Associations of radiologic characteristics of the neonatal hypothalamus with early life adiposity gain.

BACKGROUND: The mediobasal hypothalamus (MBH) is a key brain area for regulation of energy balance. Previous neuroimaging studies suggest that T2-based signal properties indicative of cellular inflammatory response (gliosis) are present in adults and children with obesity, and predicts greater adiposity gain in children at risk of obesity. OBJECTIVES/METHODS: The current study aimed to extend this concept to the early life period by considering if, in full-term healthy neonates (up to n = 35), MRI evidence of MBH gliosis is associated with changes in early life (neonatal to six months) body fat percentage measured by DXA. RESULTS: In this initial study, neonatal T2 signal in the MBH was positively associated with six-month changes in body fat percentage. CONCLUSION: This finding supports the notion that underlying processes in the MBH may play a role in early life growth and, by extension, childhood obesity risk.

In utero exposure to maternal diabetes or hypertension and childhood hypothalamic gliosis.

Exposure to maternal diabetes (DM) or hypertension (HTN) during pregnancy impacts offspring metabolic health in childhood and beyond. Animal models suggest that induction of hypothalamic inflammation and gliosis in the offspring's hypothalamus is a possible mechanism mediating this effect. We tested, in children, whether in utero exposures to maternal DM or HTN were associated with mediobasal hypothalamic (MBH) gliosis as assessed by brain magnetic resonance imaging (MRI). The study included a subsample of 306 children aged 9-11 years enrolled in the ABCD Study®; 49 were DM-exposed, 53 were HTN-exposed, and 204 (2:1 ratio) were age- and sex-matched children unexposed to DM and/or HTN in utero. We found a significant overall effect of group for the primary outcome of MBH/amygdala (AMY) T2 signal ratio (F(2,300):3.51, p = 0.03). Compared to unexposed children, MBH/AMY T2 signal ratios were significantly higher in the DM-exposed (ß:0.05, p = 0.02), but not the HTN-exposed children (ß:0.03, p = 0.13), findings that were limited to the MBH and independent of adiposity. We concluded that children exposed to maternal DM in utero display evidence of hypothalamic gliosis, suggesting that gestational DM may have a distinct influence on offspring's brain development and, by extension, children's long-term metabolic health.

The Significance of Hypothalamic Inflammation and Gliosis for the Pathogenesis of Obesity in Humans.

Accumulated preclinical literature demonstrates that hypothalamic inflammation and gliosis are underlying causal components of diet-induced obesity in rodent models. This review summarizes and synthesizes available translational data to better understand the applicability of preclinical findings to human obesity and its comorbidities. The published literature in humans includes histopathologic analyses performed postmortem and in vivo neuroimaging studies measuring indirect markers of hypothalamic tissue microstructure. Both support the presence of hypothalamic inflammation and gliosis in children and adults with obesity. Findings predominantly point to tissue changes in the region of the arcuate nucleus of the hypothalamus, although findings of altered tissue characteristics in whole hypothalamus or other hypothalamic regions also emerged. Moreover, the severity of hypothalamic inflammation and gliosis has been related to comorbid conditions, including glucose intolerance, insulin resistance, type 2 diabetes, and low testosterone levels in men, independent of elevated body adiposity. Cross-sectional findings are augmented by a small number of prospective studies suggesting that a greater degree of hypothalamic inflammation and gliosis may predict adiposity gain and worsening insulin sensitivity in susceptible individuals. In conclusion, existing human studies corroborate a large preclinical literature demonstrating that hypothalamic neuroinflammatory responses play a role in obesity pathogenesis. Extensive or permanent hypothalamic tissue remodeling may negatively affect the function of neuroendocrine regulatory circuits and promote the development and maintenance of elevated body weight in obesity and/or comorbid endocrine disorders.

Greater radiologic evidence of hypothalamic gliosis predicts adiposity gain in children at risk for obesity.

