Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Silver-Russell Syndrome.

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.

Scoliosis and BMI in patients with Prader-Willi syndrome.

Although scoliosis is commonly seen in patients with Prader-Willi syndrome, the patterns and extent of the deformity may change along their growth. Increased body weight is another issue in these patients, and its relationship with scoliosis is still controversial. The aim of this study was to evaluate scoliosis in patients with PWS, and its relationship with BMI. This was a retrospective cohort study in which a series of radiographic images and BMI from each patient were collected, and the data were rearranged following the age at which they were recorded. These patients were subsequently labeled as non-Scoliotic (<10°), Moderate (10° - 39°), and Severe (≥40°) according to their final Cobb angle, also as Normal (≤85%), Overweight (86%-95%), and Obese (≥95%) according to final BMI percentage. Thirty-four patients with age from 1 to 20 years old were recruited for this study, and the mean length of follow-up was 6.6 years. The prevalence of scoliosis was 71% (24 patients in Moderate, and 9 patients in Severe), and 65.6% were either overweight (11 patients) or obese (10 patients). The mean BMI percentage in non-scoliotic patients was 93.10 ± 13.84, which was significantly higher than that of the scoliotic groups ( P = 0.0180). When looking at the longitudinal change, the non-Scoliotic group had high BMI since childhood, and obese patients had less spine deformity also from early childhood. In this study, we found that the prevalence of scoliosis in Taiwanese population with PWS was 71% without gender preference. Not every patient had a high BMI, and obese patients seemed to have significantly less chance to develop scoliosis. Level III.

Accelerometer-Measured Physical Activity and Sedentary Behavior of Adults with Prader-Willi Syndrome Attending and Not Attending a Small-Scale Community Workshop.

This cross-sectional study aimed to compare the accelerometer-assessed physical activity (PA) and sedentary behavior (SB) of adults with Prader-Willi syndrome (PWS) attending or not attending a small-scale community workshop (SSCW). A total of 18 adults with PWS were recruited in this study. Of these participants, 10 regularly attended an SSCW and 8 did not. All of the participants were asked to wear accelerometers for eight continuous days for measuring their PA and SB. The independent sample t-test was used. The results showed that the adults with PWS who attended the SSCW engaged in more moderate-to-vigorous PA (MVPA) and daily steps than those who did not. By stratifying between daytime/nighttime on weekdays, we found the participants who attended the SSCW had higher total PA, MVPA, daily steps, as well as lower total sedentary time, during the daytime on weekdays than those who did not. Policies or programs promoting PA and reducing SB among adults with PWS should thus consider providing structured programs or courses in a community center.

Progression of Obstructive Sleep Apnea Syndrome in Pediatric Patients with Prader-Willi Syndrome.

Obstructive sleep apnea syndrome (OSAS) is one of the most common comorbidities in patients with Prader-Willi syndrome (PWS) and causes significant consequences. This observational study was conducted to investigate the progression of OSAS in pediatric patients with PWS, who had not undergone upper airway surgery, through a longitudinal follow-up of their annual polysomnography results. Annual body mass index (BMI), BMI z-score, sleep efficiency and stages, central apnea index (CAI), obstructive apnea-hypopnea index (OAHI), and oxygen saturation nadir values were longitudinally analyzed. At enrollment, of 22 patients (10 boys and 12 girls) aged 11.7 ± 3.9 years, 20 had OSAS. During the 4-year follow-up, only two patients had a spontaneous resolution of OSAS. The average BMI and BMI z-score increased gradually, but CAI and OAHI showed no significant differences. After statistical adjustment for sex, age, genotype, growth hormone use, and BMI z-score, OAHI was associated with the BMI z-score and deletion genotype. In conclusion, OSAS is common in patients with PWS, and rarely resolved spontaneously. Watchful waiting may not be the best OSAS management strategy. Weight maintenance and careful selection of surgical candidates are important for OSAS treatment in patients with PWS.

Dynamic Changes in the Quantitative Electroencephalographic Spectrum During Attention Tasks in Patients With Prader-Willi Syndrome.

