Variants in C-reactive protein and IL-6 genes and susceptibility to obstructive sleep apnea in children: a candidate-gene association study in European American and Southeast European populations.

BACKGROUND: Preliminary evidence indicates that variants of the C-reactive protein (CRP) and IL-6 genes might be associated with the presence of obstructive sleep apnea (OSA) in childhood. Thus a candidate-gene association study was conducted to investigate the association of four variants of the CRP gene (1444C/T, -717T/C, 1861C/T, and 1919A/T) and two variants of the IL-6 gene (-174G/C and 597G/A) with OSA in a cohort of European American and Greek children. METHODS: The genetic risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (ORG), which is a model-free approach. The mode of inheritance was assessed using the degree of dominance index. The impact of haplotypes was also examined. RESULTS: In the American population, the allele contrast and the model-free approach produced significant ORs for the CRP 1444C/T variant (OR, 3.82 [95% confidence interval {CI}, 1.91-7.63] and ORG, 4.37 [95% CI, 1.96-9.76]), respectively, and the mode of inheritance was recessiveness of allele T. Significance was also shown for the CRP 1919A/T variant (OR, 2.45 [95% CI, 1.23-4.85] and ORG, 2.76 [95% CI, 1.26-6.03]) with the mode of inheritance being nondominance of allele T. For the IL-6-174G/C variant, there was an indication of recessiveness of allele C. Finally, the IL-6-174C/IL-6 597A haplotype was associated with OSA. In the Greek population, no association was detected for any variant or haplotype. CONCLUSIONS: Genetic variation in the IL-6/CRP pathway was associated with increased risk for OSA in European American children and may account for the higher CRP levels in the context of pediatric OSA compared to Greek children.

Macrophage migration inhibitory factor gene polymorphisms and plasma levels in children with obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) is associated with increased risk for cardiovascular and metabolic dysfunction in both adults and children. In adults with OSA, serum levels of macrophage migration inhibitory factor (MIF) are elevated. Therefore, we assessed plasma MIF levels and MIF allelic variant frequencies in children with and without OSA (NOSA). METHODS: A total of 614 consecutive children ages 5-8 years were recruited. Children were divided into those with OSA and NOSA based on the apnea-hypopnea index (AHI). In addition to lipid profile, hsCRP, and fasting insulin and glucose levels, plasma MIF levels were assayed using ELISA, and 28 single nucleotide polymorphisms (SNPs) covering the region were genotyped. Linkage disequilibrium and haplotype blocks were analyzed using Haploview version 4.2 software. RESULTS: Morning plasma MIF levels were increased in children with OSA. Of the 28 SNPs tested, the frequency of rs10433310 minor allele was significantly decreased in OSA. This SNP was also associated with reduced fasting insulin and hsCRP levels in OSA. The minor allele frequency of all other 27 SNPs was similar in OSA and NOSA groups. CONCLUSIONS: Childhood OSA is associated with higher plasma MIF, hsCRP, and fasting insulin levels that promote cardiometabolic risk, and the MIF gene SNP rs10433310 may account for some of the variance in such risk.

Cognitive function in prepubertal children with obstructive sleep apnea: a modifying role for NADPH oxidase p22 subunit gene polymorphisms?

Pediatric obstructive sleep apnea (OSA) may lead to neurocognitive dysfunction, but not in everyone affected. The frequencies of NADPH oxidase (NOX) polymorphisms in the p22phox subunit were similar between children with OSA and controls, except for rs6520785 and rs4673, the latter being significantly more frequent among the OSA children without deficits than with deficits (p<0.02). Similarly, 8-hydroxydeoxyguanine urine levels and NOX activity were lower among children without cognitive deficits and particularly among those with the rs4673 polymorphism. Thus, polymorphisms within the NOX gene or its functional subunits may account for important components of the variance in cognitive function deficits associated with OSA in children.

Endothelial dysfunction in children without hypertension: potential contributions of obesity and obstructive sleep apnea.

