Three siblings with Prader–Willi syndrome caused by imprinting center microdeletions and review

Prader–Willi syndrome (PWS) is a complex genetic imprinting disorder characterized by childhood obesity, short stature, hypogonadism/hypogenitalism, hypotonia, cognitive impairment, and behavioral problems. Usually PWS occurs sporadically due to the loss of paternally expressed genes on chromosome 15 with the majority of individuals having the 15q11‐q13 region deleted. Examples of familial PWS have been reported but rarely. To date 13 families have been reported with more than one child with PWS and without a 15q11‐q13 deletion secondary to a chromosome 15 translocation, inversion, or uniparental maternal disomy 15. Ten of those 13 families were shown to carry microdeletions in the PWS imprinting center. The microdeletions were found to be of paternal origin in nine of the ten cases in which family studies were carried out. Using a variety of techniques, the microdeletions were identified in regions within the complex SNRPN gene locus encompassing the PWS imprinting center. Here, we report the clinical and genetic findings in three adult siblings with PWS caused by a microdeletion in the chromosome 15 imprinting center inherited from an unaffected father that controls the activity of genes in the 15q11‐q13 region and summarize the 13 reported cases in the literature.

     

Daily patterns of symptom reporting in families with adolescent children

Objectives. This study was designed to investigate how symptom reporting varies by time of day, day of the week, gender and generation. Design. Concurrent symptom reporting was assessed prospectively using a computer‐assisted self‐report method. Methods. A computer‐assisted self‐observation method was used to assess concurrent somatic complaints six times a day for 7 consecutive days. Parents and adolescents from 173 families (568 individuals) filled in questionnaires during a normal workweek. A generalized linear model approach for multi‐level models was used to analyse the multiple daily observations. Results. Results show a curvilinear within‐day pattern for the reporting of somatic complaints, such that complaints were reported most in the morning and evening and least in the middle of the day. On weekends, participants reported fewer complaints in the evening. Women reported more symptoms throughout the day. Adolescents show an earlier and more pronounced increase in symptom reporting towards the evening. In addition, a slight decline in symptom reporting over the observation period was observed. Conclusion. Symptom reporting changes throughout the day, and is influenced by gender, generation and day of the week.     

Contributing factors of mortality in Prader–Willi syndrome

Prader–Willi syndrome (PWS) is a multi‐system disorder resulting from a lack of paternal gene expression in the 15q11.2‐q13 region. Using databases compiled through response questionnaires completed by families known to the Prader‐Willi Syndrome Association (USA), this study tested the hypothesis that PWS genetic subtype, BMI, age of diagnosis, clinical symptoms, and growth hormone treatment differ among deceased and living individuals with PWS. Categorical and continuous variables were compared using chi‐square and two‐group t tests, respectively. Deceased individuals had higher rates of clinical features, including increased weight concerns, heart problems, sleep apnea, other respiratory complications, diabetes, osteoporosis, high pain tolerance, and severe skin picking, when compared to living individuals. Meanwhile, living individuals had higher rates of growth hormone use and early puberty. Obesity and subsequent consequences are the primary contributors to increased mortality in PWS. Additional emphasis on areas to decrease mortality is needed.     

Cognitive–emotional hyperarousal in the offspring of parents vulnerable to insomnia: a nuclear family study

Cognitive–emotional hyperarousal is believed to be a predisposing factor for insomnia; however, there is limited information on the association of familial vulnerability to insomnia and cognitive–emotional hyperarousal. The aim of this study was to estimate the heritability of stress‐related insomnia and examine whether parental vulnerability to stress‐related insomnia is associated with cognitive–emotional hyperarousal in their offspring. We studied a volunteer sample of 135 nuclear families comprised of 270 middle‐aged (51.5 ± 5.4 years) fathers and mothers and one of their biological offspring (n = 135, 20.2 ± 1.1 years). We measured vulnerability to stress‐related insomnia (i.e. Ford Insomnia Response to Stress Test: FIRST), perceived stress, depression and anxiety in all participants, and arousability, presleep cognitive and somatic arousal, coping and personality in the offspring. We found a heritability estimate of 29% for FIRST scores. High FIRST parents had three to seven times the odds of having offspring highly vulnerable to stress‐related insomnia. Offspring of high FIRST parents showed higher arousability, presleep cognitive arousal and emotion‐oriented coping. Furthermore, high FIRST mothers contributed to offspring's higher anxiety and lower task‐oriented coping, while high FIRST fathers contributed to offspring's higher presleep somatic arousal and conscientiousness. Vulnerability to stress‐related insomnia is significantly heritable. Parents vulnerable to stress‐related insomnia have offspring with cognitive–emotional hyperarousal who rely upon emotion‐oriented coping. These data give support to the notion that arousability and maladaptive coping are key factors in the aetiology of insomnia.     

