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Many genetic disorders associated with intellectual disability are characterized by unique behavioral phenotypes which may have serious psychological consequences such as increasing the risk for sexual abuse (SA). Prader–Willi Syndrome (PWS), a severe neurogenetic syndrome with uncontrollable hyperphagia and high threshold for pain, is an excellent example of this issue. The absence of reports on SA in PWS highlights the lack of awareness to the topic. Our aim was to report on SA in individuals with PWS, describe its unique characteristics, and offer recommendations for its prevention. Caregivers of all individuals with genetically confirmed PWS living in the only two residential facilities designated for PWS in Israel were interviewed for a history of sexual behavior and abuse, and medical data were collected from their files. SA was reported in a quarter of the sample. In most of the cases (78%), food reward was used by the perpetrators to attract their victims. Age at SA ranged from 11 to 29 years. Most of the individuals did not disclose the event and some continued to initiate inappropriate sexual activity to obtain food. Characteristics unique to PWS, such as food-seeking behaviors and high threshold for pain, likely contribute to the risk for SA. These findings suggest that syndrome-specific programs for SA prevention should be considered for individuals with any genetic syndrome with behavioral problems that may increase SA risk.

Childhood adversity (CA) may alter reactivity to stress throughout life, increasing risk for psychiatric and medical morbidity, yet long-term correlates of milder CA levels among high functioning healthy adolescents are less studied. The current study examined the prevalence and impact of CA exposure among a cohort of healthy motivated elite parachute unit volunteers, prospectively assessed at rest and at the height of an intensive combat-simulation exposure. We found significantly reduced gene expression levels in resting mononuclear cell nuclear receptor, subfamily 3, member 1 (NR3C1), and its transactivator spindle and kinetochore-associated protein 2 (SKA2), that predict blunted cortisol reactivity to combat-simulation stress among CA exposed adolescents. Long-term alterations in endocrine immune indices, subjective distress, and executive functions persist among healthy high functioning adolescents following milder CA exposure, and may promote resilience or vulnerability to later real-life combat exposure.

Background Pediatric surgical procedures involve traumatic stress that may cause psychological distress, leading to decreased adherence to continued surgical follow-up and delayed physical recovery. Risk factors for pediatric medical trauma, however, have not been studied enough. We aim to define the risk factors detectable during hospitalization in pediatric surgery and characterize children at risk of developing PTSD, in order to focus preventive interventions on these children. Methods The participants in this prospective study were parents of 235 children aged 1–13 years hospitalized in a pediatric surgical ward, who form a representative sample of patients of this age in the ward. They completed questionnaires measuring symptoms of psychological distress, 3–5 months after discharge. Results Higher parental stress, parental concerns regarding family social support, and parental concerns regarding sibling problems had a significant positive correlation with the children’s emotional distress measured 3–5 months after hospitalization. Among children aged 1–5 years, emergency (as opposed to elective) operation and a higher number of invasive procedures were also positively correlated with the children’s PTSS. Conclusions There is a need to develop measurements for identifying children at high risk for developing posttraumatic stress following surgical intervention; guidelines for developing such a screening instrument are outlined. Type of study Prognosis study (level of evidence – 1).

After a traumatic medical event, such as surgery or hospitalization, a child may develop a phobia of medical care, sometimes preventing future medical adherence and impairing recovery. This study examined the correlation of Pediatric Medical Traumatic Stress (PMTS) on the development of Medical Phobia (MP) and subsequent treatment adherence. We enrolled 152 parents of children aged 1–6 hospitalized in a surgical ward. During hospitalization, parents completed questionnaires that identified post-traumatic stress symptoms. Four months post hospitalization, parents completed questionnaires on post-traumatic stress, medical phobia, psychosocial variables and medical adherence. We found a positive correlation between PMTS and MP and low adherence to medical treatment. In addition, MP mediated the relationship between PMTS severity and adherence, indicating that PMTS severity is associated with stronger medical phobia, and lower pediatric adherence to medical treatment. Our findings suggest that medical phobia serves as an essential component of PMTS. It is important to add medical phobia to medical stress syndrome definition. In addition, as MP and PMTS are involved in the rehabilitation and recovery process and subsequent success, it is an important aspect of treatment adherence.

