RESUMEN
BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.
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Estenosis Aórtica Supravalvular , Síndrome de Williams , Humanos , Síndrome de Williams/genética , Estudio de Asociación del Genoma Completo , Proteómica , Enfermedades Raras , Estenosis Aórtica Supravalvular/genética , Estenosis Aórtica Supravalvular/metabolismo , Estenosis Aórtica Supravalvular/cirugíaRESUMEN
Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.
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Hernias Diafragmáticas Congénitas , Osteoporosis , Adulto , Humanos , Masculino , Animales , Ratones , Hernias Diafragmáticas Congénitas/genética , Actinas/genética , Mutación Missense/genética , Osteoporosis/genéticaRESUMEN
PURPOSE: This study describes participant diversity in Williams syndrome (WS) intervention studies. METHODS: A literature search was conducted to identify prospective treatment studies including participants with WS. Data was extracted on the reporting of and information provided on age, sex, cognitive ability, socioeconomic status, race, and ethnicity. RESULTS: Eleven eligible articles were identified. Reporting rates of demographic factors varied considerably, with the highest rates for age and sex (100%) and the lowest reporting rates for race (18%) and ethnicity (9%). Combining demographic data from the two studies that reported on race and/or ethnicity (n = 33), 88% of participants were White. The combined participant mean age was 20.9 years. CONCLUSION: There is a low frequency of reporting on several demographic factors including socioeconomic status, race, and ethnicity in WS intervention studies. There is a need for increased representation of racial and ethnic minority groups, older participants, and more cognitively impaired patients in WS research.
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Background: Dietary intake and body weight are important predictors of long-term health. However, few studies have focused on these topics in adults with genetic syndromes that have associated intellectual disability, such as Williams syndrome (WS). Objective: In adults with WS, describe predicted dietary intake, food-related problems, and associations between body mass index (BMI) and possible factors contributing to differences in weight status. Design: In this study of 82 participants (median age of 30 years, range 18-69), we cross sectionally investigated associations between BMI, predicted dietary intakes (Dietary Screener Questionnaire), food-related behaviors (Food-Related Problem Questionnaire), and anxiety (Spence Children's Anxiety Scale). Longitudinal patterns of weight change were further studied in a subset (n = 41). Results: BMI variation was observed with median BMI of 27.3 kg/m2 (range 16.7-55.5 kg/m2). Several components of dietary intake deviated from recommendations in the WS cohort. When compared with WS participants with either normal or overweight BMI, WS participants with obesity had reduced daily intake of fruits and vegetables of 0.15 cup equivalents (P = 0.049), while participants with underweight BMI had reduced daily intake of fruits and vegetables of 0.44 cup equivalents (P = 0.026) and additionally had reduced intake of dietary fiber of 2.12 grams per day (P = 0.019). A one-point increase in the 'preoccupation with food' sub-score was associated with a 0.57 unit increase in BMI (P = 0.16), while a one-point increase in the 'takes and stores food' sub-score was associated with a 0.72 unit increase in BMI. In the longitudinal weight subset, a weight gain group and a weight stable group were identified. The former was associated with increased 'takes and stores food' sub-score but not with dietary intakes. Conclusion: We observed considerable BMI variability. While few dietary intakes were associated with BMI, increased BMI and weight gain were associated with 'preoccupation with food' and with 'takes and stores food' behavior sub-scores.
RESUMEN
QTc prolongation (≥ 460 ms), according to Bazett formula (QTcB), has been identified to be increased in Williams syndrome (WS) and suggested as a potential cause of increased risk of sudden cardiac death. The Bazett formula tends to overestimate QTc in higher heart rates. We performed a retrospective chart review of WS patients with ≥ 1 electrocardiogram (EKG) with sinus rhythm, no evidence of bundle branch blocks, and measurable intervals. A total of 280 EKGs from 147 patients with WS were analyzed and 123 EKGs from 123 controls. The QTc was calculated using Bazett formula. The average QTcB for individuals with WS and controls was 444 ± 24 ms and 417 ± 26 ms, respectively (p < 0.001). In our WS cohort 34.4% had at least 1 EKG with a QTcB ≥ 460 ms. The mean heart rate (HR) from patients with WS was significantly higher than controls (96 bpm vs 76 bpm, p < 0.001). Linear regression showed that HR contributed 27% to QTcB prolongation in the patients with WS. Patients with WS have a mean QTcB in the normal range but higher than controls, and a higher than expected frequency of QTc ≥ 460 ms compared to the general population. HR is also higher in WS and contributes modestly to the WS QTcB prolongation. Future studies are needed to assess if these findings contribute risk to sudden cardiac death but in the interim we recommend routine EKG testing, especially when starting QTc prolonging medications.