Somatic symptoms, peer and school stress, and family and community violence exposure among urban elementary school children

Somatic symptoms are a common physical response to stress and illness in childhood. This study assessed 409, primarily African American (85.6 %), urban elementary school children to examine the association between: (1) somatic symptoms and potential external stressors (school and peer stress, family conflict, and community violence) and (2) parent and child agreement on children’s self-report of somatic symptoms. The odds of self-report of somatic complaints were significantly associated with family conflict, school and peer stress, and community violence exposure (OR = 1.26, 95 % CI: 1.05–1.50; OR = 1.18, 95 % CI 1.08–1.28; and OR = 1.02, 95 % CI: 1.00–1.05, respectively). Identifying the associations between social, family, and community based stress and somatic symptoms may improve the quality of life for children living in urban environments through early identification and treatment.     

Problem Behaviors and Personality of Children and Adolescents With Prader-Willi Syndrome

Objective: Compare behavioral and emotional problems of childrenand adolescents with Prader-Willi Syndrome (PWS) and clientsconsulting mental health centers (MHC) and related behavioraland emotional problems to the children's personality in thePWS group. Methods: Participants were 39 children with PWS and 585 matchedMHC dlents. Child Behavior Checklist (CBCL) syndromes were relatedto the Big-Five personality factors measured with the CaliforniaChild Q-sort (CCQ). Results: Mean CBCL Total Problems scores were not differentfor the PWS and MHC groups, but differences were found for severalof the CBCL subscales. Patterns of correlations among CBCL scaleswere similar In both groups, although coefficients were generallyhigher in the PWS group, indicating higher comorbidity or co-absenceof CBCL syndromes in children and adolescents with PWS. Personalityprofiles were specific for Internalizing and Externalizing problemsof children and adolescents with PWS.     

Glycemic control in youth with type 1 diabetes: family predictors and mediators

OBJECTIVE: This study examined predictive and mediated relationships among youth perception of critical parenting, Child Behavior Checklist Externalizing Subscale (CBCL) externalizing problem scores, adherence, and (hemoglobin A(1c) HbA(1c)), in youth with type 1 diabetes from low socioeconomic status families. METHODS: Caregiver/youth dyads (n = 120) completed diabetes specific measures of family functioning regarding diabetes management and structured adherence interviews. Parents completed the CBCL, while assays of youth HbA(1c) were performed. Analyses were conducted using hierarchical linear regression. RESULTS: Combined measures predicted 44% of the variance in HbA(1c). Adherence partially mediated critical parenting and HbA(1c), while critical parenting and adherence mediated CBCL externalizing problem scores and HbA(1c). CBCL externalizing problem scores did not mediate critical parenting and HbA1(c). CONCLUSIONS: The presence of youth perceptions of critical parenting and youth externalizing behavior problems may interfere with adherence, leading to increases in HbA(1c).     

Parental PTSD,adverse parenting and child attachment in a refugee sample

In contrast with traumatic experiences, there is a dearth of studies on the link between trauma symptoms, disconnected (frightened, threatening and dissociative) parenting behavior, extremely insensitive parenting behavior and child attachment. This study extends previous work on the impact of posttraumatic stress disorder (PTSD) on families by studying the unique contribution of disconnected and extremely insensitive parenting behavior on child attachment in a highly traumatized sample of 68 asylum seekers and refugees and their children (18–42 months). The results show that parental symptoms of PTSD are directly related to children’s insecure attachment and disorganized attachment. The greatest proportion of the risk could be attributed to factors related to the dyad and not the family. A mediation effect of adverse parenting behavior was not confirmed. On the one hand the results indicate the need for an effective treatment of PTSD symptomatology while on the other hand the results indicate the need for clinical attention to insecure attachment relationships.     

