RESUMO
Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by a variety of mechanisms which include large deletions (70%-75%), maternal uniparental disomy (UPD) (20%-30%), and imprinting defects (2%-5%) or balanced translocations. Individuals often have a characteristic behavior disorder with mild intellectual disability, infantile hypotonia associated with poor sucking, short stature, and obesity. PWS is characterized by hypothalamic-pituitary axis dysfunction with growth hormone (GH) deficiency, hypogonadism, and several other hormonal deficiencies resulting in short stature, centrally driven excessive appetite (hyperphagia), central obesity, cryptorchidism, and decreased lean body mass. In this study, we determined and sought differences in the incidence of thyroid abnormalities among the common genetic subtypes in a cohort of 52 subjects with PWS because there was limited literature available. We also sought the effects of growth hormone (GH) treatment on the thyroid profile. Fifty-two subjects with a genetically confirmed diagnosis of PWS were included in this study at the University of California, Irvine. Blood samples for baseline thyroxine stimulating hormone (TSH) and free thyroxine (fT4) levels were obtained in the morning after an overnight fast for 8-12 h. Statistical analyses were performed with SPSS (SPSS Inc., 21.0). Mean values were analyzed by one-way ANOVA, and student's t-test and statistical significance were set at p < 0.05. The subjects included 26 males and 26 females with an age range of 3-38 years. There were 29 subjects with chromosome 15q11-q13 deletions and 23 with UPD; 28 were GH treated currently or in the past, and 24 never received GH. There was no significant difference in age or body mass index (BMI) (kg/m2) between GH-treated versus non-GH-treated groups. BMI was higher in the deletion group compared to the UPD group (p = 0.05). We identified two individuals who were clinically diagnosed and treated for hypothyroidism, one of whom was on GH supplements. We identified two additional individuals with subclinical hypothyroidism who were not on GH treatment, giving a frequency of 7.6% (4/52) in this cohort of patients. We did not find significant differences in thyroid function (TSH) in the deletion versus UPD groups. We found significant differences in thyroid function, however, between GH-treated and non-GH-treated groups. The mean TSH was lower (2.25 ± 1.17 uIU/M, range 0.03-4.92 uIU/M versus 2.80 ± 1.44 uIU/M, range 0.55-5.33 uIU/M respectively, p = 0.046), and the free T4 levels were significantly higher (1.13 ± 0.70 and 1.03 ± 0.11 ng/dL, respectively, p = 0.05) in the GH-treated individuals compared to non-GH-treated individuals. In this cohort of subjects with PWS, we identified two previously diagnosed individuals with hypothyroidism and two individuals with subclinical hypothyroidism (4/52, 7.6%), three of whom were not receiving GH treatment. We did not find any significant differences in thyroid function between molecular subtypes; however, we found that euthyroid status (lower TSH levels and higher free T4 levels) was significantly higher in individuals who were treated with GH compared to the untreated group. We recommend that individuals with PWS should be screened regularly for thyroid deficiency and start treatment early with GH in view of the potentially lower incidence of thyroid deficiency.
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Prader-Willi syndrome (PWS) is a complex genetic disorder with three genetic classes. Patients with PWS are characterized by severe hypotonia, developmental delay, behavioral problems, learning disabilities and morbid obesity in early childhood if untreated. Data were collected through Rare Disease Clinical Research Network (RDCRN) from four study centers which evaluated patients with PWS. The Behavior Assessment System for Children 2nd edition (BASC-2) was chosen to provide behavioral assessment. Data from 330 participants ((64% 15q11-q13 deletion (DEL), 36% maternal disomy 15 (UPD)) were separated into three age groups and analyzed, 68% of whom were still actively receiving recombinant human growth hormone (rhGH) treatment. When comparing the BASC results by molecular subtype, parent-reported aggression was higher for the deletion than for the UPD cohort (p = 0.007). Participants who were on rhGH treatment showed lower scores for parent-reported hyperactivity and aggression (p = 0.04, 0.04, respectively), and a trend for anger control (p = 0.06) and teacher-reported attention problems and aggression (p = 0.01, 0.004, respectively). Additional adjusted analyses were undertaken and significant differences were noted in the GH versus non-GH treated groups for only teacher-reported aggression, which increased in the No GH treated patient group (p = 0.03). This study showed documented differences in PWS behavior by molecular class and rhGH treatment. RhGH therapy may be beneficial for certain behaviors in patients with PWS; however, observed differences need more studies for confirmation in the future.
