growing attention has been given to the periodic assessment of the joint status in hemophilia patients with the aim to identify early arthropathic changes and to prevent the development of a clinically overt arthropathy. Besides clinical examination, X-ray and magnetic resonance imaging (MRI) are currently used to evaluate joint status and to monitor the disease progression in hemophilia. Considering the limitations of X-ray and MRI, growing interest has been given to ultrasound (US) as a possible tool to assess joint status and identify early arthropathic changes in hemophilia patients. In the present review, we summarize major literature evidence on the use of joint US for the evaluation of markers of disease activity (joint effusion and synovial hypertrophy) and of degenerative damages (osteochondral changes) in patients with hemophilia. On the whole, being able to identify the presence of intra- or extra-articular fluid, US examination is the fastest and most reliable technique to identify acute conditions, such as hemarthrosis. In addition, the information on joint involvement provided by US in the patient follow-up may influence treatment decisions on a personalized basis. The use of US as part of a routine clinical examination by hemophilia experts may optimize the diagnostic workflow, avoiding additional costs and long waiting lists for patients referred to imaging departments. In the frame of a comprehensive care approach, US might represent a strategy to early detect and monitor synovial hypertrophy and osteochondral changes in hemophilia, thus extending the clinical examination and helping identify joints to be studied with a second-level examination such as MRI.

A Web Site to Improve Management of Patients with Inherited Bleeding Disorders in the Emergency Department: Results at 2 Years.

Treatment of patients with inherited bleeding disorders (PWIBD) in the emergency department (ED) is challenging. In 2010, a project was started involving all eight hemophilia centers (HC) and all 44 EDs of the Region of Emilia-Romagna (Italy) to improve emergency care for PWIBD. The project incorporates guidelines for emergency treatment, education for ED staff, and a dedicated Web site providing extensive information, proposing treatments, and sharing data with patients' electronic clinical records. A Web algorithm, accessible to PWIBD as well as ED and HC staff, suggests the first dose of concentrate for each type and severity of bleed or trauma. Following training courses in each ED, the network was activated. During 2012 and 2013, the site was visited 14,000 times, the EDs accessed the Web site 1,739 times, and used the algorithms 206 times. In two reference EDs, triage-assessment and triage-treatment times were reduced in 2013 and 2012 (27/20 and 110/71.5 minutes, respectively) and medical advice from the HC increased (54 vs. 24% cases). The main advantages of this system are better management of patients in ED (shorter triage-to-treatment times) and improved collaboration between HCs and EDs. The most critical point remaining is staff turnover in EDs, necessitating continual training.

Cancers in Patients with von Willebrand Disease: A Survey from the Italian Association of Haemophilia Centres.

Besides its essential role in hemostasis, there is growing evidence that von Willebrand factor (VWF) has an additional antitumor effect. To elucidate the clinical significance of this biological activity we conducted a retrospective study on cancers among Italian patients with von Willebrand disease (VWD) on behalf of the Italian Association of Haemophilia Centres (AICE). A questionnaire to collect demographic, clinical, and treatment data of VWD patients with cancer was sent to all the 54 Italian Haemophilia Treatment Centres (HTCs) members of AICE. Overall, 18 HTCs (33%) provided information on 92 VWD patients (61 alive and 31 deceased) with 106 cancers collected during the period 1981 to 2014. Of them, 19 (18%) were hematological cancers and 87 (82%) were solid cancers. A total of 61% of patients had type 1, 36% type 2 (12% type 2A, 14% type 2B, 9% type 2M, and 1% type 2N), and 3% type 3 VWD: this distribution was significantly different from that observed in the whole VWD population (79% type 1, 16% type 2 [8% type 2A, 4% type 2B, 2% type 2M, 2% type 2N], and 5% type 3; type 2 vs. non-type 2: p < 0.001). Overall, VWD patients with cancer underwent 52 invasive and 72 surgical procedures, were treated with VWF/factor VIII (FVIII) concentrates in 77 cases, with desmopressin (DDAVP) alone in 24 cases and with DDAVP and VWF/FVIII concentrates in 7 cases. Hemorrhagic complications were observed only rarely (2% of invasive procedures and radiotherapy and 6% of surgical interventions). The data collected by this survey document that a substantial number of cancers are recorded among VWD patients and that these patients are safely managed by HTC physicians through a multidisciplinary approach.

Cryptic 13q34 and 4q35.2 Deletions in an Italian Family.

Variations of DNA sequences in the human genome range from large, microscopically visible chromosome anomalies to single nucleotide changes. Submicroscopic genomic copy number variations, i.e. chromosomal imbalances which are undetectable by conventional cytogenetic analysis, play an intriguing clinical role. In this study, we describe the clinical consequences of the concurrent presence of an interstitial deletion in 13q34 and a terminal deletion in 4q35.2 in an Italian family. The index patient, a 19-year-old male, as well as his 12-year-old sister are carriers of both deletions, one of maternal and the other of paternal origin. The phenotype includes language delay, multiorgan involvement and bleeding diathesis with mild deficiency of factors X and VII. In the sister, the concomitant presence of Noonan syndrome may partly explain the clinical symptoms. The deleted region on chromosome 13 involves several genes (ATP11A, MCF2L, F7, F10, PROZ, PCID2, CUL4A, and LAMP1); some of these seem to play a role in the proband's phenotype. The terminal deletion in 4q35.2 contains other OMIM genes (FRG1, FRG2 and DBET); moreover, the 4q region is reported as a susceptibility locus for Crohn's disease, diagnosed in the proband's father. To our knowledge, this is the first report of a family with these 2 submicroscopic copy number changes. We tried to relate the clinical phenotype of the proband and his family to the molecular function of the involved genes.