Introduction: Attention problems are frequently observed in patients with Prader-Willi syndrome (PWS); however, only few studies have investigated the severity and mechanisms of attention problems in them. In this study, we aim to evaluate dynamic changes in the quantitative electroencephalographic (EEG) spectrum during attention tasks in patients with PWS. Method: From January to June 2019, 10 patients with PWS and 10 age-matched neurotypical control participants were recruited at Taipei Tzu Chi Hospital. Each participant completed Conners' continuous performance test, third edition (CPT-3), tasks with simultaneous EEG monitoring. The dynamic changes in the quantitative EEG spectrum between the resting state and during CPT-3 tasks were compared. Results: Behaviorally, patients with PWS experienced significant attention problems, indicated by the high scores for several CPT-3 variables. The theta/beta ratio of the resting-state EEG spectrum revealed no significant differences between the control participants and patients with PWS. During CPT-3 tasks, a significant decrease in the alpha power was noted in controls compared with that in patients with PWS. The attention-to-resting alpha power ratio was positively correlated with many CPT-3 variables. After adjusting for genotype, age, intelligence, and body mass index, the attention-to-resting alpha power ratio was still significantly correlated with participants' commission errors. Conclusion: This study provides evidence that attention problems are frequently observed in patients with PWS, while attention impairment can be demonstrated by dynamic changes in the quantitative EEG spectrum.

Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding ERCC6 Gene in a Taiwanese Boy with Cockayne Syndrome.

BACKGROUND: Cockayne syndrome (CS) is a rare form of dwarfism that is characterized by progressive premature aging. CS is typically caused by mutations in the excision repair cross-complementing protein group 6 (ERCC6) gene that encodes the CS group B (CSB) protein. Using whole exome sequencing, we recently identified a novel homozygous missense mutation (Leu536Trp) in CSB in a Taiwanese boy with CS. Since the current database (Varsome) interprets this variant as likely pathogenic, we utilized a bioinformatic tool to investigate the impact of Leu536Trp as well as two other variants (Arg453Ter, Asp532Gly) in similar articles on the CSB protein structure stability. METHODS: We used iterative threading assembly refinement (I-TASSER) to generate a predictive 3D structure of CSB. We calculated the change of mutation energy after residues substitution on the protein stability using I-TASSER as well as the artificial intelligence program Alphafold. RESULTS: The Asp532Gly variant destabilized both modeled structures, while the Leu536Trp variant showed no effect on I-TASSER's model but destabilized the Alphafold's modeled structure. CONCLUSIONS: We propose here the first case of CS associated with a novel homozygous missense mutation (Leu536Trp) in CSB. Furthermore, we suggest that the Asp532Gly and Leu536Trp variants are both pathogenic after bioinformatic analysis of protein stability.

Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver-Russell Syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. METHODS: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the "IC1 hypomethylation" and "mUPD7" groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). CONCLUSIONS: The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.

High prevalence of lower urinary tract dysfunction in patients with Prader-Willi syndrome.

AIMS: To report the first noninvasive urodynamic screening of lower urinary tract dysfunction (LUTD) in children, adolescents, and young adults with Prader-Willi Syndrome (PWS). METHODS: We recruited 37 PWS patients with/without lower urinary tract symptoms (LUTS) from our hospital. Uroflowmetry was performed in 36 patients. In addition, 20 patients underwent postvoid residual urine (PVR) measurement by transabdominal ultrasound. LUTD is defined as abnormal uroflow patterns, low peak flow rate (Qmax ), or elevated PVR by age. Videourodynamic study (VUDS) was performed in selected cases. RESULTS: Mean and median age of the patients were 17.7 ± 7.8 years and 16 years. Male to female ratio was 15/22. Two patients were excluded from the following analysis because of voided volume less than or equal to 50 ml. Of the remaining 34 uroflowmetry examination, normal voiding pattern (bell shape) was observed in 22 (64.7%) patients. Abnormal uroflowmetry pattern were obstructive in 6 (17.6%), staccato in 3 (8.8%), intermittent in 2 (5.8%), tower in 1 (2.9%), and plateau in 0 patients. Ten (29.4%) patients had a Qmax less than 15 ml/s. Of 20 patients undergoing PVR tests 10 (50%) had elevated PVR by age ( > 6% of estimated bladder volume). In all, 17/34 (50.0%) PWS patients had at least one abnormality of the noninvasive tests. Of the three cases undergoing VUDS all showed detrusor sphincter dyssynergia. CONCLUSIONS: Half of PWS patients with/without LUTS had LUTD. Noninvasive study such as uroflowmetry and postvoid residual urine by ultrasound is recommended to all patients with PWS.