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Síndrome de QT Prolongado , Síndrome de Williams , Adulto , Niño , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Electrocardiografía , Frecuencia Cardíaca/fisiología , Humanos , Síndrome de QT Prolongado/complicaciones , Síndrome de QT Prolongado/etiología , Estudios Retrospectivos , Síndrome de Williams/complicacionesRESUMEN
BACKGROUND: Williams syndrome (WS) is a neurodevelopmental disorder associated with several medical and psychiatric comorbidities. OBJECTIVE: To describe the clinical presentation and treatment course of functional neurological symptom disorder (FNSD) in 3 adult patients with WS. METHODS: This report describes the clinical presentation and long-term follow-up of 3 individuals with WS and FNSD who experienced a range of clinical presentations and responses to treatment. The literature on the clinical assessment and treatment of FNSD as it applies to patients with neurodevelopmental disorders is reviewed. RESULTS: FNSD treatment strategies used in the general population were successfully adapted for these 3 patients. Literature on the diagnosis and treatment of FNSD in patients with neurodevelopmental disorders is lacking. CONCLUSIONS: FNSD may be more common in individuals with WS than previously appreciated, and future studies describing the prevalence, clinical presentation, risk factors, and treatment of FNSD in WS are needed.
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Trastornos de Conversión , Síndrome de Williams , Adulto , Comorbilidad , Humanos , Prevalencia , Factores de Riesgo , Síndrome de Williams/complicaciones , Síndrome de Williams/diagnóstico , Síndrome de Williams/psicologíaRESUMEN
The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The parents of 60 subjects with WS completed the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or Children's Y-BOCS, the Yale Global Tic Severity Scale, the Stereotyped Behavior Scale, and the Spence Children's Anxiety Scale-Parent Version. Nineteen males and 41 females participated in the study. Six subjects (10%) had obsessions only, six (10%) had compulsions only, and eleven (18%) had at least one obsession and at least one compulsion. None of the subjects had tics. Fifty subjects (83.3%) endorsed at least one stereotypy. Increased anxiety was associated with increased severity of obsessions, but not severity of compulsions or stereotypies.
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Trastorno del Espectro Autista , Trastorno Obsesivo Compulsivo , Tics , Síndrome de Williams , Niño , Femenino , Humanos , Masculino , Conducta Obsesiva/diagnóstico , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/epidemiología , Escalas de Valoración Psiquiátrica , Índice de Severidad de la EnfermedadRESUMEN
Williams syndrome (WS) is a relatively rare microdeletion disorder that occurs in as many as 1:7,500 individuals. WS arises due to the mispairing of low-copy DNA repetitive elements at meiosis. The deletion size is similar across most individuals with WS and leads to the loss of one copy of 25-27 genes on chromosome 7q11.23. The resulting unique disorder affects multiple systems, with cardinal features including but not limited to cardiovascular disease (characteristically stenosis of the great arteries and most notably supravalvar aortic stenosis), a distinctive craniofacial appearance, and a specific cognitive and behavioural profile that includes intellectual disability and hypersociability. Genotype-phenotype evidence is strongest for ELN, the gene encoding elastin, which is responsible for the vascular and connective tissue features of WS, and for the transcription factor genes GTF2I and GTF2IRD1, which are known to affect intellectual ability, social functioning and anxiety. Mounting evidence also ascribes phenotypic consequences to the deletion of BAZ1B, LIMK1, STX1A and MLXIPL, but more work is needed to understand the mechanism by which these deletions contribute to clinical outcomes. The age of diagnosis has fallen in regions of the world where technological advances, such as chromosomal microarray, enable clinicians to make the diagnosis of WS without formally suspecting it, allowing earlier intervention by medical and developmental specialists. Phenotypic variability is considerable for all cardinal features of WS but the specific sources of this variability remain unknown. Further investigation to identify the factors responsible for these differences may lead to mechanism-based rather than symptom-based therapies and should therefore be a high research priority.
