Diagnosis Of Prader-Willi Syndrome Research Articles

Outcomes of growth hormone treatment in children with Prader-Willi syndrome over a 30-year period: a single tertiary center experience.

Clinical benefits of growth hormone (GH) in Prader-Willi syndrome (PWS) are proven and scoliosis is a known association of both PWS and GH therapy. The aims of this study were to assess GH prescribing practices and growth outcomes over time, the prevalence and predictors of scoliosis in GH-treated PWS children, and the near-final height of GH-treated PWS patients. This is a retrospective, descriptive study evaluating data from all clinic visits of patients aged 0-18 years with PWS, seen through the Children's Hospital at Westmead between March 1992 and May 2022 (n=75). A total of 64 patients were treated with GH (visits = 1,414). In the recent decade, the diagnosis of PWS and GH commencement were made significantly earlier in life. The prevalence of scoliosis was 41 %, in which age was the only significant predictor for scoliosis (odds ratio 1.19: 95 % CI [1.08-1.31; p=0.001]) adjusted for other predictors. In patients with data available at the age 16 years (23/28 treated with GH), those who were GH treated had significantly higher height SDS vs. nontreated group (SDS-0.67 vs.-2.58; p=0.0001) and lower BMI SDS (1.18 vs. 2.37; p<0.001). Significant improvements in growth and body composition were seen in the GH-treated group vs. non-treated group of children with PWS. There were no significant modifiable clinical predictors of scoliosis in children with PWS, but our findings confirm the high prevalence of scoliosis in GH-treated children with PWS reinforcing the need for close surveillance.

Relationship of thyroid function with genetic subtypes and treatment with growth hormone in Prader-Willi syndrome.

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.

Postural-motor development, spinal range of movement and caregiver burden in Prader-Willi syndrome-associated scoliosis: an observational study.

Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by hypothalamic dysfunction, hypotonia, cognitive deficits, and hyperphagia, primarily resulting from genetic abnormalities on chromosome 15. Among its varied manifestations, musculoskeletal issues, notably scoliosis, pose important challenges in management. This study aims to investigate differences in postural-motor development and spinal range of movement between preadolescents and adolescents with PWS, with and without scoliosis, while also exploring the potential impact of scoliosis on caregiving burden, an aspect yet to be thoroughly explored in existing literature. This observational study evaluated 13 individuals diagnosed with PWS, including 5 with scoliosis (PWS-Sc) and 7 without (PWS-NSc). Inclusion criteria comprised ages 8 to 18 years, confirmed PWS diagnosis through genetic testing, and scoliosis diagnosis. Anamnestic data, physical examinations, and surface measurements were collected, along with parental burden assessments using the Zarit Burden Interview (ZBI). Both groups displayed delays in achieving postural-motor milestones, with the PWS-Sc group exhibiting a more pronounced delay, although statistical significance was not achieved. The main curve magnitude in the PWS-Sc group averaged 31.5° Cobb, with 60% of cases presenting an S-shaped curve. Surface measurements of physiological curves did not differ significantly between groups, but the scoliosis-affected group exhibited lower lumbar extension values (p=0.04). The overall ZBI revealed higher scores in the PWS-Sc group, although statistical significance was not reached. However, significant differences were observed in single questions score evaluating aspects such as social life and caregiver uncertainty (p=0.04 and p=0.03, respectively). Despite the small sample size, delays in achieving postural-motor milestones, particularly in individuals with scoliosis, were observed. The differences recorded in lumbo-pelvic movement suggest that tailored interventions may be beneficial. The heightened caregiving burden in the scoliosis group underscores the need for targeted support. Early intervention and ongoing monitoring should be important for accurate diagnosis and appropriate care, potentially with psychological support for caregivers.

The Diagnosis and Genetic Mechanisms of Prader-Willi Syndrome: Findings From a Moroccan Population Study.