Parenting stress in families of children with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple endocrine, metabolic, respiratory, cognitive, and behavioral/psychiatric symptoms that may lead to severe emotional strain in their caregivers. In this study, we evaluated parenting stress by the Parenting Stress Index-short form (PSI/SF) and parent-reported behavioral symptoms by the Child Behavior Checklist (CBCL/6-18) in families of children with PWS. Sixty-seven home-resident PWS patients and their families were recruited in this study. The patients' mean age was 14.9 ± 8.3 years, and 33 (50.8%) were male. High parenting stress was reported by 41.5% families, as determined by high total stress scores of PSI/SF. The patients in high stress families were significantly older than those in low stress families (18.2 ± 8.0 vs. 12.6 ± 7.8 years, p = .007). CBCL/6-18 was used to evaluate the somatic and neuropsychiatric symptoms of PWS patients aged between 6 and 18 in the subgroup of the 35 families. In this subgroup, 37.1% of families reported high parenting stress. High stress families reported a higher T-score in anxiety/depression, withdrawn behavior, somatic complaints, thought problems, attention problems, and delinquent and aggressive behavior of their children with PWS. After multivariate stepwise logistic regression analysis, the T-score of somatic complaints was the only factor related to high parenting stress, with an odds ratio of 1.279. Our data demonstrated the high care burden of families with PWS and highlighted the importance of having dedicated medical care for both somatic and neuropsychiatric symptoms.

Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple respiratory, cognitive, endocrine, and behavioral symptoms, such as central apnea, intellectual disabilities, exaggerated stress responses, and temper tantrums. The locus coeruleus noradrenergic system (LC-NE) modulates a diverse range of behaviors, including arousal, learning, pain modulation, and stress-induced negative affective states, which are possibly correlated with the pathogenesis of PWS phenotypes. Therefore, we evaluated the LC-NE neuronal activity of necdin-deficient mice, an animal model of PWS. METHODS: Heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygotes (+m/-p) animals, which were examined of LC-NE neuronal activity, developmental reflexes, and plethysmography. RESULTS: On slice electrophysiology, LC-NE neurons of Ndntm1ky mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. Ndntm1ky mice also exhibited the neonatal phenotypes of PWS, such as hypotonia and blunt respiratory responses to hypercapnia. CONCLUSIONS: LC-NE neuronal firing activity decreased in necdin-deficient mice, suggesting that LC, the primary source of norepinephrine in the central nervous system, is possibly involved in PWS pathogenesis.

Clinical characteristics and epilepsy in genomic imprinting disorders: Angelman syndrome and Prader-Willi syndrome.

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are considered sister imprinting disorders. Although both AS and PWS congenital neurodevelopmental disorders have chromosome 15q11.3-q13 dysfunction, their molecular mechanisms differ owing to genomic imprinting, which results in different parent-of-the-origin gene expressions. Recently, several randomized controlled trials have been proceeded to treat specific symptoms of AS and PWS. Due to the advance of clinical management, early diagnosis for patients with AS and PWS is important. PWS is induced by multiple paternal gene dysfunctions, including those in MKRN3, MAGEL2, NDN, SNURF-SNPRPN, NPAP1, and a cluster of small nucleolar RNA genes. PWS patients exhibit characteristic facial features, endocrinological, and behavioral phenotypes, including short and obese figures, hyperphagia, growth hormone deficiency, hypogonadism, autism, or obsessive- compulsive-like behaviors. In addition, hypotonia, poor feeding, failure to thrive, and typical facial features are major factors for early diagnosis of PWS. For PWS patients, epilepsy is not common and easy to treat. Conversely, AS is a single-gene disorder induced by ubiquitin-protein ligase E3A dysfunction, which only expresses from a maternal allele. AS patients develop epilepsy in their early lives and their seizures are difficult to control. The distinctive gait pattern, excessive laughter, and characteristic electroencephalography features, which contain anterior-dominated, high-voltage triphasic delta waves intermixed with epileptic spikes, result in early suspicion of AS. Often, polytherapy, including the combination of valproate, levetiracetam, lamotrigine, and benzodiazepines, is required for controlling seizures of AS patients. Notably, carbamazepine, oxcarbazepine, and vigabatrin should be avoided, since these may induce nonconvulsive status epilepticus. AS and PWS presented with distinct clinical manifestations according to specific molecular defects due to genomic imprinting. Early diagnosis and teamwork intervention, including geneticists, neurologists, rehabilitation physicians, and pulmonologists, are important. Epilepsy is common in patients with AS, and after proper treatment, seizures could be effectively controlled in late childhood or early adulthood for both AS and PWS patients.