BACKGROUND: Endothelial dysfunction can develop in the context of both obesity and obstructive sleep apnea (OSA) in children. However, the potential interactions between OSA and obesity have not been defined. METHODS: Children who were prepubertal and nonhypertensive were recruited. Endothelial function was assessed in a morning fasted state, using a modified hyperemic test involving cuff-induced occlusion of the radial and ulnar arteries, and blood was drawn for assessment of myeloid-related protein 8/14 (MRP8/14) levels using a commercial enzyme-linked immunosorbent assay. Overnight polysomnography defined the presence of OSA or absence of OSA (NOSA) in subjects investigated for sleep-disordered breathing. Anthropometric measurements were performed to assign subjects to obese (OB) and nonobese (NOB) categories. RESULTS: Fifty-four children with OSA who were obese and nonobese (mean age, 7.90 ± 0.26 years; mean BMI z-score, 1.70 ± 0.3; obstructive apnea-hypopnea index [OAHI], 7.36 ± 1.09) were compared with 54 children without OSA who were obese and nonobese (mean age, 8.26 ± 0.24 years; mean BMI z-score, 1.41 ± 0.18; OAHI, 0.86 ± 0.07). Of those subjects, 62.5% of the OB-OSA category, 38.7% of the OB-NOSA category, and 20.0% of the NOB-OSA category had evidence of endothelial dysfunction, compared with 0.0% of the NOB-NOSA category (P < .01). The degree of endothelial dysfunction in all groups was associated with circulating MRP8/14 levels (r = 0.343, P < .001). CONCLUSIONS: Both obesity and OSA can independently increase the risk for endothelial dysfunction, and the concurrent presence of both markedly increases such risk. Although the mechanisms underlying endothelial dysfunction remain unclear, a potential role for MRP8/14 as an inflammatory biomarker of endothelial dysfunction is suggested.

DNA methylation in inflammatory genes among children with obstructive sleep apnea.

BACKGROUND: Pediatric obstructive sleep apnea (OSA) leads to multiple end-organ morbidities that are mediated by the cumulative burden of oxidative stress and inflammation. Because not all children with OSA exhibit increased systemic inflammation, genetic and environmental factors may be affecting patterns of DNA methylation in genes subserving inflammatory functions. METHODS: DNA from matched children with OSA with and without high levels of high-sensitivity C-reactive protein (hsCRP) were assessed for DNA methylation levels of 24 inflammatory-related genes. Primer-based polymerase chain reaction assays in a case-control setting involving 47 OSA cases and 31 control subjects were conducted to confirm the findings; hsCRP and myeloid-related protein (MRP) 8/14 levels were also assayed. MEASUREMENTS AND MAIN RESULTS: Forkhead box P3 (FOXP3) and interferon regulatory factor 1 (IRF1) showed higher methylation in six children with OSA and high hsCRP levels compared with matched children with OSA and low hsCRP levels (P < 0.05). In the case-control cohort, children with OSA and high CRP levels had higher log FOXP3 DNA methylation levels compared with children with OSA and low CRP levels and control subjects. IRF1 did not exhibit significant differences. FOXP3 DNA methylation levels correlated with hsCRP and MRP 8/14 levels and with apnea-hypopnea index (AHI), BMI z score, and apolipoprotein B levels. A stepwise multiple regression model showed that AHI was independently associated with FOXP3 DNA methylation levels (P < 0.03). CONCLUSIONS: The FOXP3 gene, which regulates expression of T regulatory lymphocytes, is more likely to display increased methylation among children with OSA who exhibit increased systemic inflammatory responses. Thus, epigenetic modifications may constitute an important determinant of inflammatory phenotype in OSA, and FOXP3 DNA methylation levels may provide a potential biomarker for end-organ vulnerability.

