Legius syndrome in fourteen families.

Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome.

Motor learning in children with neurofibromatosis type I.

The aim of this study was to quantify the frequently observed problems in motor control in Neurofibromatosis type 1 (NF1) using three tasks on motor performance and motor learning. A group of 70 children with NF1 was compared to age-matched controls. As expected, NF1 children showed substantial problems in visuo-motor integration (Beery VMI). Prism-induced hand movement adaptation seemed to be mildly affected. However, no significant impairments in the accuracy of simple eye or hand movements were observed. Also, saccadic eye movement adaptation, a cerebellum dependent task, appeared normal. These results suggest that the motor problems of children with NF1 in daily life are unlikely to originate solely from impairments in motor learning. Our findings, therefore, do not support a general dysfunction of the cerebellum in children with NF1.

Health-related quality of life in children with neurofibromatosis type 1: contribution of demographic factors, disease-related factors, and behavior.

OBJECTIVE: To investigate health-related quality of life (HR-QOL) in children with neurofibromatosis type 1 (NF1) with parental reports and children's self-reports, and to investigate the potential contribution of demographic factors, disease-specific factors, and problems in school performance or behavior. STUDY DESIGN: In a prospective observational study, parents of 58 children with NF1 (32 boys, 26 girls, age 12.2 +/- 2.5 years) visiting a university clinic, and their 43 children 10 years or older were assessed with the Child Health Questionnaire (CHQ). Potential determinants of domain scores were assessed in 3 explorative regression models. RESULTS: Parents reported a significant impact of NF1 on 9/13 CHQ scales, with moderate effect sizes on 8 (general health perceptions, physical functioning, general behavior, mental health, self esteem, family activities, role functioning emotional/behavioral, and parent emotional impact). Children report an impact on bodily pain, and an above average general behavior. Multiple CHQ scales were sensitive to demographic factors and behavioral problems, and 1 to NF1 severity. NF1 visibility and school problems did not influence HR-QOL. CONCLUSIONS: Parents, but not the children with NF1, report a profound impact of NF1 on physical, social, behavioral, and emotional aspects of HR-QOL. Multiple HR-QOL domains were most sensitive to behavioral problems, which points to an exciting potential opportunity to improve HR-QOL in children with NF1 by addressing these behavioral problems.

Physical fitness in children with haemophilia and the effect of overweight.

Although children with haemophilia are advised to participate in physical activities, their physical fitness has not been studied in a large group. In addition, children with haemophilia may be at increased risk for becoming overweight as a result of inactivity because of joint bleedings or because of overprotection. This study aimed to assess physical fitness (aerobic capacity), joint status, muscle strength, quality of life (QoL), self-reported motor competence and also prevalence of overweight and its association with physical parameters. Weight and height were measured. Skin folds were measured unilaterally at biceps, triceps, subscapular and supra-iliac sites. Aerobic capacity was determined on a cycle ergometer or with a 6-min walk test (6MWT). Muscle strength and active range of motion of elbows, knees and ankle joints were measured. Self-reported motor competence was measured with the 'Competentie BelevingsSchaal voor Kinderen'. Joint pain was scored on a Visual Analogue Scale. The Haemo-QoL Index was used to measure QoL. In 158 Dutch boys with haemophilia, with a mean age of 12.7 years (SD 2.9), normal aerobic capacity and muscle strength were found. Joint pain was reported by 16% of the participants. The prevalence of overweight (16%) was slightly increased when compared with healthy Dutch boys (13.5%). Being overweight had a negative association with the6MWT and QoL. Dutch children with haemophilia have normal aerobic exercise capacity and muscle strength. The majority also has normal joint mobility. Prevalence of overweight is slightly increased.

Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial.

CONTEXT: Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. OBJECTIVE: To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. DESIGN, SETTING, AND PARTICIPANTS: Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. INTERVENTION: Simvastatin or placebo treatment once daily for 12 weeks. MAIN OUTCOME MEASURES: Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. RESULTS: No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (beta = 0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (beta = -0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (beta = 0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (beta = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (beta = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment. CONCLUSION: In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration isrctn.org Identifier: ISRCTN14965707.

Parental reports of health-related quality of life in young children with neurofibromatosis type 1: influence of condition specific determinants.