Genetic Architecture Associated With Familial Short Stature.

CONTEXT: Human height is an inheritable, polygenic trait under complex and multilocus genetic regulation. Familial short stature (FSS; also called genetic short stature) is the most common type of short stature and is insufficiently known. OBJECTIVE: To investigate the FSS genetic profile and develop a polygenic risk predisposition score for FSS risk prediction. DESIGN AND SETTING: The FSS participant group of Han Chinese ancestry was diagnosed by pediatric endocrinologists in Taiwan. PATIENTS AND INTERVENTIONS: The genetic profiles of 1163 participants with FSS were identified by using a bootstrapping subsampling and genome-wide association studies (GWAS) method. MAIN OUTCOME MEASURES: Genetic profile, polygenic risk predisposition score for risk prediction. RESULTS: Ten novel genetic single nucleotide polymorphisms (SNPs) and 9 reported GWAS human height-related SNPs were identified for FSS risk. These 10 novel SNPs served as a polygenic risk predisposition score for FSS risk prediction (area under the curve: 0.940 in the testing group). This FSS polygenic risk predisposition score was also associated with the height reduction regression tendency in the general population. CONCLUSION: A polygenic risk predisposition score composed of 10 genetic SNPs is useful for FSS risk prediction and the height reduction tendency. Thus, it might contribute to FSS risk in the Han Chinese population from Taiwan.

Is prone sleeping dangerous for neonates? Polysomnographic characteristics and NDN gene analysis.

OBJECTIVE: Prone sleep is an identified risk factor for sudden infant death syndrome, possibly due to reduced blood pressure, cerebral oxygenation, and impaired cerebral vascular control. Cardiac and respiratory responses in neonates during supine and prone sleep have not been reported. MATERIALS AND METHODS: In this study, daytime polysomnography (PSG) data from 17 neonates aged 2-3 days during supine and prone sleep were reported and the NDN gene, an important gene for neonatal respiratory control, was sequenced for correlation with neonatal respiratory parameters. Heart rate (HR), oxygen saturation, carbon dioxide concentration, sleep stages, central apnea index (CAI), obstructive apnea/hypopnea index (OAHI), and oxygen nadir were compared between supine and prone sleep and between participants with different single-nucleotide polymorphisms (SNPs) in the NDN gene. RESULTS: During prone sleep, neonates had a faster HR, decreased oxygen saturation, and a longer duration of oxygen saturation <90% than during supine sleep, suggesting that cardiopulmonary responsiveness was impaired. Sleep efficiency, sleep stages, oxygen nadir, and carbon dioxide tension were not different during supine and prone sleep. Central apnea occurred more significantly than obstructive apnea. During supine and prone sleep, the CAI was 3.3 ± 2.9/h and 2.3 ± 2.6/h and the OAHI was 0.6 ± 0.7/h and 0.6 ± 0.8/h, respectively. We found one SNP rs3743340 in the NDN gene that had no effect on the sleep and respiratory parameters of PSG. CONCLUSION: Tachycardia and respiratory instability were recorded in neonates during prone sleep, suggesting that neonates are vulnerable to cardiopulmonary events during prone sleep. Therefore, young neonates should be kept in the supine sleep position unless there are contraindications.

Functional independence of Taiwanese children with Prader-Willi syndrome.

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

Motor performance in Prader-Willi syndrome patients and its potential influence on caregiver's quality of life.