Background: Illness, surgery, and surgical hospitalization are significant stressors for children. Children exposed to such medical events may develop post-traumatic medical syndrome (PMTS, pediatric medical traumatic stress) that could slow their physical and emotional recovery. Objective: This study examined the relationship between the level of parental psychological resilience and the development of PMTS in young children. Method: We surveyed 152 parents of children aged 1–6 who were admitted to the pediatric surgery department. Parents completed questionnaires in two phases. In the first phase, one of the parents completed the Acceptance and Action Questionnaire (AAQ-ll) and the Parental Psychological Flexibility (PPF) Questionnaire. In the second phase, about three months after discharge, the same parent completed the Young Child PTSD (Post Traumatic Stress Disorder) Checklist (YCPC) and the UCLA (Los Angeles, CA, USA) PTSD Reaction Index for DSM-5 Parent/Caregiver Version for Children Age 6 Years and Younger Evaluating Post-traumatic Disorder. In addition, the parent completed a Posttraumatic Stress Diagnostic Scale (PDS) questionnaire to assess the existence of post-traumatic symptoms in the parents. Results: The findings indicate that (1) a parent’s psychological flexibility is significantly associated with the level of personal distress (r = −0.45, p &lt, 0.001), (2) a parents’ level of distress is significantly correlated with the child’s level of PTMS, and (3) a parent’s level of psychological flexibility is a significant mediating factor between the level of parental post-traumatic distress and the child’s level of PTMS. Conclusions: A parent’s psychological flexibility may act as a protective factor against the development of the child’s mental distress after hospitalization or surgery.

Individuals with PWS require marked caloric restriction and daily exercise to prevent morbid obesity. Lower energy expenditure, hypotonia, decreased muscle mass, and cognitive impairment make exercise challenging for this population. Exercise guidelines include resistance training as an important component. Myokine responses to resistance exercise may mediate beneficial metabolic effects. We aimed to determine if young PWS adults can perform a resistance exercise program and to measure myokine responses in PWS versus age- and BMI-matched controls. Each group included 11 participants (7M/4F). Ages and BMI for PWS and controls were 30.7 ± 4.6 versus 30.1 ± 4.3 years and 28.3 ± 4.3 versus 28.2 ± 4.2 kg/m2 , respectively. Glucose, creatine kinase (CK), lactate, and myokines were measured before, after, 30, and 60 min after completing eight resistance exercises. Myokines were assayed using a multiplex myokine panel (Merck Millipore). CK was lower in PWS versus controls (62 ± 16 vs.322 ± 100 U/L, p < .04). Peak lactate was 3.7 ± 0.7 in PWS versus 7.3 ± 0.7 mmol/Lin controls (p < .001). The increase in interleukin-6 was similar in PWS and controls (41 ± 16% and 35 ± 10%, respectively). Pre- and post-exercise levels of the six myokines assayed showed no consistent differences between the PWS and control participants. PWS young adults are capable of performing resistance/strength-building exercise. The lower CK and peak lactate levels in PWS may reflect decreased muscle mass in this population. Further studies are needed to determine optimal exercise regimens and assess the role of myokines incontributing to the metabolic phenotype of PWS.

Hyperphagia leading to severe obesity with increased morbidity and mortality is the major manifestation of Prader-Willi syndrome. Caring for these individuals in a home environment is challenging and stressful for caregivers and families. Residential hostels specifically for PWS adults offer programs of diet, exercise, and vocational opportunities, but long-term effects of PWS hostel living have not been reported. We studied long-term changes in body mass index (BMI) for PWS adults living in residential hostels compared with age-matched controls living with families at home. The study included all 34 individuals (18 men) aged >17 years with genetically confirmed PWS living in residential hostels. BMI was recorded at the time of yearly clinic visits and compared to 23 PWS adults (10 men) living at home. BMI on entering the hostel was 36.3 ± 11.0 kg/m2 and decreased to 27.0 ± 5.6 kg/m2 (p

Many genetic disorders associated with intellectual disability are characterized by unique behavioral phenotypes which may have serious psychological consequences such as increasing the risk for sexual abuse (SA). Prader-Willi Syndrome (PWS), a severe neurogenetic syndrome with uncontrollable hyperphagia and high threshold for pain, is an excellent example of this issue. The absence of reports on SA in PWS highlights the lack of awareness to the topic. Our aim was to report on SA in individuals with PWS, describe its unique characteristics, and offer recommendations for its prevention. Caregivers of all individuals with genetically confirmed PWS living in the only two residential facilities designated for PWS in Israel were interviewed for a history of sexual behavior and abuse, and medical data were collected from their files. SA was reported in a quarter of the sample. In most of the cases (78%), food reward was used by the perpetrators to attract their victims. Age at SA ranged from 11 to 29 years. Most of the individuals did not disclose the event and some continued to initiate inappropriate sexual activity to obtain food. Characteristics unique to PWS, such as food-seeking behaviors and high threshold for pain, likely contribute to the risk for SA. These findings suggest that syndrome-specific programs for SA prevention should be considered for individuals with any genetic syndrome with behavioral problems that may increase SA risk.