OBJECTIVE: This study investigated, in a large pediatric population, whether magnetic resonance imaging (MRI) evidence of mediobasal hypothalamic (MBH) gliosis is associated with baseline or change over 1 year in body adiposity. METHODS: Cross-sectional and prospective cohort analyses were conducted within the Adolescent Brain Cognitive Development Study. Study 1 included 169 children with usable baseline T2-weighted MRI images and anthropometrics from baseline and 1-year follow-up study visits. Signal ratios compared T2 signal intensity in MBH and two reference regions (amygdala [AMY] and putamen) as a measure of MBH gliosis. Study 2 included a distinct group of 238 children with overweight or obesity to confirm initial findings in an independent sample. RESULTS: In Study 1, MBH/AMY signal ratio was positively associated with BMI z score (ß = 4.27, p < 0.001). A significant interaction for the association of MBH/AMY signal ratio with change in BMI z score suggested that relationships differed by baseline weight status. Study 2 found that higher MBH/AMY signal ratios associated with an increase in BMI z score for children with overweight (ß = 0.58, p = 0.01), but not those with obesity (ß = 0.02, p = 0.91). CONCLUSIONS: Greater evidence of hypothalamic gliosis by MRI is associated with baseline BMI z score and predicts adiposity gain in young children at risk of obesity.

Reassessing relationships between appetite and adiposity in people at risk of obesity: A twin study using fMRI.

BACKGROUND: Neuroimaging studies suggest that appetitive drive is enhanced in obesity. OBJECTIVE: To test if appetitive drive varies in direct proportion to the level of body adiposity after accounting for genetic factors that contribute to both brain response and obesity risk. SUBJECTS/METHODS: Participants were adult monozygotic (n = 54) and dizygotic (n = 30) twins with at least one member of the pair with obesity. Body composition was assessed by dual-energy X-ray absorptiometry. Hormonal and appetite measures were obtained in response to a standardized meal that provided 20% of estimated daily caloric needs and to an ad libitum buffet meal. Pre- and post-meal functional magnetic resonance imaging (fMRI) assessed brain response to visual food cues in a set of a priori appetite-regulating regions. Exploratory voxelwise analyses outside a priori regions were performed with correction for multiple comparisons. RESULTS: In a group of 84 adults, the majority with obesity (75%), body fat mass was not associated with hormonal responses to a meal (glucose, insulin, glucagon-like peptide-1 and ghrelin, all P>0.40), subjective feelings of hunger (ß=-0.01 mm [95% CI -0.35, 0.34] P = 0.97) and fullness (ß=0.15 mm [-0.15, 0.44] P = 0.33), or buffet meal intake in relation to estimated daily caloric needs (ß=0.28% [-0.05, 0.60] P = 0.10). Body fat mass was also not associated with brain response to high-calorie food cues in appetite-regulating regions (Pre-meal ß=-0.12 [-0.32, 0.09] P = 0.26; Post-meal ß=0.18 [-0.02, 0.37] P = 0.09; Change by a meal ß=0.29 [-0.02, 0.61] P = 0.07). Conversely, lower fat mass was associated with being weight reduced (ß=-0.05% [-0.07, -0.03] P<0.001) and greater pre-meal activation to high-calorie food cues in the dorsolateral prefrontal cortex (Z = 3.63 P = 0.017). CONCLUSIONS: In a large study of adult twins, the majority with overweight or obesity, the level of adiposity was not associated with excess appetitive drive as assessed by behavioral, hormonal, or fMRI measures.

Pilot multi-site and reproducibility study of hypothalamic gliosis in children.