OBJECTIVE: To assess the health-related quality of life of 34 Dutch children 12 to 72 months of age with neurofibromatosis type 1 (NF1) using the Infant/Toddler Quality of Life Questionnaire (ITQOL) and to investigate the potential impact of clinical factors on parental reports of health-related quality of life. STUDY DESIGN: A parent-completed form including the ITQOL, NF1-specific questions, and sociodemographic questions was sent. ITQOL scale scores were compared for the study population against Dutch reference values. The influence of general and clinical characteristics on ITQOL scale scores was evaluated with multivariate analysis. RESULTS: A significant impact was observed on most aspects of quality of life, particularly for growth and development, general health perceptions and parental impact. The lowest scores were observed in children with complications because of NF1. ITQOL scale scores were affected by parental educational level, familial NF1, and parental reports of complications of NF1 and perceived disease severity. CONCLUSIONS: Important aspects of health-related quality of life were observed to be negatively affected in children with NF1, as measured by the ITQOL. Family-related and disease-related variables appeared to influence the quality of life in children with NF1.

Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease.

We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels ≤30 U/dl. Menorrhagia (85%), cutaneous bleeding (77%), bleeding from minor wounds (77%) and oral-cavity bleeding (62%) occurred most frequently. Higher age was associated with a higher bleeding score (BS), determined according to Tosetto, in females. A 10 year increase in age was associated with 0.8 point (95% confidence interval [CI] 0.4-1.1) higher BS. Females had higher BS than males (median 12 vs. 10, p=0.012). BS differed significantly between VWD type 1, 2 and 3: median 9 (-2-31), 13 (-1-33) and 19.5 (1-35), respectively (p<0.001). BS was strongly associated with VWF and FVIII levels: individuals with VWF:Ag levels ≤10 IU/dl, VWF:Act ≤10 IU/dl and FVIII:C ≤10 IU/dl had, respectively, 5.3 point (95%CI 3.2-7.3), 4.3 point (95%CI 2.9-5.8) and 9.6 point (95%CI 6.5-12.7) higher BS, than those with levels >30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1-1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels.

Impact of neurofibromatosis type 1 on school performance.

School functioning of 86 Dutch neurofibromatosis type 1 children (7-17 years) using teacher questionnaires was analyzed to determine the impact of neurofibromatosis type 1 on school performance. In all, 75% of the neurofibromatosis type 1 children performed more than 1 standard deviation below grade peers in at least one of the domains of spelling, mathematics, technical reading or comprehensive reading. Furthermore, neurofibromatosis type 1 children had a 4-fold increased risk for attending special education and a 6-fold increased risk for receiving remedial teaching for learning, behavior, speech, or motor problems. Children without apparent learning disabilities still frequently displayed neuropsychological deficits. Only 10% of the children did not show any school-functioning problems. Finally, it was found that the clinical severity of neurofibromatosis type 1 correlated with the cognitive deficits. Taken together, it was shown that neurofibromatosis type 1 has profound impact on school performance. Awareness of these problems may facilitate timely recognition and appropriate support.

Social participation of patients with hemophilia in the Netherlands.

The introduction of replacement therapy in the 1960s has improved medical and social circumstances gradually. The availability of prophylactic treatment has further increased the possibilities of a "normal" life for patients with hemophilia. We examined whether social participation and health-related quality of life (HRQol) of today's hemophilia patients differs from the general male population. There were a total of 721 participants in the Hemophilia in the Netherlands 5 study (HiN-5 study) ages 16 to 64 years. Patients with severe hemophilia participated less in full-time work compared with the general population. Occupational disability was reported by 35% of patients with severe hemophilia between ages 31 and 64 years, compared with 9% in the general population. HRQol of patients with severe hemophilia between ages 31 and 64 years was lower than of the general population. The differences with the general population in HRQol were least pronounced for patients between ages 16 and 30 years. Despite major improvements in treatment during the last decades, patients with hemophilia are still less involved in full-time paid work and suffer more from occupational disability than men from the general population. After the introduction of prophylactic treatment, the number of patients who are occupationally disabled is reduced.

Thirty years of hemophilia treatment in the Netherlands, 1972-2001.

Since the introduction of replacement therapy in the early 1960s by the infusion of plasma-derived factor VIII and IX preparations, important changes have occurred for hemophilia patients. We studied the medical and social developments over 30 years of hemophilia treatment. Since 1972, 5 cross-sectional national postal surveys among all hemophilia patients in the Netherlands were performed, the latest in 2001. The prestructured questionnaires included items on treatment, the presence of inhibitory antibodies against factor VIII or IX, the annual number of bleeding episodes, use of inpatient hospital care, and hepatitis C and HIV infections. Response rate in 2001 was 70%. Young patients (<16 years) with severe hemophilia showed the largest increase in use of prophylaxis, from 34% in 1972 to 86% in 2001. The occurrence of hemorrhages has gradually decreased. Hospital admissions decreased from 47% of all patients in 1972 to 18% in 2001. Our study shows that the treatment of patients with severe hemophilia in the Netherlands has focused on the use of prophylactic treatment, especially in children. This has resulted in a decrease in bleeding frequency and an improvement of the medical and social circumstances of patients.