Background Prader-Willi syndrome (PWS) is a complex genetic disorder caused by a deficit in geneexpression on the paternal inherited chromosome 15q11.2-q13. It affects various aspects of growth and development, including feeding, cognitive function, and behavior. Early diagnosis and management of PWS can significantly improve outcomes for patients and their families. Methods In this study, we analyzed a group of 29 clinically diagnosed patients suspected of PWS. All patients were referred to the medical genetics and onco-genetics service for genetic consultation and molecular analysis. We used DNA methylation analysis and fluorescence in situ hybridization (FISH) to confirm the diagnosis and identify the underlying genetic mechanisms. Results Our analysis showed that five out of seven patients (71.43%) with a positive methylation-specific PCR (MSP) had chromosomal deletion by FISH and presented major clinical signs summarized by morbid obesity in 65.21% of cases and neonatal hypotonia in 42.85% of cases. This finding indicates that paternal 15q11-q13 deletion is the most common genetic mechanism involved in PWS. Conclusion The results of this study highlight the importance of early diagnosis and molecular analysis in the management of Prader-Willi syndrome. Our findings contribute to a better understanding of the genotype-phenotype correlation in the Moroccan population and provide families with a rigorous molecular diagnosis, relevant genetic counseling, and multidisciplinary support. Further research is needed to explore the underlying mechanisms of PWS and develop effective interventions to improve outcomes for affected individuals.

Perinatal and neonatal characteristics of Prader-Willi syndrome inJapan.

Prader-Willi syndrome (PWS) is suspected at birth if extreme hypotonia, difficulty in feeding, hypogonadism, and failure to thrive are present. Genetic diagnosis of PWS can generally be made within the first few months of life; however, a delayed diagnosis of PWS is frequently reported. Although the clinical characteristics of perinatal and neonatal patients with PWS have been reported, there are no such reports on the clinical characteristics of these patients in Japan. This retrospective, single-center study involved 177 Japanese patients with PWS and their medical data regarding the perinatal and neonatal periods were evaluated. The median maternal age at birth was 34 years; 12.7% of the mothers had a history of assisted reproductive technology (ART). Of the mothers, 13.5% reported polyhydramnios and 4.3% had oligohydramnios. Decreased fetal movement during pregnancy was reported by 76% of the mothers. A total of 60.5% of patients were born by cesarean section. Genetic subtypes included deletions (66.1%), uniparental disomy (31.0%), imprinting defects (0.6%), and other or unknown subtypes (2.3%). The median birth length was 47.5 cm and the median birthweight was 2476 g. Of the 160 patients, 14 (8.8%) were classified as small for gestational age. Most patients had hypotonia (98.8%), and 89.3% required gavage feeding at birth. Breathing problems, congenital heart disease, and undescended testis were noted in 33.1%, 7.0%, and 93.5% of patients, respectively. In our study, higher rates of ART, polyhydramnios, decreased fetal movements, cesarean section, hypotonia, feeding difficulties, and undescended testis were observed in PWS.

Диагностические особенности синдрома Прадера–Вилли в неонатальном периоде

Objective. To demonstrate the clinical features of Prader–Willi syndrome (PWS) in the neonatal period, to assess the impact of perinatal factors on the development and severity of PWS, and to compare the data obtained with literary sources. Patients and methods. This cross-sectional open-label retrospective study was conducted between 2022 and 2023. It included 5 neonates with severe hypotonia and subsequently confirmed PWS. Anamnestic, anthropometric, age- and sex-related characteristics of children with PWS and anamnestic data of their mothers, as well as clinical manifestations of PWS were investigated. Results. Most of the children with PWS were born prematurely, with a mean birth weight of 2512.0 ± 549.5 g, height of 48.2 ± 5.1 cm, and head circumference of 32.9 ± 2.5 cm, which is below the standard values for preterm infants. The mean Apgar score was 5.8 ± 2.8/7.2 ± 1.9. Three out of five children were not appropriate for gestational age, having low values according to the INTERGROWTH-21st standards. Children were born to mothers aged 35 ± 5 years, and 3 (60%) out of 5 women had an aggravated somatic and/or obstetric and gynecological history. Evaluation of clinical manifestations of PWS revealed post-hypoxic injury of the central nervous system (CNS) (100%), respiratory disorders (100%), infectious toxicosis and intrauterine pneumonia (80%). Objective examination revealed hypotonia, hyporeflexia, reduced motor function in all patients, and 80% of children had poor sucking reflex. The most common phenotypic features were high forehead, almondshaped eyes, dolichocephaly, narrow temporal bones, thin upper lip, down-turned corners of the mouth; orbital hypertelorism, acromicria, and hypogonadism were observed less frequently. Conclusion. Early diagnosis of PWS is possible with a comprehensive differential diagnosis in children with the “floppy baby syndrome”. Special attention should be paid to children with intrauterine growth restriction, typical stigmas of dysembryogenesis, respiratory disorders, and hypoxic CNS injury. Genetic counseling and karyotyping should be performed as early as possible in all newborns with suspected PWS to prevent the development of complications. Key words: Prader–Willi syndrome, floppy baby syndrome, stigmas of dysembryogenesis, hypotonia, hyporeflexia, poor sucking reflex, feeding disorders, developmental delay, hypogonadism