Background Hospitalization and surgery are traumatic experiences that can result after traumatic stress symptoms (PTSS). Surgical interventions for congenital melanocytic nevus (CMN) can be very stressful, but their potential for causing PTSS has not been studied. We aim to determine prospectively whether children undergoing surgery for CMN develop PTSS and what are the specific risk factors for such an event. Objective The authors aim to determine prospectively whether children undergoing surgery for CMN develop PTSS and what the specific risk factors for such an event are. Methods Thirty children who were consecutively hospitalized in a pediatric surgery ward for CMN removal during the study period were recruited voluntarily. About 4 months after discharge from the hospital, the children and their parents were assessed for psychological distress. Results At the assessment 4 months after hospitalization, the children displayed a significant increase in symptoms of distress in comparison with baseline levels. Moreover, 33.3% met full post-traumatic stress disorder (PTSD) diagnostic criteria. The number of invasive procedures, family resources, and parental distress predicted 40% of the variance in PTSS, with parental distress predicting it most significantly. Conclusion The high prevalence of PTSS among children undergoing CMN removal and among their parents emphasizes the importance of actions for prevention and early treatment of psychological distress.

Introduction Surgical procedures involve traumatic stress. Children may develop chronic psychological distress and dysfunction after surgery, with consequent reluctance to comply with medical follow-up care. A literature review of this topic shows that it has been understudied. Our study aims to assess the frequency and characteristics of symptoms of persistent psychological distress in children following surgery, which have not been documented before, in order to promote its awareness and its early identification. Methods Parents of 79 children (aged 1–6) that were hospitalized in a pediatric surgical ward, comprising a representative sample, completed three validated questionnaires assessing their children's psychological symptoms 3–5months after the hospitalization. Results A significant portion of children suffer from psychological distress 3–5months after hospitalization. Moreover, 10.39% of the children exhibited symptoms of PTSD, and 28.6% of parents reported that the child's distress causes dysfunction. Additionally, our findings emphasize the parents' concerns regarding the child's behavior, function, and health following hospitalization. Conclusion Since a significant prevalence of hospitalization-related traumatic stress is documented, the awareness to it has to be improved, in order to reduce its frequency and increase adherence to medical follow-up care. Type of study Prognosis study. Level of evidence 1.

Background: Individuals with PWS require marked caloric restriction and daily exercise to prevent morbid obesity. Lower energy expenditure compared to BMI-matched controls along with hypotonia, decreased muscle mass, and cognitive impairment make exercise particularly challenging for this population. Exercise guidelines include resistance training as an important component. Myokine responses to resistance exercise may have beneficial metabolic effects. Objectives: Determine if young PWS adults can perform a resistance exercise program. Evaluate myokine responses to acute resistance exercise in young adults with PWS and compare responses with age and BMI-matched controls. Methods: Each study group included 11 participants (7M/4F). Mean±SD ages were 30.7±4.6 and 30.1±4.3 years for PWS and controls (NS). BMI values were 28.3±4.3 and 28.2±4.2 kg/m2 for PWS and controls, respectively (NS). Blood samples for glucose, creatine kinase (CK), lactate, hemoglobin A1c (HbA1C) and myokines were obtained before performing a program of eight resistance exercises lasting 45-60 minutes. Additional blood samples were drawn immediately after, and 30 and 60 minutes after completing the exercises. Myokines were assayed using a multiplex myokine panel (Merck Millipore). Paired t-test was used for comparing results for PWS vs controls. The unpaired t-test was used for comparing peak laboratory values with basal levels. Results: Basal levels (mean±SEM) of glucose, hemoglobin A1c, and lactate were similar for PWS and controls but CK was lower in PWS vs controls (62±16 vs 322±100 U/L, p

Introduction Since hospitalization can be a traumatic event for children, many of them may suffer from a cluster of chronic psychological and emotional difficulties called Pediatric Medical Traumatic Stress (PMTS). Although PMTS causes considerable functional impairment and psychological distress and may decrease the children's compliance with post-surgical care, awareness of this condition is low and thus not enough effort is made to prevent it. The objective of this study is to assess prospectively the prevalence and characteristics of PMTS in school-age children following hospitalization in a general pediatric surgery ward and in their parents, which has not been documented before. Materials Patients and Methods We recruited parents of 88 children aged 6 to 13 years old, hospitalized in a pediatric surgery ward and which form a representative sample of the children of this age in the ward. Three to five months after discharge from the hospital, the parents completed questionnaires measuring symptoms of psychological distress. Results About 26.4% of children displayed symptoms of PMTS, and 11.6% of parents suffered from posttraumatic stress disorder following their child's hospitalization. Moreover, we found a medium high positive correlation between the parents' level of distress and that of their child. Conclusion In view of the prevalence of PMTS among school-aged children following surgical intervention, it is necessary to promote increased awareness, preventive interventions, and early identification and treatment of this condition.