Fatty-acid binding protein 4 gene polymorphisms and plasma levels in children with obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) is associated with increased risk for metabolic syndrome in both adults and children. In adults with OSA, serum levels of fatty acid binding protein 4 (FABP4) are elevated and associated with the degree of metabolic insulin resistance, independent of obesity. Therefore, we assessed plasma FABP4 levels and FABP4 allelic variants in obese and non-obese children with and without OSA. METHODS: A total of 309 consecutive children ages 5-8years were recruited. Children were divided into those with OSA and without OSA (NOSA) based on the apnea-hypopnea index (AHI). Subjects were also subdivided into obese (OB) and non-obese (NOB) based on BMI z score. Morning fasting plasma FABP4 levels were assayed using ELISA, and 11 single-nucleotide polymorphisms (SNPs) within the FABP4 region were genotyped. RESULTS: Morning plasma FABP4 levels were increased in all children with OSA, even in NOB children. However, plasma FABP4 levels were strongly associated with BMI z score. Of the 11 SNPs tested, the frequency of rs1054135 (A/G) minor allele (A) was significantly increased in OSA. This SNP was also associated with increased plasma FABP4 levels in both OSA and obese subjects. The minor allele frequency of all other SNPs was similar in OSA and NOSA groups. CONCLUSIONS: Childhood obesity and OSA are associated with higher plasma FABP4 levels and thus promote cardiometabolic risk. The presence of selective SNP (e.g., rs1054135) in the FABP4 gene may account for increased plasma FABP4 levels in the context of obesity and OSA in children.

Peripheral blood leukocyte gene expression patterns and metabolic parameters in habitually snoring and non-snoring children with normal polysomnographic findings.

BACKGROUND: Children who snore but do not have gas exchange abnormalities or alterations of sleep architecture have primary snoring (PS). Since increasing evidence suggest that PS may be associated with morbidity, we hypothesized that assessing genome-wide gene expression in peripheral blood leukocytes (PBL) will identify a distinct signature in PS children. METHODS: Children (aged 4-9 years) with and without habitual snoring and a normal PSG were designated as either PS or controls. Whole genome expression profiles of PBL and metabolic parameters in 30 children with PS and 30 age-, gender-, ethnicity-, and BMI-matched controls were compared. Pathway-focused gene network analysis of the PBL transcriptome was performed. Metabolic parameters were measured in an independent follow-up cohort of 98 children (64 PS and 34 controls) to evaluate the computationally derived findings. RESULTS: PS was not associated with a distinct transcriptional signature in PBL. Exploratory functional network analysis of enriched gene sets identified a number of putative pathways-including those mapping to insulin signaling, adipocyte differentiation, and obesity-with significant alterations in glucose metabolism and insulin sensitivity emerging in the follow-up cohort of children with PS, but no differences in lipid profiles. CONCLUSIONS: PS children do not exhibit global perturbations in their PBL transcriptional response, suggesting that current normative PSG criteria are overall valid. However, subtle differences in functionally coherent pathways involved in glycemic homeostasis were detected and confirmed in a larger independent pediatric cohort indicating that PS may carry increased risk for end-organ morbidity in susceptible children.

TNF-α gene polymorphisms and excessive daytime sleepiness in pediatric obstructive sleep apnea.

OBJECTIVE: To assess sleepiness, TNF-α plasma levels, and genomic variance in the TNF-α gene in children with obstructive sleep apnea (OSA). STUDY DESIGN: Children being evaluated for OSA (n = 60) and matched control children (n = 80) were assessed with a modified Epworth Sleepiness Scale questionnaire and underwent a blood draw the morning after nocturnal polysomnography. TNF-α plasma concentrations were assayed using ELISA, and genomic DNA was extracted. Genotyping and allelic frequencies were determined for 4 TNF-α single nucleotide polymorphisms using real-time polymerase chain reaction genotyping assays. RESULTS: Morning TNF-α levels and Epworth Sleepiness Scale scores were increased in the presence of OSA, but substantial variability was present. Although TNF-α plasma concentrations were globally increased in OSA, most of the variance was attributable to the presence or absence of TNF-α -308G gene polymorphism. CONCLUSIONS: TNF-α levels are increased in a subset of children with OSA, particularly among those harboring the TNF-α -308G single nucleotide polymorphism. Among the latter, significant increases in excessive daytime sleepiness symptoms are also present. The relatively high variability of excessive daytime sleepiness in pediatric OSA may be related to underlying TNF-α gene polymorphisms, particularly -308G.

Sleep measures and morning plasma TNF-alpha levels in children with sleep-disordered breathing.