Functional independence of Taiwanese children with Prader–Willi syndrome

Prader–Willi syndrome (PWS) is a genetic disorder with obesity, developmental delay, short stature, and behavioral abnormalities. The study aimed to assess the functional independence in children with PWS. The Functional Independence Measure for Children (WeeFIM) was used to evaluate 81 children with PWS (44 boys and 37 girls) with a median age of 11 years 1 month (range 2 years 8 months to 20 years 2 months) were recruited between January 2013 and December 2016. The mean total WeeFIM score was 103.8 (maximum 126). Sixty‐five patients (80%) had deletion type PWS, 16 (20.0%) had nondeletion type. The scores were 103.6 ± 18.5 for deletion and 104.8 ± 18.3 for nondeletion type (p = .405), 104.8 ± 19.3 in boys and 102.6 ± 17.3 in girls (p = .293). The mean self‐care, mobility, and cognition scores were 47 (maximum 56), 33 (maximum 35), and 24 (maximum 35), respectively. All total scores and 18 subscores in the three functional domains were positively correlated with age (p < .05). Most children required assistance in problem‐solving, comprehension, and expression. The WeeFIM identified the strengths and limitations of children with PWS and confirmed that support and supervision were needed in cognitive and self‐care tasks.     

Parenting Stress Among Caregivers of Children With Bipolar Spectrum Disorders

Caregivers of psychiatrically impaired children experience considerable parenting stress. However, no research has evaluated parenting stress within the context of pediatric bipolar spectrum disorders (BPSD). Thus, the aim of this investigation was to identify predictors and moderators of stress among caregivers in the Longitudinal Assessment of Manic Symptoms study. Participants included 640 children and their caregivers in the Longitudinal Assessment of Manic Symptoms cohort. Children had a mean age of 9.4 ± 1.9 years (68% male, 23% BPSD); parents had a mean age of 36.5 ± 8.3 years (84% mothers). Children with BPSD had more service utilization, psychiatric diagnoses, mood and anxiety symptoms, and functional impairment but fewer disruptive behavior disorders. Caregivers of children with BPSD were more likely than caregivers of children without BPSD to have a partner, elevated depressive symptoms, antisocial tendencies, and parenting stress (Cohen’s d = .49). For the whole sample, higher child IQ, mania, anxiety, disruptive behavior, and caregiver depression predicted increased parenting stress; maternal conduct disorder predicted lower stress. Child anxiety and disruptive behavior were associated with elevated caregiver stress only for non-BPSD children. Caregivers of children with BPSD experience significant burden and thus require specialized, family-focused interventions. As stress was also elevated, to a lesser degree, among depressed caregivers of children with higher IQ, mania, anxiety, and disruptive behavior, these families may need additional supports as well. Although parents with conduct/antisocial problems evidenced lower stress, these difficulties should be monitored. Thus, parenting stress should be evaluated and addressed in the treatment of childhood mental health problems, especially BPSD.     

Subjective sleep disturbance and its correlates in middle-aged Hong Kong Chinese women

OBJECTIVES: To examine the factors associated with subjective sleep disturbance in middle-aged Hong Kong Chinese women. METHODS: A total of 305 women aged 45-55 years were recruited at community-based women's clubs. Eligible subjects were of Chinese ethnicity and not taking oral contraceptives, hormone therapy or had received surgical removal of ovary. Standardized questionnaires, including sociodemographic, health and life-style variables, Pittsburgh Sleep Quality Index (PSQI), Greene Climacteric Scale (GCS) and Perceived Stress Scale were administered. RESULTS: About 18% of the sample complained of difficulty initiating sleep, difficulty maintaining sleep or early morning awakening at least three times per week in the past month. About 26% of the women were poor sleepers as defined by a global PSQI score >5. Sleep difficulty was one of the five most commonly reported climacteric symptoms. Cross-sectional analysis found that significantly more peri- and postmenopausal women had subjective sleep disturbance than premenopausal women. Multiple logistic regression analysis showed that women who had high levels of somatic complaints, psychological symptoms and perceived stress had a four to sixfold increased risk of reporting disturbed sleep. Menopausal status was not an independent predictor. CONCLUSIONS: Comparison of our findings with recent literatures suggested a lower prevalence of insomnia in Hong Kong Chinese middle-aged females than Caucasian women. Somatic complaints, psychological symptoms and perceived stress were independent risk factors for sleep disturbance. Clinicians should screen for sleep problems in middle-aged Chinese women with prominent somatic and psychological symptoms and perceived stress.     

