[Behavioral phenotypes and recent developments in genetic technologies]. / Gedragsfenotypes en recente ontwikkelingen in het genetisch onderzoek.

BACKGROUND: Recent developments in genetic technologies make it possible to find a causative genetic defect in about 60% of patients diagnosed with neurodevelopmental disorders. A genetic etiology may provide insight into associated psychopathology, somatic comorbidity, course and direction for treatment.
AIM: To provide an overview of recent developments in genetic technologies, of genetic syndromes and their associated psychopathology. This is illustrated by describing two recently described syndromes.
METHOD: Clinical expertise combined with a search in Pubmed with the key words 'behavioural phenotype', 'intellectual disabilit*', 'next generation sequencing', 'exome' and 'genome'.
RESULTS: We provide an overview of developments in genetic technologies. A schematic overview of syndromes, which may present in clinical practice, is offered and completed with implications for treatment. Findings in recently reported syndromes are illustrated.
CONCLUSION: There is an increase in genetic diagnosis in patients with neurodevelopmental disorders. Knowledge about recent developments in genetics is helping psychiatrists to deal with considerations about referral for genetic diagnostics and putting a genetic syndrome in the context of psychiatric treatment.

[Patients with ARHGEF9-mutation: a case report and implications of genetic disorders in child psychiatry]. / Patiënten met ARHGEF9-mutatie: rol van genetica in de psychiatrische praktijk.

We describe two patients, who were assessed at a child psychiatry clinic, with a known genetic disorder in the ARHGEF9 gene on the long arm of the X chromosome. The boys presented with developmental delay, hyperactivity, autism spectrum disorder and epilepsy. This prompted us to conduct a literature search on previously identified patients with the same mutation and its impact on psychiatric symptoms in children. Recent evolutions in genetic technologies have led to the possibility of identifying and investigating more children with developmental disorders with or without psychiatric disorders. Child psychiatrists are confronted with the question what role genetics play in the child's clinical presentation. A basic knowledge of genetic principles is now required.

[Intellectual developmental disorder and child psychiatry]. / Verstandelijke beperking en kinder- en jeugdpsychiatrie.

BACKGROUND: Intellectually disabled children have a high risk of developing psychiatric disorders. Until recently, this comorbidity was not recognised and remained undiagnosed and untreated. AIM: To give an overview of the prevalence, etiology, clinical symptoms, diagnostic assessment and treatment of psychiatric disorders in intellectually disabled children. METHOD: Research of the scientific literature through PubMed and books. RESULTS: There is an increased prevalence of psychiatric disorders in intellectually disabled children. The etiology is multifactorial and the clinical symptoms are atypical. Diagnosis is based on a multitude of factors and many types of assessment. The latter include the assessment of emotional and behavioral problems, cognitive functioning, medical and genetic background and the role played by environmental factors. Most psychiatric disorders are treated with psychopharmacological medication and psychotherapy. CONCLUSION: The diagnosis and treatment of the psychiatric problems in intellectually disabled children requires specific expertise, taking into account the complex clinical image inherent to children with impaired cognitive and verbal possibilities.

Neuropsychopathology in 7 Patients with the 22q13 Deletion Syndrome: Presence of Bipolar Disorder and Progressive Loss of Skills.

The 22q13 deletion syndrome is characterised by intellectual disability (ID), delayed or absent speech, autistic-like behaviour and minor, nonspecific dysmorphic features. The deletion of the SHANK3 gene is thought to be responsible for these features. In this study, the clinical data of 7 patients with the 22q13 deletion syndrome are presented, obtained by clinical genetic examination, direct behavioural observation and by interview of family members and/or caregivers, complemented by behavioural questionnaires. The specific focus was on behaviour, psychopathology and the level of functioning during life course in order to determine common features that might contribute to the delineation of the syndrome. Major findings were a high incidence of psychiatric disorders, more in particular bipolar disorder (BPD) and attention deficit hyperactivity disorder (ADHD), and a sudden deterioration after acute events, in addition to a progressive loss of skills over years. Therefore, a deletion of SHANK3 may result in a dysfunctional nervous system, more susceptible to developmental problems and psychiatric disorders on the one hand, less able to recuperate after psychiatric and somatic events, and more vulnerable to degeneration at long term on the other hand. These results are exploratory and need to be confirmed in a larger sample.