BACKGROUND: Sleep disordered breathing in children is associated with severity-dependent increases in excessive daytime sleepiness (EDS). TNF-alpha is an inflammatory cytokine that has been implicated in EDS. Since, at any given level of apnea-hypopnea index, there is significant variability in EDS, we hypothesized that morning tumor necrosis factor (TNF)-alpha plasma levels may provide a biologic correlate of EDS. METHODS: Children being evaluated for sleep disordered breathing underwent a blood draw after nocturnal polysomnography, and TNF-alpha plasma concentrations were assayed using ELISA. In a subset of 15 children with sleep disordered breathing and in 15 matched control subjects, whole blood cultures in the presence of lipopolysaccharide and Multiple Sleep Latency Test were conducted. Furthermore, 22 children with obstructive sleep apnea had TNF-alpha levels assayed and underwent nocturnal polysomnography and Multiple Sleep Latency Test before and after adenotonsillectomy. RESULTS: In 298 children, morning TNF-alpha levels were globally increased in the presence of obstructive sleep apnea, particularly in more severe cases, and correlated with obstructive apnea-hypopnea index and sleep pressure score, a measure of respiratory-induced sleep fragmentation, but not with nadir Sa02. A stepwise logistic regression analysis revealed that sleep pressure score and body mass index accounted for 36.2% of the adjusted variance in TNF-alpha levels (P < 0.0001). Furthermore, multiple sleep latencies were correlated with whole blood culture-derived TNF-alpha levels (n = 15), and morning TNF-alpha levels decreased after adenotonsillectomy in 22 children. CONCLUSIONS: TNF-alpha levels are increased in pediatric obstructive sleep apnea, are primarily driven by sleep fragmentation and body mass index, and are closely associated with the degree of sleepiness, as measured by Multiple Sleep Latency Test. Furthermore, surgical treatment of obstructive sleep apnea results in significant reductions in TNF-alpha levels with reciprocal prolongations in sleep latency.

Uric acid excretion in North American and Southeast European children with obstructive sleep apnea.

BACKGROUND AND OBJECTIVES: Responses to nocturnal hypoxemia accompanying sleep-disordered breathing (SDB) may vary in different populations. Aims of this study were to (1) assess whether severity of SDB is related to uric acid excretion in North American and Southeast European children and (2) evaluate the interaction between nocturnal hypoxemia and country of children's origin in uric acid excretion. METHODS: Consecutive US and Greek children with snoring who were referred for polysomnography were recruited. Uric acid excretion expressed as uric acid-to-creatinine concentrations ratio in a morning urine specimen was the primary outcome measure. RESULTS: One hundred and twenty-six US children (6.8+/-0.7years old) and 123 Greek children (6.4+/-2.5years old) were recruited. Forty-three US and 53 Greek participants had moderate-to-severe nocturnal hypoxemia (SpO(2) nadir <90%). Obstructive apnea-hypopnea index and SpO(2) nadir were related to uric acid excretion in Greek (but not US) children after adjustment by age, gender and body mass index z-score (p<0.05). There was a significant interaction between severity of hypoxemia and country of children's origin in uric acid excretion after adjustment by age, gender and body mass index z-score (p=0.036). Greek children with moderate-to-severe hypoxemia had higher uric acid excretion (0.85+/-0.35) than those with mild/no hypoxemia (0.69+/-0.25) (p=0.005). US children with moderate-to-severe hypoxemia (0.41+/-0.20) did not differ in uric acid excretion from those with mild/no hypoxemia (0.42+/-0.22) (p=0.823). CONCLUSIONS: Uric acid excretion differs in children with SDB and different ethnic backgrounds or environmental exposures.

Endothelial dysfunction in obese non-hypertensive children without evidence of sleep disordered breathing.