Congenital ichthyosis in Prader–Willi syndrome associated with maternal chromosome 15 uniparental disomy: Case report and review of autosomal recessive conditions unmasked by UPD

Prader–Willi syndrome (PWS) is a prototypic genetic condition related to imprinting. Causative mechanisms include paternal 15q11‐q13 deletion, maternal chromosome 15 uniparental disomy (UPD15), Prader–Willi Syndrome/Angelman Syndrome (PWS/AS) critical region imprinting defects, and complex chromosomal rearrangements. Maternal UPD15‐related PWS poses risks of concomitant autosomal recessive (AR) disorders when the mother carries a pathogenic variant in one of the genes on chromosome 15 associated with autosomal recessive inherited disease. Co‐occurrence of autosomal recessive conditions in the setting of UPD leads to increased complexity of the clinical phenotype, and may delay the diagnosis of PWS. We report a patient with PWS and associated congenital ichthyosis due to maternal UPD15, and a homozygous novel pathogenic variant in ceramide synthase 3 (CERS3). We also review the literature of associated disorders reported in the setting of maternal UPD15‐related PWS and provide a summary of the previously described CERS3 variants. This represents the second case of autosomal recessive congenital ichthyosis (ARCI) in the setting of PWS and UPD15. There needs to be a high index of suspicion of this genetic mechanism when there is unexpected phenotype or evolution of the clinical course in a patient with PWS.     

Stability and change in depressive symptoms from pregnancy to two months postpartum in childbearing immigrant women

Summary The present study explored changes in mental health and functional status from pregnancy to 2 months postpartum in a sample of 106 childbearing immigrant women. Three sets of variables were examined in relation to postpartum depressive symptomatology: (1) prenatal depression, worries, and somatic symptoms; (2) social relationships (marital quality and social support), and (3) factors related to migration (premigration stress and length of stay in the host country). We found that 37.7% of the women in this community sample scored above the cutpoint of 12 on the Edinburgh Postnatal Depression Scale; prenatal depressive and somatic symptoms, as well as marital quality, were the best predictors of postpartum depressive symptomatology. An examination of differing trajectories from pregnancy to the postpartum period suggests that women with relatively few somatic complaints, low levels of perinatal stress, and satisfactory marital relations were less likely to exhibit mental health problems during pregnancy and postpartum. Women who were not depressed prenatally but reported postpartum depressive symptomatology exhibited several predisposing risk factors during pregnancy: many somatic complaints, high perinatal anxiety, and premigration stress. Women who were depressed during pregnancy but not postpartum reported improved physical function after childbirth. The implications of these findings for screening childbearing immigrant women are discussed. Correspondence: Dr. Phyllis Zelkowitz, Institute of Community and Family Psychiatry, Sir Mortimer B. Davis Jewish General Hospital, 4333 Cote Ste Catherine Road, Montréal, Québec, Canada H3T 1E4     

Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause

Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss‐of‐function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype–phenotype correlations. Most mutation‐negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.     

Myokine levels after resistance exercise in young adults with Prader–Willi syndrome (PWS)

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.     

Third Prader‐Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

We report on a boy with mosaicism for trisomy 15 and Prader‐Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype–genotype differences are useful to guide the work‐up of patients with suspected PWS and to provide prognostic counseling for families. Am. J. Med. Genet. 93:215–218, 2000. © 2000 Wiley‐Liss, Inc.     

Markers of stress and inflammation as potential mediators of the relationship between exercise and depressive symptoms: Findings from the TRAILS study

The hypothalamic‐pituitary‐adrenal axis, autonomic nervous system, and immune system have been proposed to underlie the antidepressant effect of exercise. Using a population sample of 715 adolescents, we examined whether pathways from exercise to affective and somatic symptoms of depression were mediated by these putative mechanisms. Exercise (hours/week) and depressive symptoms were assessed at age 13.5 (± 0.5) and 16.1 (± 0.6). Cortisol and heart rate responses to a standardized social stress test and C‐reactive protein levels were measured at age 16. Exercise was prospectively and inversely related to affective (B = ?0.16, 95% CI = ?0.30 to ?0.03) but not somatic symptoms (B = ?0.04, 95% CI = ?0.21 to 0.13). Heart rate during social stress partially mediated this relationship (B = ?0.03, 95% CI = ?0.07 to ?0.01). No other mediating effects were found. Hence, the autonomic stress system may play a role in the relationship between exercise and depressive symptoms.     