OBJECTIVE: Quantitative magnetic resonance imaging (MRI) evidence of mediobasal hypothalamic (MBH) gliosis positively correlates with body mass index (BMI) in adults. This has neither been well explored in children nor have other brain regions involved in appetitive processing been tested for evidence of gliosis. METHODS: Multi-site cross-sectional study in children to test for differences in quantitative T2 signal (measure of gliosis) by region and to assess relationships with age and BMI. Participants underwent brain MRI using the same equipment and protocol to quantify T2 relaxation time in six bilateral regions of interest (ROIs): putamen, caudate, ventral striatum, amygdala, hippocampus and MBH, and three control regions: white matter, motor cortex and dorsal hypothalamus. RESULTS: Thirty-one participants (61% female) were included in a combined sample from the University of Washington (N = 9) and John Hopkins University (N = 22). Mean age was 14 ± 3 years, and BMI z-score was 0.7 ± 1.1 (26% with obesity). No study site-related differences were seen in T2 relaxation time across all nine regions (chi2 (8): 9.46, P = .30). Regional differences in T2 relaxation time were present (P < .001). MBH presented longer T2 relaxation time, suggestive of gliosis, when compared to all regions (P < .001), including an intra-hypothalamic control. Physiological age-related declines in T2 relaxation times were found in grey matter ROIs, but not in the MBH (r = -0.14, P = .46). MBH was the only region with a positive correlation between T2 relaxation time and BMI z-score (r = 0.38, P = .03). CONCLUSIONS: In a multi-site study, pilot data suggest that quantitative MRI detected normal maturation-related brain variation as well as evidence that MBH gliosis is associated with increased adiposity in children.

Salience network connectivity is reduced by a meal and influenced by genetic background and hypothalamic gliosis.

BACKGROUND/OBJECTIVES: The salience network (SN) comprises brain regions that evaluate cues in the external environment in light of internal signals. We examined the SN response to meal intake and potential genetic and acquired influences on SN function. SUBJECTS/METHODS: Monozygotic (MZ; 40 pairs) and dizygotic (15 pairs) twins had body composition and plasma metabolic profile evaluated (glucose, insulin, leptin, ghrelin, and GLP-1). Twins underwent resting-state functional magnetic resonance imaging (fMRI) scans before and after a standardized meal. The strength of SN connectivity was analyzed pre- and post-meal and the percentage change elicited by a meal was calculated. A multi-echo T2 MRI scan measured T2 relaxation time, a radiologic index of gliosis, in the mediobasal hypothalamus (MBH) and control regions. Statistical approaches included intraclass correlations (ICC) to investigate genetic influences and within-pair analyses to exclude genetic confounders. RESULTS: SN connectivity was reduced by a meal ingestion (ß = -0.20; P < 0.001). Inherited influences on both pre- and post-meal connectivity were present (ICC MZ twins 26%, P < 0.05 and 47%, P < 0.001, respectively), but not percentage change in response to the meal. SN connectivity in response to a meal did not differ between participants with obesity and of normal weight (χ2(1) = 0.93; P = 0.33). However, when participants were classified as having high or low signs of MBH gliosis, the high MBH gliosis group failed to reduce the connectivity in response to a meal (z = -1.32; P = 0.19). Excluding genetic confounders, the percentage change in SN connectivity by a meal correlated to body fat percentage (r = 0.24; P < 0.01). CONCLUSIONS: SN connectivity was reduced by a meal, indicating potential participation of the SN in control of feeding. The strength of SN connectivity is inherited, but the degree to which SN connectivity is reduced by eating appears to be influenced by adiposity and the presence of hypothalamic gliosis.

Initial evidence for hypothalamic gliosis in children with obesity by quantitative T2 MRI and implications for blood oxygen-level dependent response to glucose ingestion.

