Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.

Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system.

BACKGROUND: Pitt-Hopkins syndrome (PTHS; MIM# 610954) is a genetically determined entity mainly caused by mutations in TransCription Factor 4 (TCF4). We have developed a new way to collect information on (ultra-)rare disorders through a web-based database which we call 'waihonapedia' (waihona [meaning treasure in Hawaiian] encyclopaedia). METHODS: We have built a waihonapedia system in a collaboration between physicians, social scientists, and parent support groups. The system consists of an initial extensive questionnaire for background cross-sectional data, and subsequent follow-up using small questionnaires, with a particular focus on behavioural aspects. The system was built to be used through the internet, ensuring a secure environment, respecting privacy for participants, and acting automated to allow for low costs and limiting human mistakes in data handling. Recruitment of participants is through the patient support groups. In addition, as a sub-study, we used the data from the waihonapedia system to compare the two proposed diagnostic classification systems for PTHS. RESULTS: We present here the results of the initial, cross-sectional questionnaire in which early development, physical health, cognition and behaviour are interrogated, and to which modules specific for PTHS were added on epilepsy and breathing patterns. We describe 101 individuals with a molecularly confirmed diagnosis of PTHS. Comparison of the two classification systems aimed at helping the clinical diagnosis was performed in 47 of the present PTHS individuals, with disappointing results for both. Internationally accepted clinical diagnostic criteria are needed. CONCLUSION: The present cross-sectional data on the natural history of PTHS have yielded useful information which will further increase when follow-up data will be added. No doubt this will improve both care and research.

[Cardiovascular disease risks in people with an intellectual disability: causes and interventions]. / Cardiovasculaire risico's bij mensen met een verstandelijke beperking.

Cardiovascular disease occurs as frequently in older people with intellectual disabilities as in the same aged general population. However, there are indications for underdiagnosis of myocardial infarction due to atypical or absent complaints. Obesity, diabetes and peripheral arterial disease are more common in this group than in the general population. Hypertension, metabolic syndrome and kidney disease occur as frequently as in the general population while hypercholesterolemia occurs less often. Cardiovascular disease risk factors are underdiagnosed in people with intellectual disabilities. This could be reduced by educating supporting staff and caregivers and systematic screening for cardiovascular risk factors by the general practitioner. The customary guidelines should be followed in the treatment of cardiovascular risk factors and cardiovascular disease. Lifestyle interventions and treatment of specific causal factors, such as the use of psychotropic drugs and chronic circadian rhythm disorders, require a specialised approach.

Metabolic syndrome in 25% of older people with intellectual disability.

BACKGROUND: Life expectancy of people with intellectual disabilities (IDs) is rapidly normalizing, as are prevalences of age-related cardiovascular disease in this group. We investigated the prevalence of the metabolic syndrome in the older population with ID and associations with patient characteristics. METHODS: Prevalence of the metabolic syndrome, according to National Cholesterol Education Program-Adult Treatment Panel III criteria, was assessed with standardized physical examinations in 470 Dutch adults with ID, aged ≥50 years, who receive residential care from three Dutch care providing organizations. Because of skewing towards an overrepresentation of females and more moderate to severe ID in the study population, reweighting was applied to obtain a representative population prevalence. Correlations with patient characteristics were analysed with logistic regression analyses. RESULTS: Four hundred and twelve participants completed all assessments. The weighted prevalence of the metabolic syndrome was 25.1% [95% confidence interval (CI) 21.0-29.3%], with a significantly higher risk for people with mild ID. CONCLUSIONS: The prevalence of the metabolic syndrome in the population with ID is significantly higher than that in the general Dutch population aged ≥50 years (15.7%, 95% CI 13.5-17.9%).

Prevalence of cardiovascular risk factors in older people with intellectual disability.

The prevalence and correlates of cardiovascular risk factors in older adults with intellectual disability was examined. We conducted a cross-sectional study with 50- to 90-year-old clients (N = 470) of three Dutch intellectual disability care providing organizations and found that healthy behavior was low, with 98.9% of the participants having an unhealthy diet and 68.3%, a lack of exercise. Smoking (13.6%) and alcohol abuse (0.3%) were relatively minor problems. Abdominal overweight (70.4%), diabetes (8.7%), hypertension (36.8%), and hypercholesterolemia (31.8%) were highly prevalent. These profiles have important implications in determining the risk of cardiovascular disease in people with intellectual disability. Campaigns to promote health should be focused on education and the introduction of preventive screening programs.

Childhood-onset growth hormone deficiency, cognitive function and brain N-acetylaspartate.

Cognitive deficits have been reported in adults with childhood-onset growth hormone (GH) deficiency. We evaluated cognitive deficits simultaneously with parameters for neuronal integrity using (1)H magnetic resonance spectroscopy (MRS) in a cross-sectional design. We studied 11 adults (mean age 24.5 years) with childhood-onset GH deficiency, which persisted after reaching final height. All subjects were evaluated after interruption of GH supplementation for at least 3 months. We performed neuropsychological assessment (NPA) using tests evaluating memory, mental processing speed, reading ability and executive functioning. MRS was used to assess brain N-acetylaspartate (NAA)/choline ratios. Data were compared with an age-, sex- and education-matched control group (n=9, mean age 27.3 years). NPA demonstrated attenuated performance of the patients in the delayed verbal memory recall score (P<0.05) and the trail making A test (P<0.05), a measure of planning of behavior, processing speed and attention. Other neuropsychological tests were not affected. NAA/choline ratios were significantly reduced (P<0.01) in GH deficient subjects. Specific cognitive defects indicating affected memory and attention were found in patients with childhood-onset GH deficiency. These defects occur simultaneously with reduced neuronal integrity.