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BACKGROUND: Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls. METHODS: Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale. RESULTS: Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes. CONCLUSIONS: Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.
Assuntos
Síndrome de Angelman/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Síndrome de Prader-Willi/fisiopatologia , Síndrome de Rett/fisiopatologia , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/fisiopatologia , Adolescente , Síndrome de Angelman/complicações , Criança , Pré-Escolar , Humanos , Transtornos do Neurodesenvolvimento/complicações , Síndrome de Prader-Willi/complicações , Doenças Raras , Síndrome de Rett/complicações , Transtornos do Sono-Vigília/etiologiaRESUMO
Prader-Willi syndrome (PWS) is a complex genetic disorder with three molecular classes but clinical ascertainment is based on distinctive features. The prevalence of dysmorphic features was studied in 355 PWS participants (61% deletion, 36% maternal disomy [UPD], and 3% imprinting defects) from the National Institute of Health PWS Rare Diseases Clinical Research Network. The effect of growth hormone (GH) treatment on growth and dysmorphic features was compared. Among participants, upslanting palpebral fissures were seen in 23%; strabismus in 42%; abnormal dentition in 32%; small hands in 63% and small feet in 70%; hypopigmentation in 30%; striae in 32% and skin picking in 26%. Compared to those with UPD, participants with deletions were found to be heavier (p = 0.002), had smaller head circumference (HC) (p = 0.009), higher incidence of a flat occiput (p = 0.005); low-anterior hairline (p = 0.04); abnormal dentition (p = 0.009); abdominal striae (p = 0.045), nail abnormalities (p = 0.050), and fair-haired (p < 0.001). Participants in both genetic groups receiving GH were taller (p = 0.005), had larger HCs (p = 0.005), and longer hands (p = 0.049). This study suggested that PWS genetic subtypes and GH treatment can influence growth and dysmorphic features that may impact clinical diagnosis of PWS, such as stature, head shape and appearance of the eyes, nose, and genitalia.
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Hormônio do Crescimento/uso terapêutico , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/genética , Adolescente , Adulto , Estatura/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
Prader-Willi syndrome (PWS) is a complex multisystemic condition caused by a lack of paternal expression of imprinted genes from the 15q11.2-q13 region. Limited literature exists on the association between molecular classes, growth hormone use, and the prevalence of psychiatric phenotypes in PWS. In this study, we analyzed nine psychiatric phenotypes (depressed mood, anxiety, skin picking, nail picking, compulsive counting, compulsive ordering, plays with strings, visual hallucinations, and delusions) recognized in PWS and investigated associations with growth hormone treatment (GHT), deletions (DEL) and uniparental disomy (UPD) in a cohort of 172 individuals with PWS who met the criteria for analysis. Associations were explored using Pearson chi-square tests and univariable and multivariable logistic regression analyses to control for confounding exposures. This observational study of the largest dataset of patients with PWS to date suggested the following genetic subtype and phenotype correlations in psychiatric behaviors: (1) skin picking was more frequent in those with DEL vs. UPD; (2) anxiety was more common in those with UPD vs. DEL; and (3) an increased frequency of anxiety was noted in the UPD group treated with GHT compared to the DEL group. No other significant associations were found between the genetic subtype or GHT including for depressed mood, nail picking, compulsive counting, compulsive ordering, playing with strings, and visual hallucinations. Further studies will be required before any conclusions can be reached.