Novel Case of Prader–Willi Syndrome and Ebstein's Anomaly: Implications for Complex Care Management

AbstractWe present a patient with a complex phenotype including diagnoses of Ebstein's anomaly and Prader–Willi syndrome (PWS) as well as additional congenital anomalies and genetic variants with potential clinical effects. This is the first reported case of both diagnoses present in the same patient. The diagnosis of Ebstein's anomaly was made on prenatal ultrasound. She presented with neonatal hypotonia, feeding problems, and dysmorphic features, followed by later onset weight gain, leading to a diagnosis of PWS. Further evaluations revealed Blaschkoid hyperpigmentation, laryngeal cleft, and pigmentary retinopathy. Whole exome sequencing determined a likely pathogenic variant in alkaline phosphatase gene and several mitochondrial DNA variants. We discuss the known genetic mechanisms of PWS and compare them to the heterogenous genetic associations of Ebstein's anomaly. The standard of care treatment for PWS is growth hormone therapy, which is associated with right-sided heart failure risks. This case illustrates the need to complete the diagnostic work up in all patients, as well as the necessity of a multidisciplinary approach for optimal outcomes.

MKRN3 circulating levels in Prader-Willi syndrome: a pilot study.

Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS. This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI). We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6years. MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 ± 22pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007). The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.

Demographics and medical comorbidities among hospitalized patients with Prader-Willi Syndrome: A National Inpatient Sample analysis.

Prader-Willi Syndrome (PWS) is a multi-system genetic disorder characterized by hyperphagia and a range of medical complications. While register and cohort studies have explored the natural course of the syndrome, there is little nationally-representative data. In this study the National Inpatient Sample, a de-identified all-payors database of acute care hospital discharges in the United States, was queried for patients discharged with a diagnosis of PWS in 2019. Hospitalizations involving PWS were compared to hospitalizations without a PWS diagnosis matched based on demographic and hospital factors. In total, 540 hospitalizations (95% CI: 513-567) included a diagnosis of PWS. Median age at time of admission was 22 years, with an interquartile range of 6.3-37.8 years. Respiratory conditions accounted for 110 (20.4%) of primary discharge diagnoses, with infectious conditions for 70 (13.0%) and digestive conditions for 65 (12.0%). Hospitalizations involving PWS were significantly more likely to involve respiratory failure (OR 5.49; 95% CI 3.86-7.80), septicemia (OR 2.80, 95% CI 1.97-3.96), or intestinal obstruction and ileus (OR 6.29; 95% CI 3.70-10.7) compared to matched hospitalizations without PWS. Obesity was diagnosed in 230 PWS hospitalizations (42.6%; OR 3.86, 95% CI 3.17-4.72 relative to non-PWS hospitalizations). These results point to an ongoing need for the improved diagnosis and treatment of PWS complications, and highlight the importance of specific billing codes for rare diseases to enhance the collection of real world evidence.

Detecting regions of homozygosity improves the diagnosis of pathogenic variants and uniparental disomy in pediatric patients.