Can fetal ultrasound result in prenatal diagnosis of Prader-Willi syndrome?

OBJECTIVE: To define fetal ultrasound characteristics triggering an antenatal diagnosis of Prader Willi syndrome (PWS). METHODS: Retrospective analysis of sonographic characteristics retrieved from obstetric ultrasound records. All children (n=11) had a postnatal genetically confirmed diagnosis of PWS. RESULTS: All patients (n=11) showed at least one aspecific abnormality on prenatal ultrasound. Ten out of eleven (90.9 %) had decreased fetal movements, 7 (63.6%) presented in breech position, 7 (63.6%) had severe intra-uterine growth restriction (<5th centile) and 4 (36.4%) showed a polyhydramnios. Immobile flexed limbs and clenched hands were seen in one patient (9.1%). Severe growth restriction combined with polyhydramnios favors the diagnosis in 3/11 cases. CONCLUSION: Prenatal sonographic phenotype of PWS includes decreased fetal movements, fetal malpresentation, severe intra-uterine growth restriction and polyhydramnios. These findings are not specific to PWS, but the combination of some of them (especially severe intra-uterine growth restriction and polyhydramnios) can prompt clinicians to perform invasive testing leading to a molecular cytogenomic diagnosis prenatally.

The European Prader-Willi Syndrome Clinical Research Database: an aid in the investigation of a rare genetically determined neurodevelopmental disorder.

BACKGROUND: Prader-Willi Syndrome (PWS) is a rare genetically determined neurodevelopmental disorder with a complex phenotype that changes with age. The rarity of the syndrome and the need to control for different variables such as genetic sub-type, age and gender limits clinical studies of sufficient size in any one country. A clinical research database has been established to structure data collection and to enable multinational investigations into the development of children and adults with PWS. METHODS: As part of a joint basic science and clinical study of PWS funded through Framework 6 of the European Union (EU), an expert multidisciplinary group was established that included clinicians involved in PWS research and clinical practice, expert database software developers, and representatives from two national PWS Associations. This group identified the key issues that required resolution and the data fields necessary for a comprehensive database to support PWS research. RESULTS: The database consists of six 'index' entry points and branching panels and sub-panels and over 1200 data 'fields'. It is Internet-based and designed to support multi-site clinical research in PWS. An algorithm ensures that participant data are anonymous. Access to data is controlled in a manner that is compatible with EU and national laws. The database determines the assessments to be used to collect data thereby enabling the combining of data from different groups under specifically agreed conditions. The data collected at any one time will be determined by individual research groups, who retain control of the data. Over time the database will accumulate data on participants with PWS that will support future research by avoiding the need for repeat data collection of fixed data and it will also enable longitudinal studies and treatment trials. CONCLUSION: The development of the database has proved to be complex with various administrative and ethical issues to be addressed. At an early stage, it was important to clarify the exact function of the database. It was agreed that it was primarily to support grant-funded research rather than clinical practice. The most complex issues that had to be addressed were concerned with data ownership and establishing the rules for data entry, retrieval and sharing that are compatible with data protection laws, and which are likely to be acceptable to participants and their families and to individual research groups.

Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant.

BACKGROUND: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. METHODS AND RESULTS: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). CONCLUSION: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients' phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling.

Cross-cultural comparisons of obesity and growth in Prader-Willi syndrome.