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Hormônio do Crescimento/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/genética , Dissomia Uniparental/genética , Adolescente , Adulto , Criança , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos , Humanos , Estudos Longitudinais , Masculino , Transtornos Mentais/genética , Pessoa de Meia-Idade , Síndrome de Prader-Willi/psicologia , Comportamento Problema/psicologia , Adulto JovemRESUMO
Prader-Willi syndrome (PWS) affects 1/15,000-1/30,000 live births and is characterized by lack of expression of paternally inherited genes on 15q11.2-15q13 caused by paternal deletions, maternal uniparental disomy (UPD), or imprinting defects. Affected individuals have distinct physical features, and growth hormone (GH) deficiency occurs in some individuals with PWS. The aim of this study is to test the hypotheses that (a) individuals with deletions and UPD have different physical and dysmorphic features, (b) individuals treated with GH have different physical and dysmorphic features than those not treated, and (c) GH treatment effects are different for individuals with UPD in comparison to those with deletions. Study participants included 30 individuals with deletions or UPD, who did or did not have GH treatment. Participants' molecular abnormalities were determined by molecular and cytogenetic analysis. Clinical data were obtained by a single dysmorphologist. Individuals with deletions were found to be heavier (p = .001), taller (p = .031), with smaller head circumferences (p = .042) and were more likely to have fair skin and hair than their family members (p = .031, .049, respectively) compared to UPD patients. Females with deletions more commonly had hypoplastic labia minora (p = .009) and clitoris (.030) in comparison to those with UPD. Individuals who received GH in both deletion and UPD groups were taller (p = .004), had larger hands (p = .011) and feet (p = .006) and a trend for a larger head circumference (p = .103). Interestingly, the GH-treated group also had a lower rate of strabismus (esotropia [p = .017] and exotropia [p = .039]). This study showed statistically significant correlations between phenotype and molecular subtypes and also between phenotype and GH treatment.
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Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Hormônio do Crescimento/genética , Síndrome de Prader-Willi/genética , Adolescente , Estatura/genética , Criança , Pré-Escolar , Análise Citogenética/métodos , Exotropia/genética , Exotropia/patologia , Feminino , Impressão Genômica/efeitos dos fármacos , Hormônio do Crescimento/administração & dosagem , Humanos , Masculino , Fenótipo , Síndrome de Prader-Willi/classificação , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/patologia , Dissomia Uniparental/genética , Dissomia Uniparental/patologiaRESUMO
Prader-Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11-q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS. We studied 352 subjects with PWS, recruited from the NIH Rare Disease Clinical Research Network, to determine if age at diagnosis, ethnicity, gender, and PWS molecular class influenced the age they first become heavy, as determined by their primary care providers, and the age they first developed an increased appetite and began seeking food. The median ages that children with PWS became heavy were 10 years, 6 years and 4 years for age at diagnosis < 1 year, between 1 and 3 years, and greater than 3 years of age, respectively. The age of diagnosis and ethnicity were significant factors influencing when PWS children first became heavy (p < 0.01), however gender and the PWS molecular class had no influence. Early diagnosis delayed the onset of becoming heavy in individuals with PWS, permitting early GH and other treatment, thus reducing the risk of obesity-associated co-morbidities. Non-white individuals had an earlier onset of becoming heavy.
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Diagnóstico Precoce , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/diagnóstico , Fatores Etários , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Comorbidade , Feminino , Impressão Genômica/genética , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/genética , Humanos , Lactente , Masculino , Obesidade/genética , Obesidade/prevenção & controle , Doenças Raras/genéticaRESUMO
INTRODUCTION: Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS. METHOD: This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period. RESULTS: Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide. CONCLUSION: DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.
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Diazóxido/análogos & derivados , Síndrome de Prader-Willi/tratamento farmacológico , Adolescente , Metabolismo Basal/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Criança , Preparações de Ação Retardada , Diazóxido/administração & dosagem , Diazóxido/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Hiperinsulinismo/tratamento farmacológico , Hiperfagia/tratamento farmacológico , Masculino , Obesidade/tratamento farmacológico , Projetos Piloto , Síndrome de Prader-Willi/patologia , Síndrome de Prader-Willi/psicologia , Segurança , Circunferência da Cintura/efeitos dos fármacos , Adulto JovemRESUMO
Prader-Willi syndrome (PWS) is a genomic imprinting disorder characterized by infantile hypotonia with a poor suck and failure to thrive, hypogenitalism/hypogonadism, behavior and cognitive problems, hormone deficiencies, hyperphagia, and obesity. The Stanford Binet and Wechsler (WAIS-R; WISC-III) intelligence (IQ) tests were administered on 103 individuals with PWS from two separate cohorts [University of California, Irvine (UCI) (N = 56) and Vanderbilt University (N = 47)] and clinical information obtained including growth hormone (GH) treatment, PWS molecular classes, weight and height. Significantly higher IQ scores (p < .02) were found representing the vocabulary section of the Stanford Binet test in the growth hormone (GH) treated group when compared with non-GH treatment in the pediatric-based UCI PWS cohort with a trend for stabilization of vocabulary IQ scores with age in the GH treated maternal disomy (UPD) 15 subject group. Significant differences (p = .05) were also found in the adult-based Vanderbilt PWS cohort with 15q11-q13 deletion subjects having lower Verbal IQ scores compared with UPD 15. No difference in body mass index was identified based on the PWS molecular class or genetic subtype. Medical care and response to treatment with growth hormone may influence intelligence impacted by PWS genetic subtypes and possibly age, but more studies are needed.