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Síndrome de Williams , Cognición , Elastina , Humanos , Factores de Transcripción , Síndrome de Williams/diagnóstico , Síndrome de Williams/genéticaRESUMEN
Introduction: Williams syndrome (WS) is a neurogenetic disorder characterized by a hyper-social personality, intellectual disability, and multiple medical co-morbidities. Psychiatric co-morbidities are also common. Since medical co-morbidities are common in this population, the risk-benefit of the use of psychiatric medications must be carefully considered and monitoring for safety and tolerability is needed.Areas covered: We review the cognitive profile and common medical co-morbidities in WS. We then discuss the common presentations of psychiatric disorders and review the available evidence on the use of psychiatric medications in WS. No prospective psychiatric medication trials have been conducted. We highlight the side effect profile of common psychiatric medications as they pertain to WS.Expert opinion: Psychiatric disorders can have a major effect on the quality of life of individuals with WS. The lack of long-term safety data and high likelihood of medical co-morbidities in WS make the judicious use of psychiatric medications more challenging; however, they can play an important role in decreasing distress and improving functioning. We provide recommendations for first- and second-line classes of medications based on our clinical experience and consideration of adverse effect profiles, as well as safety monitoring parameters at baseline and periodically.
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Trastornos Mentales/tratamiento farmacológico , Psicotrópicos/uso terapéutico , Síndrome de Williams/tratamiento farmacológico , Humanos , Trastornos Mentales/etiología , Psicofarmacología , Psicotrópicos/efectos adversos , Calidad de Vida , Síndrome de Williams/psicologíaRESUMEN
PURPOSE OF REVIEW: Williams syndrome is a multisystem disorder caused by a microdeletion on chromosome 7q. Throughout infancy, childhood, and adulthood, abnormalities in body composition and in multiple endocrine axes may arise for individuals with Williams syndrome. This review describes the current literature regarding growth, body composition, and endocrine issues in Williams syndrome with recommendations for surveillance and management by the endocrinologist, geneticist, or primary care physician. RECENT FINDINGS: In addition to known abnormalities in stature, calcium metabolism, and thyroid function, individuals with Williams syndrome are increasingly recognized to have low bone mineral density, increased body fat, and decreased muscle mass. Furthermore, recent literature identifies a high prevalence of diabetes and obesity starting in adolescence, and, less commonly, a lipedema phenotype in both male and female individuals. Understanding of the mechanisms by which haploinsufficiency of genes in the Williams syndrome-deleted region contributes to the multisystem phenotype of Williams syndrome continues to evolve. SUMMARY: Multiple abnormalities in growth, body composition, and endocrine axes may manifest in individuals with Williams syndrome. Individuals with Williams syndrome should have routine surveillance for these issues in either the primary care setting or by an endocrinologist or geneticist.
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Composición Corporal , Síndrome de Williams/genética , Síndrome de Williams/fisiopatología , HumanosRESUMEN
Williams-Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26-28 genes. An estimated 2-5% of patients have "atypical" deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation.
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Cromosomas Humanos Par 7/genética , Neoplasia Endocrina Múltiple/genética , Trastornos del Neurodesarrollo/genética , Síndrome de Williams/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Deleción Cromosómica , Femenino , Cabeza/anomalías , Cabeza/fisiopatología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple/epidemiología , Neoplasia Endocrina Múltiple/fisiopatología , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/fisiopatología , Tamaño de los Órganos/genética , Fenotipo , Síndrome de Williams/epidemiología , Síndrome de Williams/fisiopatología , Adulto JovenRESUMEN
Co-morbid anxiety disorders, including generalized anxiety disorder (GAD), are highly prevalent among individuals with Williams syndrome (WS). However, reports of the pharmacologic treatment of only a limited number of previous anxiety disorders in WS have appeared in the literature. Here, we review the case histories of three adolescents/young adults with WS and the treatment course of co-morbid GAD with buspirone. Treatment with buspirone was well-tolerated and resulted in sustained response in all three cases. Common medical disorders in WS are highlighted with regards to safe and appropriate pharmacologic treatment of GAD. Buspirone's generally benign side effect profile is a major benefit of its use for treating GAD in individuals with WS.