BACKGROUND: Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by a variety of physical, cognitive, and behavioral impairments. PWS is a unique sarcopenia model characterized by an abnormal increase in body fat mass and a decrease in muscle mass that predisposes patients to reduced physical activity, functional limitations, and disability. These manifestations may require both symptomatic and supportive management, thus negatively influencing their lifelong family caregiver's quality of life. The aim of this study was to examine the functional motor performance of adults with PWS in Taiwan and to measure the quality of life of their primary family caregivers. METHODS: The functional motor tests consisted of the following: (1) 30-s sit-to-stand test, (2) timed up-and-go test, (3) hand grip and lateral pinch strength tests, and (4) Berg Balance Scale. The World Health Organization Quality of Life-short form (WHOQOL-BREF) and the Short-Form 36 Health Survey Questionnaire (SF-36) were used to evaluate health-related quality of life, and the parenting stress index was used to assess the magnitude of stress within the parent-child system. RESULTS: The participants included seven adults (two females and five males) with genetically confirmed PWS and their respective main caregivers. The mean age of the adults with PWS was 25.28 years; range 18-31 years, SD 5.10; the mean BMI was 29.2 kg/m2, SD 6.43. All adults with PWS showed lower hand grip and lateral pinch strengths, fewer sit-to-stand cycles during the 30-s chair stand test, and greater average time during the timed up-and-go test when compared to the normative data on healthy adults. Balance was negatively correlated with the caregiver's health concepts of social functioning (rs -0.879, P = 0.009) and with role limitations due to physical problems (rs -0.899, P = 0.006) and emotional problems (rs -0.794, P = 0.033); hand grip strength was negatively correlated with bodily pain (rs -0.800, P = 0.031), as assessed using the SF-36 questionnaire. The timed up-and-go test was positively correlated with the social relationship domain (rs 0.831, P = 0.021), as assessed using the WHOQOL-BREF questionnaire. The parenting stress index showed no association with the PWS patient's physical activities. CONCLUSIONS: All adults with PWS showed decreased upper and lower limb strength and functional mobility when compared to healthy adults. Some of their motor performance might have negative effects on their primary family members in terms of social participation and physical and emotional role limitations. Future research should explore the relationship between physical performances, psychological difficulties of PWS and caregiver's QOL.

Association of human height-related genetic variants with familial short stature in Han Chinese in Taiwan.

Human height can be described as a classical and inherited trait model. Genome-wide association studies (GWAS) have revealed susceptible loci and provided insights into the polygenic nature of human height. Familial short stature (FSS) represents a suitable trait for investigating short stature genetics because disease associations with short stature have been ruled out in this case. In addition, FSS is caused only by genetically inherited factors. In this study, we explored the correlations of FSS risk with the genetic loci associated with human height in previous GWAS, alone and cumulatively. We systematically evaluated 34 known human height single nucleotide polymorphisms (SNPs) in relation to FSS in the additive model (p < 0.00005). A cumulative effect was observed: the odds ratios gradually increased with increasing genetic risk score quartiles (p < 0.001; Cochran-Armitage trend test). Six affected genes-ZBTB38, ZNF638, LCORL, CABLES1, CDK10, and TSEN15-are located in the nucleus and have been implicated in embryonic, organismal, and tissue development. In conclusion, our study suggests that 13 human height GWAS-identified SNPs are associated with FSS risk both alone and cumulatively.

Drug-induced sleep endoscopy in children with Prader-Willi syndrome.

PURPOSE: Review drug-induced sleep endoscopy (DISE) findings in children with Prader-Willi syndrome (PWS) and correlate the patterns of airway collapse with apnea-hypopnea index (AHI) and body mass index (BMI). METHODS: A total of nine children with PWS underwent DISE. DISE findings were recorded using the VOTE classification system. The relationship between different patterns of airway collapse with AHI and BMI was analyzed. RESULTS: The majority of children with PWS were found to have multilevel obstruction (six out of nine children, 66.6 %). The velum was the most common site of obstruction (nine out of nine children, 100 %). All of the patients had positional obstructive sleep apnea (OSA). Patients with partial or complete anterior-posterior tongue base collapse were associated with a significantly higher AHI (P = 0.016) compared to patients with no anterior-posterior tongue base collapse. Apart from tongue base collapse, no other patterns of airway collapse showed a consistent association with AHI in our results. No patterns of airway collapse showed a significant association with BMI in our study. CONCLUSIONS: In our study, partial or complete anterior-posterior tongue base collapse was associated with higher AHI values in children with PWS. Therefore, careful attention should be addressed to the management of tongue base collapse. Positional therapy could be a potential treatment for patients with PWS since it may alleviate the severity of tongue base collapse.

Adolescent onset of vertically transmitted untreated AIDS: A report of one case.

A 12-year-old adolescent girl with intractable pneumonia and desaturation was sent to our hospital. An immunocompromised state was highly suspected because of an oral thrush persisting for a year and pneumonia of unusual severity. Laboratory tests confirmed she had human immunodeficiency virus (HIV) infection and full-blown AIDS. She lived with her adopted parents and reported no history of sexual abuse, drug abuse, or blood transfusion. We contacted the Center of Disease Control and discovered that her mother had HIV and had passed away a few years ago, thus confirming that she was a case of vertically transmitted HIV patient who had only developed AIDS recently. Even though her mother had HIV, our public health department failed to follow her as a potential HIV victim, probably because routine HIV examinations for pregnant women only started in 2005, 4 years after she was born.