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Cromossomos Humanos Par 15/genética , Hormônio do Crescimento/administração & dosagem , Síndrome de Prader-Willi/tratamento farmacológico , Deleção de Sequência/genética , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Inteligência/efeitos dos fármacos , Testes de Inteligência , Masculino , Fenótipo , Síndrome de Prader-Willi/classificação , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Teste de Stanford-Binet , Escalas de Wechsler , Adulto JovemRESUMO
Prader-Willi syndrome (PWS) is generally due to sporadic paternal deletions of the chromosome 15q11-q13 region followed by maternal disomy 15. Advanced maternal age is more commonly seen in those with maternal disomy 15. Environmental factors (e.g., drug use, occupational chemical exposure, infectious agents, and irradiation) could account for chromosome changes. Previous evidence of differences in male and female gametogenesis could suggest an environmental role in the causation of the paternal 15q11-q13 deletion seen in PWS. Certain occupations such as hydrocarbon-exposing occupations (e.g., landscaping, farming, and painting) and viral exposure (e.g., human coronavirus 229E causing upper respiratory infections in adults with an incorporation site in the human genome at chromosome 15q11) can be seasonal in nature and contribute to chromosome damage. To assess, we reviewed birth seasonality data in a large cohort of individuals with PWS recruited nationally (N = 355) but no significant differences were seen by month between those with the 15q11-q13 deletion compared with maternal disomy 15 when analyzing quarterly seasonal patterns. Although early evidence supported birth seasonality differences in PWS, a larger number of individuals in our recent study using advanced genetic testing methods did not find this observation.
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Deleção Cromossômica , Cromossomos Humanos Par 15 , Síndrome de Prader-Willi/epidemiologia , Síndrome de Prader-Willi/genética , Estações do Ano , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Gametogênese/genética , Testes Genéticos , Humanos , Lactente , Masculino , Exposição Ocupacional , Ocupações , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/patologia , Fatores Sexuais , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.
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Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto JovemRESUMO
It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The original article has been updated.
RESUMO
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.
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Hormônio do Crescimento/uso terapêutico , Insuficiência Cardíaca/mortalidade , Obesidade/mortalidade , Síndrome de Prader-Willi/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Obesidade/terapia , Herança Paterna/genética , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/terapia , Adulto JovemRESUMO
BACKGROUND: Prader-Willi syndrome (PWS) is due to errors in genomic imprinting. PWS is recognised as the most common known genetic cause of life-threatening obesity. This report summarises the frequency and further characterises the PWS molecular classes and maternal age effects. METHODS: High-resolution microarrays, comprehensive chromosome 15 genotyping and methylation-specific multiplex ligation probe amplification were used to describe and further characterise molecular classes of maternal disomy 15 (UPD15) considering maternal age. RESULTS: We summarised genetic data from 510 individuals with PWS and 303 (60%) had the 15q11-q13 deletion; 185 (36%) with UPD15 and 22 (4%) with imprinting defects. We further characterised UPD15 findings into subclasses based on the presence (size, location) or absence of loss of heterozygosity (LOH). Additionally, significantly older mothers (mean age=32.5 years vs 27.7 years) were found in the UPD15 group (n=145) compared with the deletion subtype (n=200). CONCLUSIONS: We report on molecular classes in PWS using advanced genomic technology in the largest cohort to date. LOH patterns in UPD15 may impact the risk of having a second genetic condition if the mother carries a recessive mutant allele in the isodisomic region on chromosome 15. The risk of UPD15 may also increase with maternal age.