Background: As psychiatric consultants to pediatric wards, we are often asked whether to disclose to young children full information about the invasive medical procedures they face. To date, no studies have been published offering an evidence-based answer to this question. This prospective study examined whether sharing medical information with young children regarding invasive interventions correlates with the development of chronic post-traumatic stress three to five months after hospitalization. Method: The participants in this prospective study were parents of 151 children aged 3–13 who were hospitalized in a pediatric surgery ward. The sample was representative of the population hospitalized in this ward during that year. Independent of the study, parents of 104 children chose to share with them information regarding the procedure they were about to undergo, while parents of 47 children chose not to do so. t-Tests were used to assess the correlation between the children's exposure to medical information and their level of long-term post-intervention stress. Results: Findings show an inverse correlation between the children's exposure to medical information and their level of post-traumatic stress several months after their medical episode. The correlation is significant in both preschool children and school-aged children. Conclusions: We suggest the implementation of psychoeducation programs among both medical staff and parents in order to increase awareness of the importance of sharing medical information with young children facing medical challenges. Keywords: Pediatric Medical Traumatic Stress (PMTS), PTSD, Medical information, Surgical procedures

Objective: Prader–Willi syndrome (PWS) is a genetic multisystem disorder with various medical, cognitive, behavioral and psychiatric problems. PWS is caused by the lack of expression of paternal genes on chromosome 15q2-q13 due to a deletion (70–75%), uniparental disomy (25–30%) or imprinting center defect (

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by an insatiable appetite, dysmorphic features, cognitive and behavioral difficulties, and hypogonadism. The heterogeneous reproductive hormone profiles indicate that some PWS women may have symptoms of hypoestrogenism, while others may potentially be fertile. We describe our experience in the assessment and treatment of hypogonadism in adolescents and adult females with PWS. The study population consisted of 20 PWS females, age ≥16 years (27.3 ± 7.9 years), followed in our clinic (12 deletion, 7 uniparental disomy, 1 imprinting-center defect). General physical examination, pubertal assessment, body mass index (BMI), gynecological examination, ultrasonography, bone densitometry, and hormonal profiles [FSH, LH, inhibin B, estradiol, prolactin, and TSH] were performed. The relevant assessed factors were: FSH and inhibin B, menstrual cycles (oligo/amenorrhea or irregular bleeding), ultrasound findings (endometrial thickness, uterine/ovarian abnormalities), BMI, bone densitometry, and patient/caregivers attitude. We classified seven women with inhibin B >20 ng/ml as potentially fertile. Following the assessment of the above factors, we recommended the individual-specific treatment; contraceptive pills, intra-uterine device, estrogen/progesterone replacement, and cyclic progesterone, in 3, 1, 4, and 1 patients, respectively. Four patients did not follow our recommendations due to poor compliance or family refusal. We recommended contraception pills for one 26-year-old woman with inhibin B and FSH levels 53 ng/ml and 6.4 IU/L; however, she refused treatment, conceived spontaneously and had an abortion. Guidelines for hormonal replacement therapy in PWS need to be tailored individually depending on physical development, hormonal profiles, bone density, and emotional and social needs of each PWS adolescent and adult. © 2013 Wiley Periodicals, Inc.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

Cryptorchidism, incomplete pubertal development, and low testosterone are manifestations of hypogonadism in Prader-Willi syndrome (PWS). Insulin-like peptide-3 (INSL3) facilitates testicular descent in the fetus and reflects Leydig cell number in adults. INSL3 levels in PWS have not been previously reported.The objectives of the study were to characterize the age-related changes in INSL3 in PWS males and correlate INSL3 with unilateral vs. bilateral cryptorchidism, body mass index, gonadotropins, testosterone, anti-mullerian hormone (AMH), and inhibin B.We measured INSL3, LH, FSH, testosterone, AMH, and inhibin B in 40 PWS males (23 deletion, 17 uniparental disomy) aged 2 months to 36 yr. Control samples for INSL3 were obtained from 365 normal males, aged 1 d to 36 yr.INSL3 levels (mean and range) for PWS age groups younger than 6 months, 0.5-10.0 yr, 10.1-19.0 yr, and older than 19.0 yr were 217 (68-380), 42 (16-112), 390 (16-1028), and 642 (290-964) pg/ml, respectively, and did not differ significantly from values for normal males. In seven of 14 boys aged 10.1-19 yr, INSL3, testosterone, and LH were low (37.4 ± 19.4 pg/ml, 1.44 ± 0.46 nmol/liter, 0.3 ± 0.6 IU/liter). The other seven with higher INSL3, testosterone, and LH (693.1 ± 305.8 pg/ml, 5.91 ± 2.77 nmol/liter, 2.7 ±1.9 IU/liter) had more advanced pubertal development. INSL3 was normal in seven of nine males aged older than 19 yr, despite low testosterone in six. After controlling for age, INSL3 correlated with LH (P = 0.005) and testosterone (P0.001) but not with FSH, AMH, or inhibin B.Most PWS males have normal INSL3 levels. By contrast, testosterone levels after infancy are low. These findings suggest a specific defect in Leydig cell function.

