[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.

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.

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.

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.

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.

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.

Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications.

In this contribution we review current knowledge of the chromosome 22q11 deletion syndrome, with special emphasis on the clinical characteristics, including physical features, cognitive-behavioral spectrum, and psychiatric complications.

Regional localization of two genes for nonspecific X-linked mental retardation to Xp22.3-p22.2 (MRX49) and Xp11.3-p11.21 (MRX50).

Two families with nonspecific X-linked mental retardation (XLMR) are presented. In the first family, MRX49, 5 male patients in 2 generations showed mild to moderate mental retardation. Two-point linkage analysis with 28 polymorphic markers, dispersed over the X-chromosome, yielded a maximal LOD score of 2.107 with markers DXS7107 and DXS8051 at theta = 0.0, localizing the MRX49 gene at Xp22.3-p22.2, between Xpter and marker DXS8022. Multipoint linkage analysis showed negative LOD values over all other regions of the chromosome. In the second family, MRX50, 4 males in 2 generations showed moderate mental retardation. Pairwise linkage analysis with 28 polymorphic markers yielded a LOD score of 2.056 with markers DXS8054, DXS1055, and DXS1204, all at theta = 0.0. Flanking markers were DXS8012 and DXS991, situating the MRX50 gene at Xp11.3-Xp11.21, in the pericentromeric part of the short arm of the X chromosome.

Dental caries and gingivitis in second grade schoolchildren in The Hague over the period 1969-1981.

In 1969, 1972, 1975 and 1978 dental examinations were carried out in the City of The Hague on cohorts of about 800 children from kindergartens and elementary schools in order to test a (dental) health education program. Since 1980/1981 weekly fluoride mouthrinses have been done in kindergartens and elementary schools in areas with lower SES. In 1981, a baseline dental examination for a follow-up study was carried out on about 500 second grade schoolchildren from areas of low and medium SES. In this baseline examination in 1981 a considerable improvement in dental health was found compared with the earlier cohort examinations, especially in medium SES groups. The average D3MFS value in 1981 was 1.53 and 0.92 for second grade children of the low and medium social level respectively; the average d3fs values were 5.83 and 3.42. Over the 12-yr period (1969-1981) a respective D3MFS reduction of 57.6 and 76.2% was found for low and medium SES. The percentage d3fs reduction for the primary dentition was 55.3 and 72.9%, respectively. In 1978 and 1981 the percentage of children without gingivitis was 26.8 and 31.9%. The difference in the number of gingivitis-free children between 1978 and 1981 seemed to be due to an increase in the number of children without gingivitis in the medium SES groups. A greater use of fluoride tablets was found in low and medium socioeconomic levels between 1972 and 1975, followed by a decrease in the period between 1975 and 1978 and another increase by 1981 compared with 1978.

Clinical cariostatic effectiveness of a NaF rinse in a low prevalence child population.

Epidemiologic studies in which oral health in schoolchildren in the nonfluoridated city of The Hague has been monitored, have revealed a substantial decrease in caries prevalence since 1969 in groups of all socioeconomic status (SES). Because of a still significantly higher caries activity in children of lower socioeconomic classes, in 1981 a weekly fluoride mouthrinsing program in these children was started. The purpose of the present study was to investigate the cariostatic effectiveness of a weekly 0.2% neutral NaF rinse in children with low caries prevalence. A sample of 29 schools stratified according to SES and randomly assigned to two groups was selected. One group of schools (14) performed weekly rinsing and the other group (15) served as controls. After 3 yr the number of children available for re-examination had dropped from 501 to 333, of which 62.2% had written parental consent for radiographic examination. Statistical analysis of the data showed that fluoride rinsing could establish a reduction in caries incidence only in children who did not use fluoride tablets. The results of this study are of special interest for health authorities in planning and implementing public dental health measures.

Dental caries in 5-, 7-, 9- and 11-year-old schoolchildren during a 9-year dental health campaign in The Hague.

In the autumn of 1969, 1972, 1975 and 1978 clinical and radiographic dental examinations were carried out on about 800 children in The Hague of kindergartens, and 2nd, 4th and 6th grades of elementary schools. The aim of this investigation was to assess what changes, if any, in dental health may have taken place as a result of the campaign "Haagse Aktie', based on dietary and dental health education. In the 5-, 7- and 9-year-old children no differences in dental health were found between 1969 and 1972. The first considerable improvement was found in 1975, especially in children from high social levels. In 1978 the children showed an even better dental health, compared with 1975. In the 5-year-old children the average d3mfs was 6.8. The average D3MFS in children of 7, 9 and 11 years of age in 1978 was 1.8, 3.9 and 8.2. At all socioeconomic levels the improvement of dental health was due to a considerable increase in the percentage of caries free children between 1975 and 1978; 27.6% 51.8%, 21.2% and 7.4%, respectively, of the 5-, 7-, 9- and 11-year-old children were caries free in 1978, compared with 10.0%, 14.2%, 3.1% and 0.9% in 1975. However, the reason for the reduction in caries is not known: it can only be the subject of speculation.

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%).

The Prader-Willi syndrome and the Angelman syndrome.

The Prader-Willi syndrome and the Angelman syndrome are characterised by a complex clinical and behavioural phenotype resulting from loss of paternal or maternal expression, respectively, of genes located on the human chromosome 15q11-13. Different molecular mechanisms leading to this imbalance have been identified, including microdeletions, intragenic mutations, uniparental disomy and imprinting centre defects. Low copy repeat gene clusters are known to flank the 15q11-13 microdeletion. They predispose to unequal crossing-over events resulting in the deletion. Involvement of multiple disease genes is strongly suspected and traditional positional cloning techniques as well as animal models are used to identify the involved genes. In this review we include the present state of art and a delineation of future approach to study the candidate genes in these two syndromes.

The velocardiofacial syndrome: a review.

The Velocardiofacial syndrome is characterised by a complex clinical behavioural phenotype, resulting from the imbalance of normal dosage genes located on 22q11. Low copy repeat gene clusters are known to flank the microdeleted region and predispose to unequal crossing over events resulting in the interstitial 22q11 deletion. Involvement of multiple disease genes is strongly suspected and traditional positional cloning techniques as well as mouse models are used to identify the involved genes.

Pierre-Robin sequence and severe mental retardation with chaotic behaviour associated with a small interstitial deletion in the long arm of chromosome 2 (del(2)(q331q333)).

In this report we describe a severely mentally retarded male presenting an interstitial deletion in the long arm of chromosome 2 (del(2)(q331q333)). He presented a Pierre-Robin sequence at birth, and during childhood increasing behaviour problems were noted.

Craniosynostosis and low middle frequency perceptive deafness in mother and son. A distinct entity?

A distinct entity?: In this report we describe the hitherto unreported association of low and middle frequency perceptive deafness and craniosynostosis in mother and son. The occurrence of hearing loss in the craniosynostosis syndromes is briefly reviewed.