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Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 15 , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética/métodos , Marcadores Genéticos , Testes Genéticos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
OBJECTIVE: Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder with a variable phenotype. METHODS: We report 2 full siblings, a brother and sister, with a unique familial 2.4 Mb microdeletion at 14q13.1-14q13.3 by microarray (first identified in the brother, Mayo Clinical Laboratories, 2010). RESULTS: Both children presented with infantile spasms that evolved to intractable epilepsy and profound developmental delay. They share distinctive dysmorphic features: long expressionless facies, full cheeks, flattened midface, full lips, and generalized hypotonia. Only the sister has hemophagocytic lymphohistiocytosis (HLH). Testing in the brother revealed 3 variants of unknown significance (VUS) (Greenwood Genetics, epilepsy/seizure panel, 145 genes, 2015). The sister had normal results with a different gene panel (GeneDx, infantile epilepsy panel, 75 genes, 2016) but it did not include the 3 genes in which VUS were identified in her brother. Whole exome sequencing in the mother, father, and both siblings was negative without VUS (GeneDx, XomeDx, 2016). There were no variants within the deleted interval in the intact allele for both children. Parental fluorescent in situ hybridization studies for 14q13.1-14q13.3, done in 2017, were normal. Haplotype analysis of the intact chromosome 14 in the sister supported paternal origin for the deletion and likely germline mosaicism in the father. Haploinsufficiency of genes in the deleted region has not been associated with an abnormal phenotype. CONCLUSIONS: These children have a specific, recognizable neurodevelopmental phenotype and 14q13 microdeletion. This report highlights the challenges of coordinating and interpreting genetic testing in syndromic epilepsy.
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Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Genômica , Irmãos , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Criança , Deficiências do Desenvolvimento/complicações , Feminino , Genômica/métodos , Humanos , Lactente , Masculino , Espasmos Infantis/complicaçõesRESUMO
A 24-year-old woman with a history of idiopathic dilated cardiomyopathy status post heart transplant gave birth to a healthy term female infant. At 5 months of age, the infant was diagnosed with severe left ventricular dysfunction with an ejection fraction of 18% and moderate non-compaction of the left ventricle. She received a heart transplant at 7 months of age. Familial dilated cardiomyopathy was diagnosed. Genetic testing revealed a likely pathogenic variant in the TPM1 gene. Fetal cardiac screening is critical for offspring of heart transplant recipients, especially when the reason for transplant was cardiomyopathy. Early genetic consultation and counselling is necessary for all heart transplant recipients, preferably prenatally. Postnatal screening of offspring is essential at birth, at 3-month intervals until 1 year of age, and then annually until the risk for familial cardiomyopathy is assessed.
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Cardiomiopatia Dilatada/diagnóstico , Transplante de Coração/métodos , Complicações Cardiovasculares na Gravidez , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/cirurgia , Eletrocardiografia , Feminino , Seguimentos , Testes Genéticos , Coração Auxiliar , Humanos , Lactente , Linhagem , Gravidez , Reoperação , Fatores de Tempo , Adulto JovemRESUMO
INTRODUCTION: Prader-Willi syndrome (PWS) is a complex genetic disorder associated with three different genetic subtypes: deletion of the paternal copy of 15q11-q13, maternal UPD for chromosome 15 and imprinting defect. Patients are typically diagnosed because of neonatal hypotonia, dysmorphism and feeding difficulties; however, data on the prenatal features of PWS are limited. OBJECTIVE: The aim of the study was to identify and compare frequencies of prenatal and neonatal clinical features of PWS among the three genetic subtypes. METHODS: Data from 355 patients with PWS from the Rare Diseases Clinical Research Network PWS registry were used to analyse multiple maternal and neonatal factors collected during an 8-year multisite study. RESULTS: Among our cohort of 355 patients with PWS (61% deletion, 36% UPD and 3% imprinting defect) 54% were born by caesarean section, 26% were born prematurely and 34% with a low birth weight (frequencies 32%, 9.6% and 8.1%, respectively, in the general population). Fetal movements were reported as decreased in 72%. All babies were hypotonic, and 99% had feeding difficulties. Low Apgar scores (<7) were noted in 17.7% and 5.6% of patients, respectively, compared with 1% and 1.4%, respectively, in the general population. Maternal age and pre-pregnancy weight were significantly higher in the UPD group (p=0.01 and <0.001, respectively). CONCLUSION: We found a higher rate of perinatal complications in PWS syndrome compared with the general population. No significant differences in the genetic subtypes were noted except for a higher maternal age and pre-pregnancy weight in the UPD subgroup.
