Quality of life and socioeconomic and educational status in patients with congenital hypothyroidism.

BACKGROUND: The aim of this study was to investigate the influence of primary congenital hypothyroidism (CH) on quality of life, level of education and socioeconomic status (SES). METHODS: Two independent study cohorts, a national and a regional, were collected from Finnish national registers and patient records. Data on social security benefits, SES, marital status, and education were collected from Statistics Finland. Health-related quality of life (HRQoL) was studied in the regional patient cohort with the standardized 15D and 16D instruments. RESULTS: There were no statistically significant differences in education level, marital status, or SES between CH patients (n = 40) and their matched controls at the age of 25 years. The mean 15D score was both statistically significantly and clinically importantly lower in CH patients (n = 29) than controls (0.904 vs. 0.953, p = 0.008). CH patients reported significantly lower scores across various dimensions of physical and mental HRQoL, including breathing, sleeping, speech, excretion, mental function, distress, and vitality. The mean 16D score was lower in CH patients compared to controls (0.917, vs. 0.947), but without statistical significance. CONCLUSION: SES of CH patients did not differ from matched controls. Thus, most CH patients integrate well into society, but their HRQoL is impaired. IMPACT: Most patients with primary congenital hypothyroidism integrate well into society. In the current study, their socioeconomic and marital status did not differ from matched controls at the age of 25 years. However, health-related quality of life measured using 15D instrument was impaired. Every fourth patient reported that congenital hypothyroidism influenced everyday life.

Incidence of primary congenital hypothyroidism over 24 years in Finland.

BACKGROUND: A rise in the incidence of congenital hypothyroidism (CH) has been reported worldwide. This nationwide study aimed to describe the secular trends and current incidence of CH in Finland. METHODS: Two independent study cohorts, a national and a regional, were collected from national registers and patient records. The national cohort represents all CH cases born in Finland between 1994 and 2017. Birth data, results of the screening test, and the incidence of CH were reviewed. RESULTS: Between 1994 and 2017, 1,400,028 children were born in Finland. Of these children, 503 were diagnosed with primary CH (incidence 1:2783). Male-to-female sex ratio was 1:2.0. The nationwide incidence was 33 cases per 100,000 live births between 1994 and 1999, 38 cases per 100,000 live births between 2000 and 2005, 40 cases per 100,000 live births between 2006 and 2011, and 33 cases per 100,000 live births between 2012 and 2017. In the regional cohort (n = 139), the incidence of transient CH was 3.6%. The incidence of mild, moderate, and severe CH remained constant. CONCLUSIONS: In Finland, the incidence of CH has not changed during the 24-year study period. IMPACT: As opposed to recent reports worldwide, the incidence of congenital hypothyroidism has not changed between 1994 and 2017 in Finland. The proportions of mild, moderate, and severe congenital hypothyroidism did not change significantly over the study period. Lowering the TSH cut-off limit or increasing immigration did not affect the incidence rate of primary congenital hypothyroidism in Finland.

The effects of a 2-year physical activity and dietary intervention on plasma lipid concentrations in children: the PANIC Study.

PURPOSE: We studied the effects of a physical activity and dietary intervention on plasma lipids in a general population of children. We also investigated how lifestyle changes contributed to the intervention effects. METHODS: We carried out a 2-year controlled, non-randomized lifestyle intervention study among 504 mainly prepubertal children aged 6-9 years at baseline. We assigned 306 children to the intervention group and 198 children to the control group. We assessed plasma concentrations of total, LDL, HDL, and VLDL cholesterol, triglycerides, HDL triglycerides, and VLDL triglycerides. We evaluated the consumption of foods using 4-day food records and physical activity using a movement and heart rate sensor. We analyzed data using linear mixed-effect models adjusted for age at baseline, sex, and pubertal stage at both time points. Furthermore, specific lifestyle variables were entered in these models. RESULTS: Plasma LDL cholesterol decreased in the intervention group but did not change in the control group ( - 0.05 vs. 0.00 mmol/L, regression coefficient (ß) = - 0.0385, p = 0.040 for group*time interaction). This effect was mainly explained by the changes in the consumption of high-fat vegetable oil-based spreads (ß = - 0.0203, + 47% change in ß) and butter-based spreads (ß = - 0.0294, + 30% change in ß), moderate-to-vigorous physical activity (ß = - 0.0268, + 30% change in ß), light physical activity (ß = - 0.0274, + 29% change in ß) and sedentary time (ß = - 0.0270, + 30% change in ß). The intervention had no effect on other plasma lipids. CONCLUSION: Lifestyle intervention resulted a small decrease in plasma LDL cholesterol concentration in children. The effect was explained by changes in quality and quantity of dietary fat and physical activity. CLINICAL TRIAL REGISTRY NUMBER: NCT01803776, ClinicalTrials.gov.

A 2 year physical activity and dietary intervention attenuates the increase in insulin resistance in a general population of children: the PANIC study.