BACKGROUND: Endothelial dysfunction is a complication of both obesity and obstructive sleep apnea syndrome (OSAS), the latter being highly prevalent among obese children. It is unknown whether obesity causes endothelial dysfunction in children in the absence of OSAS. This study examines endothelial function in obese and non-obese children without OSAS. METHODS: Pre-pubertal non-hypertensive children were recruited. Endothelial function was assessed in a morning fasted state, using a modified hyperemic test involving cuff-induced occlusion of the radial and ulnar arteries. The absence of OSAS was confirmed by overnight polysomnography. Anthropometry was also performed. RESULTS: 55 obese children (mean age 8.6 +/- 1.4 years, mean BMI z-score: 2.3 +/- 0.3) were compared to 50 non-obese children (mean age 8.0 +/- 1.6 years, mean BMI z-score 0.3 +/- 0.9). Significant delays to peak capillary reperfusion after occlusion release occurred in obese compared to non-obese children (45.3 +/- 21.9 sec vs. 31.5 +/- 14.1 sec, p < 0.01), but no differences in the magnitude of hyperemia emerged. Time to peak reperfusion and percentage of body fat were positively correlated (r = 0.365, p < 0.01). CONCLUSIONS: Our findings confirm that endothelial dysfunction occurs early in life in obese children, even in the absence of OSAS. Thus, mechanisms underlying endothelial dysfunction in pediatric obesity are operational in the absence of sleep-disordered breathing.

Fatty-acid binding protein 4 gene variants and childhood obesity: potential implications for insulin sensitivity and CRP levels.

INTRODUCTION: Obesity increases the risk for insulin resistance and metabolic syndrome in both adults and children. FABP4 is a member of the intracellular lipid-binding protein family that is predominantly expressed in adipose tissue, and plays an important role in maintaining glucose and lipid homeostasis. The purpose of this study was to measure FABP4 plasma levels, assess FABP4 allelic variants, and explore potential associations with fasting glucose and insulin levels in young school-age children with and without obesity. METHODS: A total of 309 consecutive children ages 5-7 years were recruited. Children were divided based on BMI z score into Obese (OB; BMI z score >1.65) and non-obese (NOB). Fasting plasma glucose, lipids, insulin, hsCRP, and FABP4 levels were measured. HOMA was used as correlate of insulin sensitivity. Four SNPs of the human FABP4 gene (rs1051231, rs2303519, rs16909233 and rs1054135), corresponding to several critical regions of the encoding FABP4 gene sequence were genotyped. RESULTS: Compared to NOB, circulating FABP4 levels were increased in OB, as were LDL, hsCRP and HOMA. FABP4 levels correlated with BMI, and also contributed to the variance of HOMA and hsCRP, but not serum lipids. The frequency of rs1054135 allelic variant was increased in OB, and was associated with increased FABP4 levels, while the presence of rs16909233 variant allele, although similar in OB and NOB, was associated with increased HOMA values. CONCLUSIONS: Childhood obesity is associated with higher FABP4 levels that may promote cardiometabolic risk. The presence of selective SNPs in the FABP4 gene may account for increased risk for insulin resistance or systemic inflammation in the context of obesity.

Two-dimensional differential in-gel electrophoresis proteomic approaches reveal urine candidate biomarkers in pediatric obstructive sleep apnea.

RATIONALE: Sleep studies are laborious, expensive, inaccessible, and inconvenient for diagnosing obstructive sleep apnea (OSA) in children. OBJECTIVES: To examine whether the urinary proteome uncovers specific clusters that are differentially expressed in the urine of children with OSA. METHODS: Two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry proteomics followed by validation with western blot of ELISA. MEASUREMENTS AND MAIN RESULTS: Morning urine proteins from 60 children with polysomnographically confirmed OSA and from matched children with primary snoring (n = 30) and control subjects (n = 30) were assessed. A total of 16 proteins that are differentially expressed in OSA were identified, and 7 were confirmed by either immunoblots or ELISA. Among the latter, receiver-operator curve analyses of urinary concentrations of uromodulin, urocortin-3, orosomucoid-1, and kallikrein assigned favorable predictive properties to these proteins. Furthermore, combinatorial approaches indicated that the presence of values beyond the calculated cutoff concentrations for three or more of the proteins yielded a sensitivity of 95% and a specificity of 100%. CONCLUSIONS: Proteomic approaches reveal that pediatric OSA is associated with specific and consistent alterations in urinary concentrations of specific protein clusters. Future studies aiming to validate this approach as a screening method of habitually snoring children appears warranted.