OBJECTIVE: In adults, hypothalamic gliosis has been documented using quantitative T2 neuroimaging, whereas functional magnetic resonance imaging (fMRI) has shown a defective hypothalamic response to nutrients. No studies have yet evaluated these hypothalamic abnormalities in children with obesity. METHODS: Children with obesity and lean controls underwent quantitative MRI measuring T2 relaxation time, along with continuous hypothalamic fMRI acquisition to evaluate early response to glucose ingestion. RESULTS: Children with obesity (N = 11) had longer T2 relaxation times, consistent with gliosis, in the mediobasal hypothalamus (MBH) compared to controls (N = 9; P = 0.004). Moreover, there was a highly significant group*region interaction (P = 0.002), demonstrating that signs of gliosis were specific to MBH and not to reference regions. Longer T2 relaxation times correlated with measures of higher adiposity, including visceral fat percentage (P = 0.01). Mean glucose-induced hypothalamic blood oxygen-level dependent signal change did not differ between groups (P = 0.11). However, mean left MBH T2 relaxation time negatively correlated with glucose-induced hypothalamic signal change (P < 0.05). CONCLUSION: Imaging signs of hypothalamic gliosis were present in children with obesity and positively associated with more severe adiposity. Children with the strongest evidence for gliosis showed the least activation after glucose ingestion. These initial findings suggest that the hypothalamus is both structurally and functionally affected in childhood obesity.

Neonatal screening: 9% of children with filter paper thyroid-stimulating hormone levels between 5 and 10 µIU/mL have congenital hypothyroidism / Triagem neonatal: 9% das crianças com TSH em papel filtro entre 5 e 10 µUI/mL têm hipotireoidismo congênito

Abstract Objectives: To determine the prevalence of congenital hypothyroidism in children with filter-paper blood-spot TSH (b-TSH) between 5 and 10 µIU/mL in the neonatal screening. Methods: This was a retrospective study including children screened from 2003 to 2010, with b-TSH levels between 5 and 10 µIU/mL, who were followed-up during the first two years of life when there was no serum TSH normalization. The diagnosis of congenital hypothyroidism was defined as serum TSH ≥10 µIU/mL and start of levothyroxine treatment up to 2 years of age. Results: Of the 380,741 live births, 3713 (1.04%) had filter paper TSH levels between 5 and 10 µIU/mL and, of these, 339 (9.13%) had congenital hypothyroidism. Of these, 76.11% of the cases were diagnosed in the first three months of life and 7.96% between 1 and 2 years of age. Conclusion: The study showed that 9.13% of the children with b-TSH levels between 5 and 10 µIU/mL developed hypothyroidism and that in approximately one-quarter of them, the diagnosis was confirmed only after the third month of life. Based on these findings, the authors suggest the use of a 5 µIU/mL cutoff for b-TSH levels and long-term follow-up of infants whose serum TSH has not normalized to rule out congenital hypothyroidism.

Resumo Objetivos: Determinar a prevalência de hipotireoidismo congênito em crianças com TSH em papel filtro (TSH-f) entre 5 e 10 µUI/mL na triagem neonatal. Métodos: Estudo retrospectivo que incluiu crianças triadas de 2003 a 2010, com TSH-f entre 5 e 10 µUI/mL, acompanhadas nos dois primeiros anos de vida quando não houve normalização do TSH sérico. O diagnóstico de hipotireoidismo congênito foi definido como TSH sérico igual ou superior a 10 µUI/mL e início de tratamento com levotiroxina até os dois anos. Resultados: Dos 380.741 nascidos vivos triados, 3.713 (1,04%) apresentaram TSH-f entre 5 e 10 µUI/mL e, desses, 339 (9,13%) tinham hipotireoidismo congênito. Desses, 76,11% dos casos foram diagnosticados nos primeiros três meses de vida e 7,96% entre um e dois anos. Conclusão: O estudo mostra que 9,13% das crianças com TSH-f entre 5 e 10 µUI/mL desenvolveram hipotireoidismo e que em cerca de um quarto delas o diagnóstico só se confirmou após o terceiro mês de vida. Com base nesses achados, sugere-se, para descartar o hipotireoidismo congênito, o uso do ponto de corte de TSH-f de 5 µUI/mL e o acompanhamento em longo prazo dos lactentes cujo TSH sérico não tenha se normalizado.