Plasma cholecystokinin levels in Prader‐Willi syndrome and obese subjects

The cardinal feature of individuals with Prader‐Willi syndrome (PWS) is severe hyperphagia‐mediated obesity resulting from a faulty satiety mechanism. PWS is the most common genetic cause of marked obesity. Cholecystokinin (CCK) is a 33‐amino‐acid peptide found in high levels in the gut and brain involved in mediating the satiety response to meals. Free fatty acids (FFA) are responsible for the stimulation of CCK release after a fatty meal, and CCK and plasma FFA levels rise in tandem in normal individuals. Fasting plasma CCK levels were measured by radio‐immunoassay in 33 PWS subjects with a mean age of 22.2 years ± 8.1 years and 24 obese control subjects without a known cause of their obesity with a mean age of 28.7 years ± 12.9 years. Consistent with previous findings, neither fasting plasma FFA levels (617.5 versus 486.8 μm/mL) or CCK levels (21.0 versus 19.1 pg/mL) were significantly different in PWS or control subjects, respectively. However, there was a significant correlation between fasting plasma FFA and CCK levels in obese subjects (r = 0.64, P < 0.01), this correlation was completely lacking in PWS subjects (r = −0.06, P = 0.79). This difference in correlation coefficients constitutes a large effect. There were no significant effects observed for genetic subtypes (15q11‐q13 deletion or maternal disomy 15), body mass index, percentage of fat, plasma levels of insulin, C‐peptide, glucagon or leptin, age, or gender on CCK levels in our PWS subjects. These results suggest that differences in the peripheral CCK response to FFA levels may be a factor contributing to the altered satiety response in PWS subjects. Am. J. Med. Genet. 95:67–70, 2000. © 2000 Wiley‐Liss, Inc.     

Menopausal symptoms and symptom clustering in Chinese women

Objectives: this paper aims to report the prevalence of symptoms in the Hong Kong Chinese perimenopausal women; to construct reported symptoms into symptom groupings; and to clarify whether the symptom groups are associated with menopausal status. Methods: a random telephone survey of perimenopausal women aged 44–55 years was conducted in 1996. Eligible subjects were identified through telephone dialing of a random sample of the numbers listed in the residents’ telephone directory. Standardized questionnaire, including a 22-item symptom check list, was administered over the telephone. The principal component analysis method followed by varimax rotation was used to examine the relations among the symptoms. Results: differences in the prevalence of menstrual problems across the menopausal status were noted with perimenopausal women having the most complaints. Musculoskeletal conditions were the top complaints reported by the respondents, followed by headaches and psychological symptoms. About 10% of the women complained of hot flushes, and less than 5% of cold sweats. Five symptom clusters, namely psychological, musculoskeletal/gastrointestinal, non-specific somatic, respiratory, and vasomotor, have been identified. After adjustment for age, the analysis of variance showed that psychological, non-specific somatic and vasomotor symptoms were significantly associated with menopausal status, while musculoskeletal and respiratory were of borderline statistical significance. Conclusions: compared with pre- and post-menopausal women, perimenopausal women had the highest reports of symptom complaints. Musculoskeletal complaints were the most prevalent complaints, followed by psychological symptoms. While vasomotor symptoms were significantly associated with menopausal status, their prevalence was comparatively lower than that reported in Caucasian populations.     

Parental styles and long‐term outcome following treatment for anxiety disorders

Poor parenting has long been associated with the diagnosis of anxiety and mood disorders, but it is not clear whether perceived parenting can predict long‐term outcome following treatment. The shortened Parental Bonding Instrument (PBI) was examined in respect to outcome, 3–14 years after initial treatment, in a group of patients having an original diagnosis of generalized anxiety, panic or post‐traumatic stress disorder. All patients had been entered into one of six controlled clinical treatment trials between 1985 and 1999, which had compared cognitive behavioural therapy with other forms of treatment including psychotherapy, medication and placebo. Significantly lower levels of paternal care and higher levels of parental control were reported by patients still having a clinical diagnosis at long‐term follow‐up compared with those with no diagnosis. In addition, the parental style of ‘affectionless control’ (i.e. low care/high control) from either parent was over‐represented in those with a diagnosis at long‐term follow‐up. However, only maternal control was significant for male patients, whilst only paternal care and control were significant for females. Findings on a subgroup of patients, who completed the PBI both pre‐treatment and at long‐term follow‐up, suggest the results are not due to changes in clinical status affecting recall in the recovered patients. Copyright © 2004 John Wiley & Sons, Ltd.