Introduction The present study reports cross-cultural comparisons of body mass index (BMI) and growth in Prader-Willi syndrome, a neurodevelopmental disorder associated with obesity, growth restriction and mild learning disability. Our objectives were to: (1) compare rates of obesity in adults with Prader-Willi syndrome (PWS) in France, with data available from Belgium, the UK and the USA; (2) compare growth of French children with PWS with their counterparts in Germany and the USA; and (3) evaluate the contribution of genetic, medical and social parameters to obesity outcome in French children and adults with PWS. Method (1) Cross-sectional comparison of BMI of 40 French adults, 38 Belgian adults, 46 British adults and 292 North American adults; (2) Construction of growth curves for French children aged 2-20 years from longitudinal data for 150 individuals with PWS, and comparison with published growth curves from Germany and the USA; and (3) Longitudinal regression analysis of 141 French children and adults to determine the factors contributing to obesity outcome. Results A total of 82.5% French adults with PWS have BMI > 30 compared with 65.8% in Belgium (n.s.), 58.2% in the USA (P < 0.005), and 54.3% in the UK (P < 0.01). Higher rates of obesity in females vs. males were found in the USA sample (P < 0.001) but not in the other samples. In contrast to adults, growth curves for French children with PWS show similar rates of growth compared with children with PWS in Germany and the USA. The principal determining factors of BMI status in the French PWS population are age (P < 0.0001), cohort (born within the last 15 years vs. born over 15 years ago, P < 0.0002) and growth hormone replacement therapy (P < 0.0002). Significant subsidiary effects include domestic situation (P < 0.0001), genetic diagnosis (P < 0.0001) and age of diagnosis (P < 0.0001). Conclusions French adults with PWS have significantly higher rates of obesity than adults in the UK and the USA, but growth in French children with PWS is similar to the USA and Germany. Clinical management has a greater impact on obesity outcome in PWS than cultural factors.

Mental health problems in children with intellectual disability: use of the Strengths and Difficulties Questionnaire.

BACKGROUND: The assessment of mental health problems in children with intellectual disability (ID) mostly occurs by filling out long questionnaires that are not always validated for children without ID. The aim of this study is to assess the differences in mental health problems between children with ID and without ID, using a short questionnaire, the Strengths and Difficulties Questionnaire (SDQ). METHODS: We studied 260 children (6-12 years) selected from special education schools for trainable children (response: 57%). Parents completed the extended Dutch version of the SDQ, questions on background characteristics and on the care provided. A non-ID control group of 707 children (response: 87%) was included to compare mental health problems. RESULTS: In total, 60.9% of children with ID had an elevated score on the SDQ, compared with 9.8% of children without ID. Only 45% of the children with ID and an elevated SDQ score had visited a healthcare professional for these problems in the last 6 months. DISCUSSION: The SDQ or an adapted version could contribute to the early identification of mental health problems in children with ID. Further research is needed to confirm the validity of the SDQ when used in a sample of children with ID.

Intellectual abilities in a large sample of children with Velo-Cardio-Facial Syndrome: an update.

BACKGROUND: Learning disabilities are one of the most consistently reported features in Velo-Cardio-Facial Syndrome (VCFS). Earlier reports on IQ in children with VCFS were, however, limited by small sample sizes and ascertainment biases. The aim of the present study was therefore to replicate these earlier findings and to investigate intellectual abilities in a large sample of children with VCFS. In addition, we aimed to identify factors that may contribute to within-syndrome variability in cognitive performance, such as the mode of inheritance of the deletion, sex, the presence of a heart defect and psychiatric morbidity. METHOD: IQ data of 103 children with VCFS (56 males, 47 females) were collected. Psychiatric diagnosis was additionally recorded. RESULTS: Children with VCFS had a mean full-scale IQ (FSIQ) of 73.48 (range: 50-109). There were no effects of sex, presence of a heart defect and psychiatric condition on intellectual profile. Inheritance of the deletion affected cognitive performance in VCFS, with children with familial deletions having significant lower FSIQ than children with a de novo deletion. CONCLUSIONS: Learning disabilities are very common in children with VCFS, although marked within syndrome variability is noted. One factor contributing to this variability seems to be the mode of inheritance of the deletion.

Health-related quality of life problems of children aged 8-11 years with a chronic disease.

In paediatric research, Health-Related Quality-of-Life (HRQoL) has received increasing recognition as an important health outcome. This study aimed to investigate the nature and prevalence of HRQoL problems in children with different chronic diseases. Data were available on 318 children aged 8-11 years with different diseases: congenital heart disease (n = 50); coeliac disease (n = 105); asthma (n = 32); cancer (n = 23); juvenile chronic arthritis (n = 45); children with capillary haemangioma (n = 25) and severe meningococcal disease (n = 38). They all answered a validated generic instrument [TNO-AZL Children's Quality of life questionnaire] (TACQoL), in the outpatient clinic or at home. Analyses of variance were performed to investigate differences in mean scores for children with chronic conditions in comparison to healthy children. Prevalence of children at risk for substantial HRQoL problems was based on the 25th percentile in the norm population. In comparison to healthy children, only a small number of differences were found in mean scores of children studied. In contrast, prevalence of HRQoL problems in children with chronic diseases was higher in several domains. It is concluded that using an indicator variable of the norm 25th percentile seems important in identifying at-risk children with chronic disease.