Chromosomal microarray analysis using single nucleotide polymorphism probes can detect regions of homozygosity (ROH). This confers a potential utility in revealing autosomal recessive (AR) diseases and uniparental disomy (UPD). Results of genetic testing among pediatric patients from 2015 to 2019 were evaluated. Diagnostic findings with detected ROH from large consecutive case series in the literature were reviewed. Of 2050 pediatric patients, 65 (3%) had one or more ROH and 31 (53%) had follow-up whole exome sequencing (WES) and methylation studies. Seven homozygous variants were detected and four of them from three patients (9.6%) were within the detected ROH and classified as pathogenic or likely pathogenic variants for AR diseases. One patient (3%) had segmental UPD15q for a diagnosis of Prader-Willi syndrome. Additive diagnostic yield from ROH reporting was at least 0.2% (4/2050) of pediatric patients. These results were consistent with findings from several large case series reported in the literature. Detecting ROH had an estimated baseline predictive value of 10% for AR diseases and 3% for UPD. Consanguinity revealed by multiple ROH was a strong predictor for AR diseases. These results provide evidence for genetic counseling and recommendation of follow-up WES and methylation studies for pediatric patients reported with ROH.

The Utilization of MS-MLPA as the First-Line Test for the Diagnosis of Prader-Willi Syndrome in Thai Patients.

Prader-Willi syndrome (PWS) is a genetic disorder caused by the expression disruption of genes on the paternally inherited allele of chromosome 15q11.2-q13. Apart from clinical diagnostic criteria, PWS is confirmed by genetic testing. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is one of the molecular techniques used to analyze this syndrome. This study aimed to evaluate the concordance of the test results of MS-MLPA with conventional techniques in the diagnosis of PWS in Thai patients. Forty leftover specimens from routine genetic testing (MS-PCR and FISH) were tested to obtain MS-MLPA results. By comparison, perfect concordance was shown between the result of MS-MLPA and those of conventional techniques. In conclusion, MS-MLPA is an accurate and cost-effective assay that can be used to confirm PWS diagnosis with explicit deletion of affected genes.

Diagnosis of Prader-Willi Syndrome and Angelman Syndrome by Targeted Nanopore Long-Read Sequencing

Diagnosis of Prader-Willi Syndrome and Angelman Syndrome by Targeted Nanopore Long-Read Sequencing

Establishing the content validity of the Epworth Sleepiness Scale for Children and Adolescents in Prader-Willi syndrome.

Excessive daytime sleepiness is common in Prader-Willi syndrome (PWS), with prevalence ranging from 52% to 100%. The goal of this study was to establish the content validity (ie, evidence that an instrument measures an intended concept of interest) of the parent/caregiver version of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), a measure of daytime sleepiness, in PWS. Qualitative, dyadic semistructured video interviews were conducted with 18 caregivers and their children with PWS from April to June 2020. Concept elicitation and cognitive interview techniques were implemented. Thematic analyses allowed for examination of themes and data patterns. All caregivers (mean age 49 years) were mothers of individuals with PWS who experienced troublesome daytime sleepiness (mean age 14 years). The most prevalent observable signs/symptoms of daytime sleepiness were sleepy/sleepiness (n = 17; 94.4%), tired/tiredness (n = 16; 88.9%), exhaustion/exhausted (n = 5; 27.8%), anxious/stressed (n = 5; 27.8%), irritable/frustrated (n = 5; 27.8%), having tantrums/outbursts (n = 5; 27.8%), and lethargy (n = 4; 22.2%). Daytime sleepiness impacted various aspects of health including mental, emotional, physical, and social well-being. When caregivers were asked about the activities associated with daytime sleepiness, all salient concepts elicited mapped to the ESS-CHAD; saturation was met after the first 4 interviews. Only 2 concepts, after physical exertion and while inactive/bored, did not map. Caregiver statements indicated that these concepts, although related to daytime activities, were atypical of daily routines. The ESS-CHAD was well understood and relevant to caregivers. This study supports the content validity of the ESS-CHAD and its appropriateness for evaluating treatment efficacy of daytime sleepiness in PWS. Patel VP, Patroneva A, Glaze DG, Davis K, Merikle E, Revana A. Establishing the content validity of the Epworth Sleepiness Scale for Children and Adolescents in Prader-Willi syndrome. J Clin Sleep Med. 2022;18(2):485-496.