Catecholamine alterations in pediatric obstructive sleep apnea: effect of obesity.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) elicits increased sympathetic activity in adults and increased urinary catecholamines. Moreover, urinary catecholamine excretion is altered in obese patients. We hypothesized that morning urine catecholamine levels would be correlated with the severity of obstructive sleep apnea and degree of obesity in children. METHODS: Children referred to the pediatric sleep center for habitual snoring underwent overnight polysomnography, and the first morning voided urine sample was collected. Urinary concentrations of norepinephrine, epinephrine and dopamine were measured and corrected for creatinine levels. In a subset of children, blood samples were drawn and gene expression of catecholamine-relevant genes analyzed by quantitative real-time PCR. RESULTS: One hundred fifty-nine children were recruited and completed the protocol. Children with OSA had significantly higher urinary norepinephrine and epinephrine levels, but not dopamine, compared to habitual snorers (norepinephrine: 40.1 +/- 24.7 ng/mg creatinine vs. 31.6 +/- 16.2 ng/mg creatinine, P < 0.01; epinephrine: 6.4 +/- 10.5 ng/mg vs. 4.5 +/- 0.5 ng/mg, P < 0.01). There was a positive correlation between norepinephrine and epinephrine values and polysomnographic indices, but no effect of obesity on catecholamine levels. In addition, expression of several of the major genes involved in synthesis and transport of catecholamines, as well as in selected receptors were compatible with increased bioavailability of catecholamines. CONCLUSIONS: In children with OSA, morning urinary norepinephrine and epinephrine levels are significantly higher than those without OSA, and correlate with the severity of the disease. Gene expression patterns are in agreement with such findings. Urine catecholamine levels do not appear to be influenced by the presence of obesity. Thus, altered sympathetic activity in OSA patients appears to occur independently of the presence of obesity.

Genome-wide gene expression profiling in children with non-obese obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a multi-factorial and highly prevalent disorder in which both genetic and environmental factors may be involved. If left untreated, OSA may lead to significant cardiovascular and neurocognitive and behavioral morbidities. We hypothesized that pediatric OSA would lead to altered gene expression in circulating leukocytes. METHODS AND RESULTS: Oligonucleotide-based microarray technology was used to identify mRNAs that may be differentially regulated in non-obese children with polysomnographically-established OSA compared to matched control children. Total morning blood RNA from 40 children (20 OSA and 20 controls) was extracted, labeled, and hybridized onto independent oligonucleotide-based microarrays. Of the 44,000 transcripts, 1217 transcripts were differentially expressed in OSA (p-value <0.05), with 68 transcripts (38 RefSeq accession numbers, 30 ESTs) fulfilling high stringency criteria. False Discovery rate (FDR) was used to determine the significance-difference of OSA vs. normal samples. Microarray data were further validated using quantitative RT-PCR techniques. Biological pathways pertinent to the differentially expressed genes were explored and revealed prominent involvement of inflammatory pathways. CONCLUSIONS: RNA derived from peripheral leukocytes confirms the presence of altered expression of functionally relevant gene clusters in pediatric OSA. Large-scale genomic approaches may provide further insights into adaptive and end-organ injury related mechanisms in the context of OSA in children.

Eye movement during REM sleep in children with attention deficit hyperactivity disorder.

The current study examined eye movements during rapid eye movement (REM) sleep of children ages 6-10 with attention deficit hyperactivity disorder (ADHD) and a control group without any known medical or psychiatric diagnoses. Electro-ocular recordings from archived polysomnograms were evaluated. An in-depth analysis revealed significantly lower frequency, higher amplitude eye movement in those with ADHD (N = 13) compared to the control group (N = 16). Although the results of this study are novel, defining distinct differences in eye movement during REM sleep of children with ADHD has the potential to supplement current biopsychosocial diagnostic models and further the understanding of the neurodevelopmental basis of ADHD.

Sleep-disordered breathing and verbal skills in school-aged community children.