The del(2)(q32.2q33) deletion syndrome defined by clinical and molecular characterization of four patients.

We report four patients with an interstitial deletion of chromosome 2q32-->2q33. They presented similar clinical findings including pre- and postnatal growth retardation, distinct facial dysmorphism, thin and sparse hair and fair built, micrognathia, cleft or high palate, relative macroglossia, dacrocystitis, persisting feeding difficulties, inguinal hernia and broad based gait. All were severely mentally retarded. Three patients had a specific behavioral phenotype with hyperactivity and motor restlessness, chaotic behavior, happy-personality but with periods of aggression and anxiety, sleeping problems and self-mutilation. (head-banging). Array CGH and fluorescence in situ hybridization (FISH) allowed us to delineate the deletion size and showed that the four patients share a 8.1 Mb minimal deleted region. Reviewing additional nine case reports of patients with similar deletions showed striking phenotypic similarities which enabled the delineation of the 2q32.2q33 syndrome. Deletion of 2q32 has been also associated with the wrinkly skin syndrome (WWS) and isolated cleft palate. Although the patients presented here shared many aspects of WWS, they did not had the wrinkly skin. All patients had a cleft or high palate, most likely as a result of hemizygosity for SATB2. A potential commonly deleted interval of the three patients with behavioral problems, excluding the deletion in the patient without behavioral problems, is at most 0.5 Mb in size harboring only two genes.

Is attrition bias a problem in neonatal follow-up?

AIM: To assess whether attrition rate influences outcome in the follow-up of very preterm infants. STUDY DESIGN: In a national follow-up study of infants born alive in 1983 in the Netherlands with a gestational age less than 32 weeks and/or a birth weight less than 1500 g, outcome was assessed separately for adolescents who responded early or late to a follow-up invitation at age 14 years. Neonatal data and outcome results of earlier assessments from early and late responders were compared to those of non-responders by univariate and nominal (polytomous logistic) regression analysis. SUBJECTS: There were 723 (76%) early responders, 130 (14%) late responders and 109 (11%) non-responders. RESULTS: We found significantly more non-Dutch origin and more disabilities and school problems at age 10 years in late- and especially in non-responders. At age 14 years, the health utility index was significantly lower in late responders compared to early responders. School outcome did not show difference in relation to the response groups. CONCLUSION: The results suggest that the incidence of adverse outcome in very preterm infants is underestimated when follow-up is incomplete and hence response rate is not a negligible problem in the assessment of late outcome. Therefore, follow-up studies should include a drop-out analysis to enable comparison to other studies.

Parenting, family contexts, and personality characteristics in youngsters with VCFS.

Parenting, family contexts, and personality characteristics in youngsters with VCFS: The personality profiles for 48 youths with Velo-Cardio-Facial syndrome (VCFS) were described using the California Child Q-Set (CCQ). Associations between personality characteristics and parenting (i.e., Control and Warmth vs. Anger) and family contexts (i.e., Experienced Family Stress, Marital Conflict and Parental Consistency) were investigated. Personality characteristics were found to be related to parenting (in particular, Parental Warmth vs. Anger) but not to family contexts. Parents who reported more Parental Warmth (and less Anger) in interactions had children with higher Agreeableness, Conscientiousness and Emotional Stability and with lower Irritability and Dependency. Parental Control was positively related to children's Dependency and negatively to children's Conscientiousness. Compared to fathers, mothers exerted more Control. Differences in parenting and family contexts were related to the mode of inheritance but not to IQ, age, gender, and cardiac defects. Families in which a familial deletion occurred reported higher levels of Marital Conflict and lower Warmth in the parent-child interactions.

Psychotic disorders in Prader-Willi syndrome.