Background:Psychiatric manifestations in Prader–Willi Syndrome (PWS) are common and often are the most debilitating problem in these individuals. We present an epidemiological nation-wide survey of psychiatric diagnoses in the PWS population, based on full-range psychiatric interviews.Methods:We studied the distribution of psychiatric diagnoses (as opposed to a symptom-based approach) in the Israel national cohort of adolescents and adults with PWS. There was a total of 53 (32 males) ages 12 years and older. All individuals and their caretakers were interviewed using standardized psychiatric questionnaires. Demographic and clinical variables, Clinical Global Impression (CGI) score, IQ, severity of hyperphagia and quality of life (QOL) were also assessed and correlations with NPD (number of psychiatric diagnoses) calculated.Results:An overwhelming majority (89%) of the study participants had at least one psychiatric diagnosis. The most common were disruptive behavior disorders (DBD) (68%), obsessive compulsive disorder (OCD) (45%) and skin picking (35%). Individuals with DBD were at increased risk for OCD and skin picking. Psychotic disorders were found in 11%. NPD had a significant negative influence on QOL. There was no correlation between NPD and BMI, IQ, hyperphagia severity, hormonal profile or genetic subtypes.Conclusions:Psychiatric diagnoses are very frequent in PWS and strongly influence QOL. Furthermore, characterizing the profile of psychiatric comorbidity in PWS is crucial for planning effective interventions. Precise behavioral phenotyping in PWS in combination with a well-defined genetic etiology may aid biological research linking biological correlates to behavior.

Relentless pursuit of food is a major characteristic of Prader-Willi Syndrome (PWS). We observed voluntary fasting among PWS individuals during a religious fast. Understanding the mechanisms involved in successful fasting could be an important contribution in developing more effective treatment of this syndrome. We conducted a prospective study to assess whether genotype, motivational attitudes (e.g. religiosity) and control patterns (e.g. different eating habits) would correlate with ability to fast. Among all individuals with PWS in Israel, 32 met inclusion criteria. Prior to the fast, each participant and parents/caregivers were interviewed for demographic, medical and behavioral data and completed questionnaires assessing motivational and control factors. 22 participants completed the fast. This ability was not accounted for by religiosity, demographic, medical variables or genetic subtype. This prospective study documents that in spite of extreme hyperphagia, adolescents and adults with PWS can voluntarily abstain from food for 25 hours; our findings suggest that they are able to activate mechanisms which improve their control of eating for a longer period than expected. The observation that the degree of religiosity did not impact on the ability to fast suggests that these mechanisms may be applicable to a wider range of circumstances and populations. The ability for self-control under special circumstances deserves further study; it may be relevant to other types of severe obesity and possibly lead to improved methods of behavioral modification.

ObjectiveThe variable hypogonadism in Prader–Willi syndrome (PWS) has generally been attributed to hypothalamic dysfunction. Recent studies have documented primary testicular dysfunction in PWS males. Our aims were to characterize sexual development and reproductive hormones in PWS females and to investigate the etiology of hypogonadism.DesignA cross-sectional study.MethodsPhysical examination was performed on 45 PWS females (aged 6 weeks to 32 years) and blood samples were obtained for hormonal analyses.ResultsAge of onset and progression of puberty varied; most adults had incomplete sexual development. Spontaneous menarche was reported in four (aged 15–30 years) but all had subsequently developed secondary amenorrhea or oligomennorrhea. Anti-Mullerian hormone levels were within the normal range in all age groups. Inhibin B was consistently low or undetectable; only five women had levels in the low-normal range (20–54 pg/ml). LH was normal in most children, but low (ConclusionsPubertal development in PWS females, as in males, is characterized by normal adrenarche, pubertal arrest, and hypogonadism due to variable combinations of a unique primary gonadal defect and hypothalamic dysfunction.