Sleep-disordered breathing (SDB) has been repeatedly associated with neurocognitive deficits in children. However, impairments in verbal skills have been inconsistently reported. The effects of SDB on verbal skills of 76 age-, gender, ethnicity, and maternal education matched groups of children with habitual snoring, but normal overnight sleep studies (HS), and children with significant SDB were compared to non-snoring healthy controls. A multi-method assessment of verbal abilities, and language neurodevelopment was chosen to unravel verbal skills. Preschoolers' difficulties in processing verbal instructions of increasing linguistic complexity, and school-aged children's reduced ability of verbal concepts provide evidence of SDB effects on verbal abilities. Although overall cognitive performances of SBD children remain in normative range, their problematic verbal skills may ultimately adversely affect academic performances or socioemotional behaviors.

Inefficient or insufficient encoding as potential primary deficit in neurodevelopmental performance among children with OSA.

Memory (M) impairments have been suggested in pediatric Obstructive Sleep Apnea along with attention and executive (AE), language (L), and visuospatial (V) dysfunctions. NEPSY assessment of children aged 5-9 years who were either healthy (N = 43), or who had OSA without L, V, AE (OSA(-), N = 22) or with L (N = 6), V (N = 1), AE (N = 3) (OSA(+), N = 10) dysfunctions revealed no gross memory problems in OSA; however, over the three learning trials of cross-modal association learning of name with face, the OSA(-) progressively improved performance, whereas the OSA(+) failed to progress. No within-group differences between immediate and delayed memory tasks were apparent. The data suggest the presence of slower information processing, and/or secondary memory problems, in the absence of retrieval or recall impairments among a subset of children with OSA. We hypothesize that inefficient/insufficient encoding may account for the primary deficit.

Pediatric obstructive sleep apnea: complications, management, and long-term outcomes.

Obstructive sleep apnea (OSA) in children has emerged not only as a relatively prevalent condition but also as a disease that imposes a large array of morbidities, some of which may have long-term implications, well into adulthood. The major consequences of pediatric OSA involve neurobehavioral, cardiovascular, and endocrine and metabolic systems. The underlying pathophysiological mechanisms of OSA-induced end-organ injury are now being unraveled, and clearly involve oxidative and inflammatory pathways. However, the roles of individual susceptibility (as dictated by single-nucleotide polymorphisms), and of environmental and lifestyle conditions (such as diet, physical, and intellectual activity), may account for a substantial component of the variance in phenotype. Moreover, the clinical prototypic pediatric patient of the early 1990s has been insidiously replaced by a different phenotypic presentation that strikingly resembles that of adults afflicted by the disease. As such, analogous to diabetes, the terms type I and type II pediatric OSA have been proposed. The different manifestations of these two entities and their clinical course and approaches to management are reviewed.

Metabolic alterations and systemic inflammation in obstructive sleep apnea among nonobese and obese prepubertal children.

RATIONALE: Obstructive sleep apnea (OSA) has been associated with a higher prevalence and severity of the metabolic syndrome in adult patients, even after controlling for obesity. In contrast, OSA in prepubertal children does not appear to correlate with the magnitude of such metabolic derangements. OBJECTIVES: To further establish the potential mechanistic role of OSA in metabolic regulation in prepubertal children. METHODS: Fasting glucose, insulin, C-reactive protein, apolipoprotein B, and serum lipid concentrations were determined during the initial polysomnographic diagnosis of OSA and 6-12 months after adenotonsillectomy in both obese and nonobese children. MEASUREMENTS AND MAIN RESULTS: Sixty-two children with OSA (37 obese and 25 nonobese), age 7.40 +/- 2.6 years (mean +/- SD) completed the study. After adenotonsillectomy, significant improvements in apnea-hypopnea index and sleep fragmentation occurred, particularly among nonobese children. In nonobese children, adenotonsillectomy was associated with mild increases in body mass index z scores, no changes in either fasting glucose or insulin, significant increases in high-density lipoprotein and reciprocal decreases in low-density lipoprotein, and reductions in plasma C-reactive protein and apolipoprotein B levels. In obese children, adenotonsillectomy did not result in body mass index or glucose changes, but was associated with marked improvements in all other measures. CONCLUSIONS: OSA does not appear to induce insulin resistance in nonobese pediatric patients but seems to play a significant role in obese patients. The significant improvements in lipid profiles, C-reactive protein, and apolipoprotein B after adenotonsillectomy in the two groups suggest a pathogenic role for OSA in lipid homeostasis and systemic inflammation independent of the degree of adiposity.