The Prader-Willi syndrome (PWS) is a genetically determined developmental disorder caused by abnormalities of the proximal region of chromosome 15q11-13. In a previous study, we reported that psychotic episodes, occurring in 16% of persons with PWS, had an onset in adolescence, never occurred in persons with paternal deletion, and were exclusively associated with maternal uniparental disomy (UPD) or imprinting abnormalities (IM). In order to gain a better understanding of the psychopathology and to further refine the psychiatric diagnosis, we describe in more detail the psychopathological manifestations of six adults with a history of psychotic episodes. All these individuals had a detailed psychiatric examination, including the use of the operational criteria (OPCRIT) checklist. An identifiable subtype of psychotic disorder was associated with PWS. Characteristics include early age of onset, acute onset, polymorphous, and shifting symptomatology and a need for psychiatric hospitalization. The presence of precipitating stress factors and a prodromal phase with physiological symptoms was reported in all patients. Current diagnostic categories do not allow an unequivocal psychiatric diagnosis.

Age at diagnosis, body mass index and physical morbidity in children and adults with the Prader-Willi syndrome.

Age at diagnosis, Body Mass Index and physical morbidity in children and adults with the Prader-Willi syndrome: The medical findings of a population of 54 Prader-Willi patients with a molecular confirmed diagnosis are discussed. In the age group aged 18 or younger, a reasonably good control of weight as measured by Body Mass Index (BMI) is found. This is probably due to the fact that diagnosis was made at an early age and intensive diet management was started early. Despite their relatively low BMI, these children remain at high risk for developing scoliosis requiring active treatment (28% of the children). Adults (older than 18) diagnosed at the age of 10 or later have a high risk for developing obesity and obesity related health problems such as hypertension (38%), non-insulin dependant diabetes mellitus (11%) and cardio respiratory failure (16%).

Early detection of psychosocial problems in adolescents: how useful is the Dutch short indicative questionnaire (KIVPA)?

BACKGROUND: Psychosocial problems, such as behavioural, emotional, and educational problems, are highly prevalent among children and adolescents. Early treatment may reduce these problems, if accurately identified. Validated questionnaires may support identification. The aim of this study is to assess the psychometric qualities of such a questionnaire, the Short Indicative Questionnaire for Psychosocial problems among Adolescents (KIVPA,) and to determine whether it is suitable for and adds to the early detection of psychosocial problems among adolescents. METHODS: Data came from a national sample of 1,440 Dutch adolescents, using the KIVPA, the Child Behavior Checklist (CBCL), and the Youth Self-Report (YSR). Of these, 1,248 provided data on all questionnaires (77.8%). The scale structure of the KIVPA was assessed; its sensitivity and specificity using CBCL, YSR and referral for psychosocial problems as criteria; and its contribution to detecting CBCL and YSR problems. RESULTS: The KIVPA is mostly uni-dimensional but the variance explained by its main factor is relatively low. The total KIVPA score discriminates between adolescents with and without problems on the three criteria. Using a clinical YSR total problem score as criterion, sensitivity and specificity are 0.82 and 0.85, respectively, at the proposed cut-off (area under the ROC curve: 0.92; 95% confidence interval (CI) 0.90-0.95). The odds ratio of a clinical YSR score for an elevated KIVPA score is 29.1 (95% CI: 14.4-59.1), although the KIVPA mainly covers internalizing problems. CONCLUSION: The KIVPA has added value in the early detection of internalizing psychosocial problems, but is not sufficiently efficient.

Personality profiles of children and adolescents with neurofibromatosis type 1.

The personality profile of 44 youngsters (24 males, 20 females; mean age 11 years, 3 months) with neurofibromatosis type 1 (NF1) was compared with a group of 220 non-NF1 control youngsters (matched on age and gender). Personality characteristics of each youngster were rated by both parents, using the California Child Q-set (CCQ); [Block and Block, 1980]. The scores on eight personality dimensions were compared, i.e., Extraversion, Agreeableness, Conscientiousness, Emotional Stability, Openness, Motor Activity, Irritability, and Dependency. Moreover, personality of NF1 youngsters was related to IQ level, severity of medical problems, the presence or absence of visible cosmetic disfiguring, and de novo versus familial origin of NF1. The personality profile of NF1 youngsters was markedly different from the non-NF1 youngsters. Compared to the 220 control children, they were equally agreeable, but less conscientious, less emotionally stable, less open for new experience, with less motor activity, and more extravert, more dependent, and more irritable. Personality characteristics were similar for children with maternally or paternally inherited NF1, or for children with a new mutation. There was no association with gender, the severity of medical and cosmetic problems, and IQ.