Influence of molecular classes and growth hormone treatment on growth and dysmorphology in Prader-Willi syndrome: A multicenter study.

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.

Secondary diabetes mellitus in Prader-Willi syndrome

Prader-Willi Syndrome (PWS) is a rare autosomal dominant disorder on the 15q11.2-q13 chromosome. PWS may impact metabolic, endocrine, and neurologic systems and combine with hypotonia, sleep disturbances, cognitive disability, central adrenal insufficiency, hypothyroidism, hypogonadism, short stature, and other diseases. Here ,we report a PWS patient with secondary diabetes mellitus. Clinical and laboratory features are summarized. The patient had typical manifestations of PWS including almond-shaped eyes, narrow temples, narrow nasal bridge, and short hands and feet. Lab test revealed hypogonadism and growth hormone deficiency. SNP array revealed one copy of chromosome 15 q11.2q13.1 was missing, with a length of about 6.4 mbp. This case emphasizes the importance of considering PWS in the differential diagnosis of an adolescent with diabetes. Antenatal history of neonatal hypotonia and childhood history of feeding disorder are the keys to the diagnosis of PWS.

The use of growth hormone therapy in adults with Prader-Willi syndrome: A systematic review.

Despite clear benefits in the management of children with Prader-Willi syndrome (PWS), the role of growth hormone (GH) in adults is unclear. The aim of this study was to conduct a systematic review to evaluate the effects of GH on body composition, bone health and cardiovascular health in adults with PWS. A systematic computerized literature search of the PubMed database was conducted by two independent reviewers. Inclusion criteria were individuals over the age of 16years with a genetic diagnosis of PWS who had received GH therapy, together with assessment of body composition, bone health or cardiovascular health. Twenty full-text papers met the inclusion criteria, encompassing 364 unique patients. No differences in body mass index (BMI) were noted, although 2 studies reported increased BMI after GH cessation. Data demonstrated statistically significant increases in lean body mass and reductions in percentage fat mass. Studies reported inconsistent effects of GH on cholesterol and echocardiography parameters. No studies reported differences in bone mineral density, although one reported improved bone geometry. Minor adverse events including pretibial oedema, headache and transient impaired glucose tolerance were reported in 7 studies. These data suggest that GH is safe and well tolerated in adults with PWS, with evidence of improvement in body composition. Further longitudinal studies are still required to investigate the effects of GH on bone and cardiovascular health. Where GH is used in adults with PWS, this should be managed by a specialist multidisciplinary team with regular monitoring initiated.

Clinical practice guidelines for Prader-Willi syndrome

Prader-Willi syndrome (PWS) is the first multi-systemic genetic disorder known to be caused by imprinting defect. The clinical manifestations of PWS vary with age. At the prenatal stage, decreased fetal movements are frequent. The major clinical manifestations during neonatal period include hypotonia, weak cry, poor suck and feeding difficulties. Growth retardation and delayed language and motor development are observed during infancy. Short stature, small hands and feet, cognitive deficiency are noticed in the childhood. At adolescence, prominent growth retardation, obesity, gonadal dysplasia, abnormal behavior and learning difficulties are the major issues. Morbid obesity caused by insatiable appetite is the major factor for prognosis. Early diagnosis and intervention play a significance role in improving the quality of life, preventing serious complications and prolonging survival. This guideline covers the clinical manifestations, developmental process, pathogenesis, molecular diagnosis and genetic counseling of PWS, with an aim to provide reference for clinicians for early identification, proper intervention and genetic counseling for this disease.

Клинические трудности диагностики синдрома Прадера–Вилли

Клинические трудности диагностики синдрома Прадера–Вилли

Age Distribution, Comorbidities and Risk Factors for Thrombosis in Prader-Willi Syndrome.