This study explored the contribution of two psychosocial factors, locus of control (LOC) and perceived parenting style, to symptoms of internalizing disorders in children with Tourette syndrome (TS). This contribution was further evaluated in relation to TS severity.Sixty-five children (53 boys, 12 girls) ages 9.0-16.9 years, of normal intelligence, completed questionnaires evaluating their depression and anxiety symptoms, LOC, and maternal parenting style. Their mothers rated TS severity, determined by tic severity, symptoms of attention-deficit hyperactivity disorder (ADHD) and obsessive compulsive symptoms (OCS).Higher rates of symptoms of anxiety and depression were associated with a more external LOC and a more rejecting and controlling parenting style. Additionally, depression correlated significantly with tic severity, ADHD and OCS, whereas anxiety correlated only with ADHD symptoms and OCS, but not with tics. Regression analyses showed that LOC, OCS and ADHD symptoms each significantly contributed to predicting anxiety level, whereas LOC and ADHD symptoms significantly contributed to predicting depression symptoms.Rates of symptoms of anxiety and depression in children with TS are markedly influenced by psychosocial factors, extending beyond the influence of ADHD and OCD, both common comorbid disorders in TS. An internal LOC, which is associated with an accepting and autonomy-granting parenting style, appears to be a protective factor against anxiety and depression.

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders Polygenic score analyses identified a significant polygenic component for OCD (p=2x10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring burette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Atomoxetine and OROS methylphenidate were successfully used concomitantly in a 10-year-old boy suffering from attention-deficit/hyperactivity disorder (ADHD) with comorbid bipolar disorder and Tourette syndrome (TS). The child received valproic acid, clonidine, and ziprasidone concurrently. Because possible side effects of pharmacological treatment for one diagnosis may exacerbate a comorbid condition, contingent management strategies, when using polypharmacy, are mandated.

Two hundred and sixty young terror victims were evaluated in the Emergency Room (ER) of a general hospital immediately after several terrorist attacks in Jerusalem. The developmental perspective is presented through descriptions of the psychological presentation in different ages. Less than 20% of the victims presented with a pathological acute stress reaction. Detailed examples of the clinical reactions are included. Issues of the intrapsychic difficulties stemming from the traumatic experience are raised. Finally, the role of the parent in the formulation and intensity of the child's psychological reaction is discussed.

Tourette syndrome (TS) is a chronic disorder characterized by motor and vocal tics. Previous studies reported a substantial lag period between disease onset and diagnosis ranging from 3 to 11.9 years.To determine the lag period and factors associated with diagnosis delay of TS.All files of 185 children with TS attending one neuropediatric unit in Jerusalem were reviewed. Lag time between disease onset, according to DSM criteria, and diagnosis was determined and the contributions of the disease course, comorbidities and epidemiological factors were assessed.A relatively short lag to diagnosis following the onset of diagnosable TS was documented (mean 13.2+/-15.9 months, median 6 months). A relatively longer gap was associated with older age at TS onset (r=0.161, p0.05) and vocal tics as the first manifestation rather than motor or combined motor and vocal tics (mean=20.3+16.3 months vs 11.9+16.5 and 12.6+15.2, respectively, p0.05). A relatively shorter gap was associated with tic severity (r=0.13, p0.05) and presence of comorbid obsessive-compulsive disorder (OCD) (9.5+14.7 months vs. 14.1+16 without OCD, p0.05).Lag time to diagnosis is relatively short in our population. Factors associated with a shorter lag (early age of TS onset, motor tics as the first manifestation, greater tics severity and the presence of OCD) may be perceived as disruptive, prompting patient and families to seek medical care. Conversely, vocal tics as the first manifestation, associated with a longer lag, may be misdiagnosed as features of common pediatric conditions, thus delaying diagnosis.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures., Author Summary Family and twin studies have shown that genetic risk factors are important in the development of Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). However, efforts to identify the individual genetic risk factors involved in these two neuropsychiatric disorders have been largely unsuccessful. One possible explanation for this is that many genetic variations scattered throughout the genome each contribute a small amount to the overall risk. For TS and OCD, the genetic architecture (characterized by the number, frequency, and distribution of genetic risk factors) is presently unknown. This study examined the genetic architecture of TS and OCD in a variety of ways. We found that rare genetic changes account for more genetic risk in TS than in OCD; certain chromosomes contribute to OCD risk more than others; and variants that influence the level of genes expressed in two regions of the brain can account for a significant amount of risk for both TS and OCD. Results from this study might help in determining where, and what kind of variants are individual risk factors for TS and OCD and where they might be located in the human genome.

Background We characterized the spectrum and etiology of hypogonadism in a cohort of Prader-Willi syndrome (PWS) adolescents and adults. Methods Reproductive hormonal profiles and physical examination were performed on 19 males and 16 females ages 16–34 years with PWS. Gonadotropins, sex-steroids, inhibin B (INB) and anti-Mullerian hormone (AMH) were measured. We defined 4 groups according to the relative contribution of central and gonadal dysfunction based on FSH and INB levels: Group A: primary hypogonadism (FSH >15 IU/l and undetectable INB (20 pg/ml); Group D: mild central and severe gonadal dysfunction (FSH 1.5–15 IU/l, INB Results There were 10, 8, 9 and 8 individuals in Groups A-D respectively; significantly more males in group A (9, 4, 4 and 2; P = 0.04). Significant differences between the groups were found in mean testosterone (P = 0.04), AMH (P = 0.003) and pubic hair (P = 0.04) in males and mean LH (P = 0.003) and breast development (P = 0.04) in females. Mean age, height, weight, BMI and the distribution of genetic subtypes were similar within the groups. Conclusions Analysis of FSH and inhibin B revealed four distinct phenotypes ranging from primary gonadal to central hypogonadism. Primary gonadal dysfunction was common, while severe gonadotropin deficiency was rare. Longitudinal studies are needed to verify whether the individual phenotypes are consistent.