Assuntos
Índice de Apgar , Síndrome de Prader-Willi/patologia , Fatores Etários , Peso Corporal , Cesárea , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Síndrome de Prader-Willi/diagnóstico , Gravidez , Resultado da Gravidez , PrognósticoRESUMO
Prader-Willi syndrome (PWS) is caused by a deficiency of imprinted genes in the 15q11-q13 region and is characterized by prenatal onset of hypotonia, poor feeding, childhood-onset obesity, hyperphagia, short stature, facial dysmorphism, intellectual disability, and behavioral problems. We studied perinatal factors in a cohort of 64 people with PWS resulting from paternal deletion of 15q11-q13 and maternal uniparental disomy (UPD) for chromosome 15. We recruited 34 individuals with deletion and 30 with UPD. We compared the frequency of multiple prenatal and neonatal factors with the general population as well as between the two genetic subtypes. Of the 64 individuals with PWS, fetal movements were decreased in 82.8%, 31.7% were born prematurely, 42.1% by Cesarean section, and 35.9% required oxytocin induction. Apgar scores were low in 34.6%, 96.8% had feeding difficulty, 50% needed tube feeding, and 6.2% subsequently had gastrostomy tube placement. On comparing findings in the deletion versus the UPD groups, we did not find many significant differences. We, however, found a higher maternal age, and also later age at diagnosis in the UPD versus the deletion group. PWS subjects have higher rates of perinatal complications, especially Cesarean section rate, hypotonia, and low Apgar scores compared to the general population. We did not find many differences between the genetic subtypes, except for later age of diagnosis of the UPD 15 group suggesting a milder phenotype. We also found that the mothers in the UPD were older, supporting the hypothesis that UPD results from nondisjunction associated trisomy rescue.
Assuntos
Deleção Cromossômica , Exposição Materna/efeitos adversos , Síndrome de Prader-Willi/etiologia , Dissomia Uniparental/genética , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fenótipo , Síndrome de Prader-Willi/diagnóstico , Gravidez , Complicações na Gravidez , Fatores de RiscoRESUMO
Prader-Willi syndrome (PWS) is a rare, complex multisystem genetic disorder which includes hypothalamic dysfunction, hyperphagia, cognitive and behavioral problems, increased anxiety, and compulsive behaviors. Individuals with PWS have a deficit of oxytocin producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin plays a role in regulation of feeding behaviors, social interactions, and emotional reactivity, which are all issues that significantly affect the quality of life for individuals with this syndrome. We performed a double-blind, placebo-controlled, crossover study in 24 children with PWS at three academic institutions using 5 days of intranasal oxytocin (IN-OT) or 5 days of intranasal placebo spray, followed by a 4 week washout period, and then patients returned for 5 days of treatment with the alternate source. Questionnaires, including the Aberrant Behavior Checklist, Social Responsiveness Scale, Repetitive Behavior Scale - Revised, and the Hyperphagia Questionnaire, as well as Clinical Global Impression scales were administered. Blood testing for sodium, potassium, and glucose levels on days 2, 4, and 6, and a 24 hr diet recall. All scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. No single factor showed a statistically significant difference (P < 0.05) between groups at Day 6. The drug effect appeared to be diminished at Day 14. There was no evidence of a difference between oxytocin and placebo in safety lab parameters, 60 min post dose vital signs, weight, or diet parameters. The results from this study suggest that low dose intranasal oxytocin is safe for individuals with PWS and may result in reduction in appetite drive, and improvements in socialization, anxiety, and repetitive behaviors. Further, long-term studies with a larger population of participants are necessary to confirm these findings. The results of this study are encouraging that oxytocin may be a safe and effective treatment for many of the issues that negatively impact individuals with PWS.