Neonatal screening: 9% of children with filter paper thyroid-stimulating hormone levels between 5 and 10µIU/mL have congenital hypothyroidism.

OBJECTIVES: To determine the prevalence of congenital hypothyroidism in children with filter-paper blood-spot TSH (b-TSH) between 5 and 10µIU/mL in the neonatal screening. METHODS: This was a retrospective study including children screened from 2003 to 2010, with b-TSH levels between 5 and 10µIU/mL, who were followed-up during the first two years of life when there was no serum TSH normalization. The diagnosis of congenital hypothyroidism was defined as serum TSH ≥10µIU/mL and start of levothyroxine treatment up to 2 years of age. RESULTS: Of the 380,741 live births, 3713 (1.04%) had filter paper TSH levels between 5 and 10µIU/mL and, of these, 339 (9.13%) had congenital hypothyroidism. Of these, 76.11% of the cases were diagnosed in the first three months of life and 7.96% between 1 and 2 years of age. CONCLUSION: The study showed that 9.13% of the children with b-TSH levels between 5 and 10µIU/mL developed hypothyroidism and that in approximately one-quarter of them, the diagnosis was confirmed only after the third month of life. Based on these findings, the authors suggest the use of a 5µIU/mL cutoff for b-TSH levels and long-term follow-up of infants whose serum TSH has not normalized to rule out congenital hypothyroidism.

Prader-Willi syndrome: a case report with atypical developmental features.

OBJECTIVE: To describe the case of a male Prader-Willi syndrome (PWS) patient with atypical development features. DESCRIPTION: We report the case of a male adolescent with confirmed diagnosis of PWS which presents atypical phenotype. The patient progressed with spontaneous and complete pubertal development, stature in the normal range, and weight control without any pharmacological treatment, except metformin. COMMENTS: PWS is an imprinting paternally inherited disorder of 15q11-13 characterized by hypotonia in infant age, hyperphagia, varied degrees of mental retardation, behavior problems, hypogonadism, short stature, and other less common findings.

Performance of phalangeal quantitative ultrasound parameters in the evaluation of reduced bone mineral density assessed by DX in patients with 21 hydroxylase deficiency.

The purpose of this study was to verify the performance of quantitative ultrasound (QUS) parameters of proximal phalanges in the evaluation of reduced bone mineral density (BMD) in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21 OHD). Seventy patients with 21 OHD (41 females and 29 males), aged between 6-27 y were assessed. The QUS measurements, amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and ultrasound bone profile index (UBPI) were obtained using the BMD Sonic device (IGEA, Carpi, Italy) on the last four proximal phalanges in the non-dominant hand. BMD was determined by dual energy X-ray (DXA) across the total body and lumbar spine (LS). Total body and LS BMD were positively correlated to UBPI, BTT and AD-SoS (correlation coefficients ranged from 0.59-0.72, p < 0.001). In contrast, when comparing patients with normal and low (Z-score < -2) BMD, no differences were found in the QUS parameters. Furthermore, UBPI, BTT and AD-SoS measurements were not effective for diagnosing patients with reduced BMD by receiver operator characteristic curve parameters. Although the AD-SoS, BTT and UBPI showed significant correlations with the data obtained by DXA, they were not effective for diagnosing reduced bone mass in patients with 21 OHD.

Klinefelter syndrome: an unusual diagnosis in pediatric patients.