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Ansiolíticos/uso terapéutico , Trastornos de Ansiedad/complicaciones , Trastornos de Ansiedad/tratamiento farmacológico , Buspirona/uso terapéutico , Síndrome de Williams/complicaciones , Síndrome de Williams/tratamiento farmacológico , Adolescente , Trastornos de Ansiedad/diagnóstico , Comorbilidad , Femenino , Humanos , Síndrome de Williams/diagnóstico , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the occurrence and estimate the frequency of macrocytosis in Williams-Beuren syndrome (WBS). STUDY DESIGN: Complete blood count (CBC) data from 179 subjects with WBS aged 1-69 were collected, with common parameters assessed for trends. Z-transformed mean corpuscular volume (MCV) was compared with each laboratory's reference range as well as with control data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 data archives. RESULTS: Just over a third (35%) subjects had at least one recorded incidence of macrocytosis. In comparisons of CBC parameters with an expected population mean, MCV and MCH were greater than, while Hct and RDW were lower than, expected values. The distribution of erythrocyte MCV is shifted to the right in WBS compared to controls, as was the mean value. Despite this, anemia was absent, except in a single medically complex WBS subject. Though there was a paucity of data available of variables that could potentially cause an elevated MCV, no obvious etiology could be elucidated. CONCLUSIONS: Mild macrocytosis without anemia affects a moderate subset of WBS patients, leading to a rightward shift in the MCV distribution curve. Providers encountering isolated mild macrocytosis in WBS can consider observation over further workup.
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Índices de Eritrocitos , Enfermedades Hematológicas/sangre , Síndrome de Williams/sangre , Adolescente , Adulto , Anciano , Anemia , Recuento de Células Sanguíneas , Niño , Preescolar , Estudios de Cohortes , Eritrocitos/citología , Eritrocitos/metabolismo , Femenino , Enfermedades Hematológicas/metabolismo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Síndrome de Williams/etiología , Síndrome de Williams/genética , Síndrome de Williams/metabolismoRESUMEN
OBJECTIVE: We assessed body composition, bone mineral density (BMD), glucose and lipids in Williams syndrome (WS), a rare microdeletion disorder. DESIGN: Individuals with WS had outpatient assessment at Massachusetts General Hospital. Controls were selected from the National Health and Nutrition Examination Survey (NHANES 2005-2006). PATIENTS: A total of 22 individuals with WS, each matched by age, sex and race to four NHANES controls. MEASUREMENTS: Blood sampling, oral glucose tolerance test, dual-energy X-ray absorptiometry scan. RESULTS: WS and control groups were 59% female and 29 ± 8 years old. Compared to controls, individuals with WS were shorter but had similar body weight, with more fat and less lean mass. Per cent body fat was higher in WS even after adjusting for BMI (+2.1% [95% CI 0.4, 3.9%]). Four WS patients had abnormal lower extremity fat accumulation resembling lipedema. HbA1c (+0.5% [0.2, 0.7]) and 2-hour glucose (+68 mg/dL [44, 93]) were higher in WS vs controls, differences which persisted after adjusting for BMI. Fasting glucose was comparable between groups. LDL (-18 mg/dL [-35, -2]) and triglycerides (-45 mg/dL [-87, -2]) were significantly lower in WS. Whole-body BMD was significantly lower (-0.15 g/cm2 [-0.20, -0.11]) in WS, and this remained true controlling for height (-0.06 g/cm2 [-0.11, -0.02]). Vitamin D was <30 ng/mL in 81% of those with WS. CONCLUSIONS: On average, adults with WS have increased fat, decreased lean mass, impaired glucose homeostasis and reduced BMD. Clinical efforts to build muscle and bone mass, and to ensure vitamin D sufficiency, are warranted. Genotype-phenotype research efforts are also warranted.