Prader–Willi syndrome (PWS) is an imprinting disorder caused by lack of expression of the paternally inherited 15q11.2–q13 chromosome region. The risk of death from obesity-related complications can worsen with age, but survival trends are improving. Comorbidities and their complications such as thrombosis or blood clots and venous thromboembolism (VTE) are uncommon but reported in PWS. Two phases of analyses were conducted in our study: unadjusted and adjusted frequency with odds ratios and a regression analysis of risk factors. Individuals with PWS or non-PWS controls with exogenous obesity were identified by specific International Classification of Diseases (ICD)-9 diagnostic codes reported on more than one occasion to confirm the diagnosis of PWS or exogenous obesity in available national health claims insurance datasets. The overall average age or average age per age interval (0–17 year, 18–64 year, and 65 year+) and gender distribution in each population were similar in 3136 patients with PWS and 3945 non-PWS controls for comparison purposes, with exogenous obesity identified from two insurance health claims dataset sources (i.e., commercial and Medicare advantage or Medicaid). For example, 65.1% of the 3136 patients with PWS were less than 18 years old (subadults), 33.2% were 18–64 years old (adults), and 1.7% were 65 years or older. After adjusting for comorbidities that were identified with diagnostic codes, we found that commercially insured PWS individuals across all age cohorts were 2.55 times more likely to experience pulmonary embolism (PE) or deep vein thrombosis (DVT) than for obese controls (p-value: 0.013; confidence interval (CI): 1.22–5.32). Medicaid-insured individuals across all age cohorts with PWS were 0.85 times more likely to experience PE or DVT than obese controls (p-value: 0.60; CI: 0.46–1.56), with no indicated age difference. Age and gender were statistically significant predictors of VTEs, and they were independent of insurance coverage. There was an increase in occurrence of thrombotic events across all age cohorts within the PWS patient population when compared with their obese counterparts, regardless of insurance type.

126: Prader-Willi syndrome: fetal phenotype can lead to prenatal diagnosis

Prader-Willi syndrome (PWS) is a severe neurogenetic disorder characterized by morbid obesity, mental retardation and severe behavioral disorders. PWS can be diagnosed by methylation analysis during invasive prenatal diagnosis procedures, however, prenatal diagnosis is rare. We aimed to characterize PWS fetal phenotype, in order to offer the possibility of prenatal diagnosis. All 99 PWS patients treated at the Israel National Multidisciplinary PWS clinic under the age of 10 years were studied. Clinical features of PWS pregnancies were reported by the mothers. Medical records including ultrasound reports, obstetric records, and genetic results were collected. Results were compared both to normal PWS sibling's pregnancies (n=70) and to the Israeli general population. PWS pregnancies were complicated by higher rates of decreased fetal movements (DFM), small for gestational age (SGA), polyhydramnios, breech presentation and cryptorchidism in males (80.4%, 56.6%, 37.4%, 36.4%, 88% respectively, (Table 1). A combination of 2,3 and 4 features was found in 35,34,15% respectively. In 52% of PWS pregnancies at least 3 features were found and in 87% at least two. High rates of asymmetric fetal growth during the 3rd trimester with increased head to abdominal circumference (HC/AC) ratio were found (38%). When evaluating AC as a marker of asymmetric growth, in 64% of the pregnancies the AC was < 10th% and in 32% < 3rd%. The most common feature accompanying abnormal HC/AC ratio or AC< 5th% was DFM. Doppler studies were mostly normal (84.4%) (Table 2). Amniocentesis was performed in 17 cases (17.2%). Methylation test was not offered and the diagnosis of PWS was missed. We describe distinct prenatal phenotype in PWS. A combination of asymmetric fetal growth with normal Doppler studies and DFM, specifically if accompanied with polyhydramnios/ breech presentation or cryptorchidism. Such phenotype should alert obstetricians to consider the possibility of PWS and perform the diagnostic methylation test when amniocentesis is pursued.View Large Image Figure ViewerDownload Hi-res image Download (PPT)