OBJECTIVE: To identify clinical and laboratory data which differentiate Klinefelter syndrome (KS) patients according to age group. METHODS: The study included all cases of hypogonadism, gynecomastia and/or infertility whose karyotype was performed at a university hospital from January 1989 to December 2011, in a total of 105 subjects. The following data were retrospectively analyzed: age at first visit, ratio of arm span to height, pubic hair, gynecomastia, testicular volume, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (T), and spermiogram. RESULTS: During the study period, 33 patients were diagnosed with Klinefelter syndrome (KS+) and 72 were not (KS-). Out of all KS cases, only seven (21.2%) were diagnosed before 20 years old and two (6.1%) before 10 years old. Age at first consultation (in years) was similar in both groups (KS+ = 31.3±12.9 and KS- = 27.6±12.1), as were ratio of arm span to height and frequency of gynecomastia. However, in KS+ patients, pubic hair was less developed, testicular volume was smaller and testosterone levels were lower, while LH and FSH levels and frequency of azoospermia were higher. CONCLUSIONS: Klinefelter syndrome is both an under and late diagnosed condition. The most important data for diagnosis are testicular volume, hormone levels and presence of azoospermia in spermiogram, especially in puberty and adult life.

Síndrome de Klinefelter: diagnóstico raro na faixa etária pediátrica / Klinefelter syndrome: an unusual diagnosis in pediatric patients

OBJETIVO: Identificar dados clínicos e laboratoriais que diferenciam os casos com síndrome de Klinefelter de acordo com a faixa etária. CASUÍSTICA E MÉTODOS: Foram incluídos todos os casos de hipogonadismo, ginecomastia e/ou infertilidade avaliados em hospital universitário cujo cariótipo foi realizado entre janeiro de 1989 e dezembro de 2011, totalizando 105 pacientes. Foram avaliados: idade na primeira consulta, relação entre envergadura e altura, pilificação pubiana, ginecomastia, tamanho testicular, hormônio luteinizante (LH), hormônio folículo-estimulante (FSH), testosterona e espermograma. RESULTADOS: Foram diagnosticados três casos com síndrome de Klinefelter (SK+) e 72 sem a síndrome (SK-). Dos casos com síndrome de Klinefelter, apenas sete (21,2%) foram diagnosticados antes dos 20 anos e dois (6,1%) antes dos 10 anos de idade. A idade na primeira consulta (em anos) foi semelhante nos dois grupos (SK+ = 31,3±12,9 e SK- = 27,6±12,1), o mesmo ocorrendo com a relação entre envergadura e altura e a presença de ginecomastia. No entanto, a pilificação pubiana foi menor no grupo SK+, o mesmo ocorrendo com a média do volume bitesticular e a testosterona, enquanto que o LH e o FSH foram mais elevados neste grupo, o mesmo ocorrendo com a frequência de azoospermia. CONCLUSÕES: A síndrome de Klinefelter ainda é pouco e tardiamente diagnosticada em nosso meio, sendo os dados de tamanho testicular, LH, FSH, testosterona e presença de azoospermia no espermograma os mais importantes para o seu diagnóstico, principalmente na puberdade e na vida adulta.

OBJECTIVE: To identify clinical and laboratory data which differentiate Klinefelter syndrome (KS) patients according to age group. METHODS: The study included all cases of hypogonadism, gynecomastia and/or infertility whose karyotype was performed at a university hospital from January 1989 to December 2011, in a total of 105 subjects. The following data were retrospectively analyzed: age at first visit, ratio of arm span to height, pubic hair, gynecomastia, testicular volume, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (T), and spermiogram. RESULTS: During the study period, 33 patients were diagnosed with Klinefelter syndrome (KS+) and 72 were not (KS-). Out of all KS cases, only seven (21.2%) were diagnosed before 20 years old and two (6.1%) before 10 years old. Age at first consultation (in years) was similar in both groups (KS+ = 31.3±12.9 and KS- = 27.6±12.1), as were ratio of arm span to height and frequency of gynecomastia. However, in KS+ patients, pubic hair was less developed, testicular volume was smaller and testosterone levels were lower, while LH and FSH levels and frequency of azoospermia were higher. CONCLUSIONS: Klinefelter syndrome is both an under and late diagnosed condition. The most important data for diagnosis are testicular volume, hormone levels and presence of azoospermia in spermiogram, especially in puberty and adult life.