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Composición Corporal/fisiología , Metabolismo de los Lípidos/fisiología , Síndrome de Williams/sangre , Síndrome de Williams/metabolismo , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Peso Corporal/fisiología , Densidad Ósea/fisiología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Williams/fisiopatología , Adulto JovenRESUMEN
Descriptions of individuals with Williams syndrome (WS) and co-morbid major depressive disorder (MDD) with psychotic features have not appeared in the literature. In addition to reviewing previous reports of psychotic symptoms in persons with WS, this paper introduces clinical histories and therapeutic management strategies for three previously unreported adults with WS diagnosed with co-morbid MDD with psychotic features. Co-morbid medical disorders common in WS are highlighted with regard to safe and appropriate pharmacological treatment. The importance of assessment for co-morbid MDD with psychotic features in individuals with WS is emphasized.
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Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/diagnóstico , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/diagnóstico , Síndrome de Williams/complicaciones , Síndrome de Williams/diagnóstico , Adulto , Comorbilidad , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Trastornos Psicóticos/psicología , Síndrome de Williams/psicologíaRESUMEN
Williams-Beuren syndrome (WBS) is a chromosomal microdeletion syndrome typically presenting with intellectual disability, a unique personality, a characteristic facial appearance, and cardiovascular disease. Several clinical features of WBS are thought to be due to haploinsufficiency of elastin (ELN), as the ELN locus is included within the WBS critical region at 7q11.23. Emphysema, a disease attributed to destruction of pulmonary elastic fibers, has been reported in patients without WBS who have pathogenic variants in ELN but only once (in one patient) in WBS. Here we report a second adult WBS patient with emphysema where the diagnosis of WBS was established subsequent to the discovery of severe bullous emphysema. Haploinsufficiency of ELN likely contributed to this pulmonary manifestation of WBS. This case emphasizes the contribution of rare genetic variation in cases of severe emphysema and provides further evidence that emphysema should be considered in patients with WBS who have respiratory symptoms, as it may be under-recognized in this patient population.
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Elastina/genética , Enfisema Pulmonar/genética , Síndrome de Williams/genética , Deleción Cromosómica , Cromosomas Humanos Par 7 , Variación Genética , Haploinsuficiencia/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Fenotipo , Enfisema Pulmonar/complicaciones , Enfisema Pulmonar/fisiopatología , Síndrome de Williams/complicaciones , Síndrome de Williams/fisiopatologíaRESUMEN
Williams Syndrome (WS) is a contiguous gene deletion disorder, caused by the deletion of approximately 26-28 genes from chromosome 7 (7q11.23). Individuals with WS have complex medical, developmental, and behavioral features, requiring multidisciplinary and interdisciplinary collaboration. Guidelines detailing the identification, evaluation, and monitoring of individuals with WS need clarification, especially for primary care providers who are first-line in their management. This report summarizes the proceedings of the 2016 Professional Conference on WS in Columbus, OH. Presentations were directed towards primary care providers and subspecialists, emphasizing evidence-based practices for treating the prevalent medical and behavioral features of WS. Included in this report are findings from a panel of cardiovascular experts discussing three case studies on treatment of hypertension and the use of sedation or anesthesia for non-cardiac procedures. Abstracts from individual expert presenters are included, covering various medical and behavioral topics, and providing updates in management of WS individuals. The following topics were discussed: differences in phenotypes of 7q11.23 deletion versus duplication, growth parameters, endocrine concerns, sleep difficulties, behaviors to monitor, and pharmacological options, the neurodevelopmental profile of WS individuals, and the importance of monitoring medical and behavioral concerns as WS individuals transition to adulthood.
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Eliminación de Gen , Guías como Asunto , Síndrome de Williams/genética , Cromosomas Humanos Par 7/genética , Humanos , Síndrome de Williams/diagnóstico , Síndrome de Williams/terapiaAsunto(s)
Composición Corporal/fisiología , Densidad Ósea/fisiología , Lipedema/etiología , Síndrome de Williams/complicaciones , Síndrome de Williams/fisiopatología , Adolescente , Adulto , Factores de Edad , Anciano , California , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study. STUDY DESIGN: Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities. RESULTS: On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported. CONCLUSIONS: Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.