The Study Of Clinical Phenotype, Growth Hormone Receptor (GHR) Exon 3 Polymorphism And Early Screening And Prevention Of Prader-Willi Syndrome

Comparative analysis of domestic and foreign studies on clinical phenotype of Prader-Willi SyndromeObjectiveThe clinical phenotype of Prader-Willi Syndrome (PWS) changes with age and varies between patients. The clinical diagnostic criteria for PWS was proposed by Holm et.al. in 1993. Recent advances in molecular biology boosted the genetic diagnosis of PWS. The most developed applications in PWS genetic diagnosis are the methylation specific polymerase chain reaction (MS-PCR) and the methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). However in Chinese population, PWS study using the above molecular diagnostic tools is sparse. In order to improve the diagnosis and screening of PWS in China, we designed the present study using the above genetic tests to analyze PWS clinical phenotype and phenotype-genotype relationship in Chinese PWS patients.MethodsFrom Jan-2007 to Jun-2012, seventy suspected PWS patients diagnosed clinically according to Holm et.al. were enrolled in our study. We compared the clinical manifestations of our patients with previous reports. Subsequently we used MS-PCR assay for molecular diagnosis. Patients diagnosed with PWS by MS-PCR were then genotyped using MS-MLPA and short tandem repeat (STR) to understand the underlying genetic mechanism.ResultsAmong our enrolled subjects,31 were confirmed by MS-PCR. Further analysis using MS-MLPA showed that 26 were associated with paternal deletion while the rest 5 were maternal uniparental disomy (mUPD). There were 25 out of the 31 patients met the Holm clinical diagnostic criteria, the rest 6 patients were younger than 9 months at diagnosis whose scores were below 5. All patients had reduced fetal movement, hypotonia and infant feeding difficulties. Compared to mUPD patients, patients with paternal deletion presented more obesity, hyperphagia, articulation defects, small hands and/or feet. When compared with studies in western populations, Chinese PWS patients presented less development delay, short stature, thick viscous saliva, hypopigmentation, characteristic facial appearance, skin picking, behavioral issues, sleep disturbance, small hands and/or feet. However reduced fetal movement, infant feeding difficulties and hypogonadism were found more among Chinese PWS patients.ConclusionPWS can be efficiently diagnosed using MS-PCR screening followed by MS-MLPA and STR genetic linkage analysis. Reduced fetal movement, hypotonia and infant feeding difficulties are key clinical manifestations in Chinese PWS patients.Study of Growth Hormone Receptor (GHR) exon 3 polymorphism in children with Prader-Willi SyndromeObjectiveThe role of genetic polymorphisms in exon 3 of growth hormone receptor (GHR) gene has been implicated in diseases treated with growth hormone (GH). We designed the present study by analyzing those polymorphisms in Chinese PWS patients. By comparing our results with previous studies, we aimed to identify the association between the effect of recombinant human growth hormone (rhGH) and genetic polymorphism in Chinese PWS patients.MethodsWe designed the present retrospective study involved 57 PWS patients diagnosed genetically. We used a multiplex PCR method for the genotyping of polymorphisms in exon 3 of GHR gene. We then compared out genotype results with data from previous studies on patients with obesity or short stature.ResultsIn our PWS patient cohort, the genotype frequencies of fl/f, fl/d3 and d3/d3 in GHR exon 3 (70%,23% and 7% respectively) were not different from general population in Chinese. However the frequencies of d3/d3 and fl/d3 genotype were lower than European general population. We did not find difference between genotype distribution when compared either with patients with idiopathic short stature and Turner syndrome or with patients with obesity and overweight. However, difference in genotype distribution was found in comparison with growth hormone deficiency (GHD) patients.ConclusionNo differences in distribution of GHR exon 3 polymorphisms were found between Chinese PWS patients and general population. Less common phenotype of short stature manifested among Chinese PWS patients could be due to the lower frequence of d3 genotype in GHR gene.Multicenter study of early screening and prevention of Prader-Willi SyndromeObjectiveThe current diagnostic criteria for Prader-Willi syndrome (PWS) is proposed by Holm et.al. in 1993. Although the criteria are widely accepted, it was challenging to be implemented in Chinese population. The present study collected PWS cases from 12 centers across China. By analyzing the clinical manifestation during early infancy, we aimed to provide data for clinical characteristics, screening strategy and effect of growth hormone (GH) treatment in Chinese PWS patients.MethodsWe screened 63 suspected PWS cases in 12 centers from May-2012 to Aug-2013 using MS-PCR. Patients diagnosed by MS-PCR further underwent analysis by MS-MPLA and STR to identify PWS genetic markers. Data on patients’ history, clinical manifestation, anthropometrics and clinical biochemistry test before/after GH treatment were collected for analysis.ResultsAmong our enrolled subjects,16 were confirmed by MS-PCR. Further analysis using MS-MLPA and STR analysis showed that 13 were associated with paternal deletion while the rest 3 were maternal uniparental disomy (mUPD). Among the 16 diagnosed PWS,13 were delivered at full term,1 were preterm birth,2 postterms,4 delivered vaginally,12 delivered by cesarean section. Fetal distress was diagnosed in 10 cases while abnormal fetal position found in 5 cases. All patients had reduced fetal movement, hypotonia and infant feeding difficulties. Characteristic facial appearance was found in 6 cases when 13 showed hypogonadism,8 had hypopigmentation. There were 4 patients received rhGH treatment. When we found patients treated with GH had improved physical development, no difference was found in thyroid function, plasma IGF-1 levels, fasting blood glucose, fasting insulin levels and blood lipid levels.ConclusionPWS might account for 25% of infants with idiopathic hypotonia and infant feeding difficulties. Screening using MS-PCR in suspected cases is critical to identify PWS patients. Hypogonadism and hypopigmentation are important clues for diagnosis. GH treatment during infancy can improve physical development in PWS patients, however how to improve cognitive development and function of endocrine system in PWS patients requires future studies.