Background Hypogonadism is a major feature of Prader-Willi syndrome (PWS), but clinical manifestations are variable. Sexual interests and behavior in this population have not been previously described. Objectives We studied PWS adolescents and young adults to assess 1) satisfaction with physical and sexual development, 2) frequency of romantic and sexual experiences, 3) aspirations and expectations regarding marriage, 4) possible relationships between sexual interests and hormone levels, and 5) the desire for hormonal replacement therapy. Methods The study population consisted of 27 individuals (13 males) ages 17-32 (mean 23.5) years with genetically confirmed PWS. Mean intelligence quotient (IQ) was 75 (range 50-100). We conducted structured interviews using questionnaires specifically designed for this study. Results There was a significant negative correlation between IQ and body image in both males and females. IQ showed a positive correlation with interest in dating and romantic activities. Approximately half of PWS males and females reported having been on a date and kissing romantically. All males and 64% of the females wished to be married. Seventy-seven per cent of PWS males wanted hormonal treatment to increase phallic size. We found no correlation between hormone levels and sexual interests. Only 43% of PWS females wanted hormonal medication to achieve regular menstruation. Conclusion Despite documented hypogonadism, PWS young adults are interested in sexual and romantic issues. The range of sexual activities and expectations is variable. Understanding specific sexual characteristics of each individual is important in order to offer proper anticipatory sexual guidance counseling and for appropriate recommendations for hormone replacement.

Objective: Individuals with Tourette syndrome (TS) often display comorbid symptoms of attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), as well as externalizing and internalizing behaviors. This study was aimed to examine the impacts of tic severity, ADHD symptoms, and OCD on internalizing (e.g., anxiety) and externalizing (e.g., aggression) psychopathology. Methods: Using linear regressions, we examined how tics, ADHD, and OCD symptoms predicted the externalization and internalization behaviors measured by the Child Behavior Checklist in a clinical sample of children and adolescents with TS. In addition, Child Behavior Checklist scales were compared among children with TS without ADHD, TS and ADHD, ADHD without TS, and unaffected control group. Results: In the TS group, externalizing behaviors were predicted by tic severity, inattention, and hyperactivity/impulsivity but not by OCD symptoms, whereas internalizing behaviors were predicted by inattention and OCD symptoms but not by tic severity or hyperactivity/impulsivity. Comparison among different clinical groups revealed main effects of TS and ADHD on both externalizing and internalizing behaviors. Conclusion: These findings suggest that tics, ADHD, and OCD symptoms differentially explain the variance in externalizing and internalizing behavioral problems in individuals with TS. In addition, the data support the notion that TS is itself a risk factor for behavioral problems, mandating that children with TS even without ADHD and OCD still need to be assessed and treated for psychopathology.

Recent studies challenge the assumption that hypogonadism in Prader-Willi syndrome (PWS) is due only to hypothalamic dysfunction.The aims of the study were to characterize sexual development and reproductive hormones in PWS males and investigate the etiology of hypogonadism.Physical examination and blood sampling were performed on 37 PWS males, ages 4 months to 32 yr.All had a history of undescended testes; age at orchiopexy ranged from 2 months to 6 yr. Pubertal signs were variable, but none achieved full genital development. Anti-Mullerian hormone (AMH) levels in PWS boys were near the lower limits of normal, decreasing from 44.4 +/- 17.8 ng/ml (mean +/- sd) in young children to 5.9 +/- 4.7 ng/ml in adolescents, similar to normal males. In contrast, inhibin B was consistently low (27.1 +/- 36.1 pg/ml) or undetectable in all age groups. In adult males, FSH levels were high (20.3 +/- 18.3 IU/liter), LH levels were normal (4.2 +/- 4.3 IU/liter), and testosterone levels were low (1.87 +/- 1.17 ng/ml). Only two adults had severe hypogonadotropic hypogonadism with undetectable levels of LH and FSH and high AMH levels (34.9 and 36.7 ng/ml), unlike the other nine adults with AMH levels 2.6 +/- 2.1 ng/ml. Androstenedione (1.06 +/- 0.30 ng/ml) and DHEAS (281.1 +/- 143.6 microg/dl) in adult PWS were normal.Pubertal development in PWS is characterized by normal adrenarche, variable hypothalamic dysfunction, and hypogonadism due to a unique testicular defect. Primary testicular dysfunction is a major component of hypogonadism in PWS.

Background/Aims: To investigate the etiology of hypogonadism in women with Prader-Willi Syndrome (PWS). Methods: Ten women aged 23 ± 5.5 years with PWS and 10 age- and BMI-matched controls were included. Blood samples were drawn and abdominal ultrasounds were performed on days 2–4 of spontaneous cycles or at random from amenorrheic women. Anti-Müllerian hormone (AMH), inhibin B (INB), gonadotropins, sex steroids, TSH, prolactin, ovarian volume and antral follicle count (AFC) in PWS women were compared with results from controls and the reference ranges. Results: Compared to controls, PWS women had lower INB (mean ± SD = 17.6 ± 12.8 pg/ml vs. 110.6 ± 54.5; p = 0.0002) and AMH levels (1.18 ± 0.86 ng/ml vs. 3.53 ± 2.42; p = 0.01). INB levels were exceptionally low in all PWS women, but individual AMH levels overlapped with the levels in the controls. Ovarian volume (mean ± SD = 3.7 ± 2.3 ml vs. 30.5 ± 28.8; p = 0.03) and AFC (6.4 ± 6.9 vs. 14.0 ± 8.2; p = 0.01) were lower in the PWS group compared to the controls. Three PWS patients had abnormally high follicle-stimulating hormone levels, while only 1 had hypogonadotropic hypogonadism. Conclusions: Our results suggest a unique follicular stage-specific insult in women with PWS. Thus, primary ovarian dysfunction is a major component of hypogonadism in PWS.

In this article the authors discuss the genetic, medical, and endocrinologic issues of Prader-Willi syndrome and their treatment. The authors also present the typical cognitive profile characterized by specific strengths and areas of disability. The behavioral phenotype of Prader-Willi syndrome affects four domains: food-seeking related behaviors; traits that indicate lack of flexibility; oppositional behaviors, and interpersonal problems. The management of the maladaptive behaviors is challenging and requires lifelong restrictive supervision (to prevent morbid obesity), addressing psychiatric comorbidity, psychopharmacologic management exacerbated by metabolic abnormalities, ongoing medical care, and, in many cases, institutional treatment. The multiple facets of the clinical problems demand a multidisciplinary approach with anticipatory medical and psychiatric care, oriented to enhancing the quality of life of individuals who have Prader-Willi syndrome.

Tourette Syndrome (TS) is a chronic, familial disorder, characterized by involuntary motor and phonic tics that wax and wane in severity. TS is frequently accompanied by behavioral, emotional and cognitive problems that are often more incapacitating than the tic disorder itself. After a review of the disorder, in which the multidisciplinary aspects are emphasized, the article describes the clinical features of 60 children with TS, 49 boys and 11 girls, aged 13 +/- 3.6 years (mean SD), treated in the Neuropediatric Unit at Shaare Zedek Medical Center. The children described had both motor and vocal tics, but also had ADHD (n = 44), obsessive-compulsive disorder (n = 32), learning disabilities (with 12 children learning in special education frameworks) and behavioral disorders (n = 36). The clinical profile of this group of children with TS is similar to that reported on referred patients regardless of cultural background. Since children with TS manifest multiple comorbidities, optimal therapy mandates the cooperation of a multidisciplinary team including a pediatric neurologist, a child psychiatrist, a psychologist and a family therapist. Working in concert, these specialists can implement a multimodal approach, addressing the neurological and psychiatric aspects of TS as well as enhancing the child's coping skills with the disorder itself and its consequences.

We studied the academic, cognitive, and behavior profile of 18 patients with Prader-Willi syndrome. All had severe learning disabilities in arithmetic and writing, and the majority were also dyslexic. Their average Full-Scale IQ was 73.7 ± 8.9, which was 1 SD below normal range, whereas their performance on executive, memory, and visuospatial tasks ranged from 2.1 to 7.0 SD below the expected means. Behavioral problems were measured using the Child Behavior Checklist, on which the majority scored in the pathologic range for social and attention problems, delinquent and aggressive behavior, somatic complaints, and thought problems. Genotypes of the children did not predict cognitive or behavioral profile, nor could behavior be associated with parameters of weight or IQ. In summary, we found that patients with Prader-Willi syndrome have profound learning disabilities and cognitive deficits, greater than expected for their IQ. Behavioral problems, including attention-deficit hyperactivity disorder (ADHD), are also prevalent and impede the overall management of this group of patients. The genotypes were not helpful in predicting cognitive or behavioral patterns. ( J Child Neurol 2001;16:288-290).