AIMS/HYPOTHESIS: We studied for the first time the long-term effects of a combined physical activity and dietary intervention on insulin resistance and fasting plasma glucose in a general population of predominantly normal-weight children. METHODS: We carried out a 2 year non-randomised controlled trial in a population sample of 504 children aged 6-9 years at baseline. The children were allocated to a combined physical activity and dietary intervention group (306 children at baseline, 261 children at 2-year follow-up) or a control group (198 children, 177 children) without blinding. We measured fasting insulin and fasting glucose, calculated HOMA-IR, assessed physical activity and sedentary time by combined heart rate and body movement monitoring, assessed dietary factors by a 4 day food record, used the Finnish Children Healthy Eating Index (FCHEI) as a measure of overall diet quality, and measured body fat percentage (BF%) and lean body mass by dual-energy x-ray absorptiometry. The intervention effects on insulin, glucose and HOMA-IR were analysed using the intention-to-treat principle and linear mixed-effects models after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The measures of physical activity, sedentary time, diet and body composition at baseline and 2 year follow-up were entered one-by-one as covariates into the models to study whether changes in these variables might partly explain the observed intervention effects. RESULTS: Compared with the control group, fasting insulin increased 4.65 pmol/l less (absolute change +8.96 vs +13.61 pmol/l) and HOMA-IR increased 0.18 units less (+0.31 vs +0.49 units) over 2 years in the combined physical activity and dietary intervention group. The intervention effects on fasting insulin (regression coefficient ß for intervention effect -0.33 [95% CI -0.62, -0.04], p = 0.026) and HOMA-IR (ß for intervention effect -0.084 [95% CI -0.156, -0.012], p = 0.023) were statistically significant after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The intervention had no effect on fasting glucose, BF% or lean body mass. Changes in total physical activity energy expenditure, light physical activity, moderate-to-vigorous physical activity, total sedentary time, the reported consumption of high-fat (≥60%) vegetable oil-based spreads, and FCHEI, but not a change in BF% or lean body mass, partly explained the intervention effects on fasting insulin and HOMA-IR. CONCLUSIONS/INTERPRETATION: The combined physical activity and dietary intervention attenuated the increase in insulin resistance over 2 years in a general population of predominantly normal-weight children. This beneficial effect was partly mediated by changes in physical activity, sedentary time and diet but not changes in body composition. TRIAL REGISTRATION: ClinicalTrials.gov NCT01803776 Graphical abstract.

Child-related and parental predictors for thelarche in a general population of girls: the PANIC study.

BACKGROUND: Obesity has been associated with earlier thelarche, whereas other predictors for it remain unclear. METHODS: We studied child-related and parental predictors for earlier thelarche in 195 girls aged 6-8 years followed up for 2 years. A physician evaluated breast development by inspection and palpation. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry, diet by food records, and physical activity and sedentary time by body movement and heart rate monitors. Parental education, smoking, and alcohol consumption and household income were assessed by questionnaires. Gestational age, birth weight, and maternal prepregnancy BMI were obtained from hospital registers. Predictors for thelarche were examined using logistic regression analysis adjusted for age and follow-up time. RESULTS: The incidence of thelarche during 2 years increased by 11% (OR 1.11, CI 1.06-1.17, p < 0.001) for 1 unit increase in baseline BF%. Girls with a smoking parent had a 2.64 (95% CI 1.21-5.77, p = 0.015) times higher incidence of thelarche than other girls. The associations of lower parental education and higher maternal prepregnancy BMI with the higher incidence of thelarche were largely explained by BF%. Other possible predictors were not associated with thelarche. CONCLUSIONS: Higher BF% and exposure to tobacco smoke are independent predictors for earlier thelarche.

The effect of hypoglycaemia on neurocognitive outcome in children and adolescents with transient or persistent congenital hyperinsulinism.

AIM: To examine the hypoglycaemic effect on neurodevelopmental outcome in patients with transient and persistent congenital hyperinsulinism (CHI) born in the 21st century. METHOD: A cohort of 117 patients (66 males, 51 females) with CHI aged 5 to 16 years (mean age 8y 11mo, SD 2y 7mo) were selected from a Finnish nationwide registry to examine all the patients with similar methods. Neurodevelopment was first evaluated retrospectively. The 83 patients with no risk factors for neurological impairment other than hypoglycaemia were recruited and 44 participated (24 males, 20 females; mean age 9y 7mo, SD 3y 1mo) in neuropsychological assessment with the Wechsler Intelligence Scale for Children, Fourth Edition and the Finnish version of the Developmental Neuropsychological Assessment, Second Edition domains of attention, language, memory, sensorimotor, and visual functioning. RESULTS: In retrospective analysis, transient and persistent CHI groups had similar prevalences of mild (22% and 18% respectively) or severe (5% and 7% respectively) neurodevelopmental difficulties. In clinical assessment, the neurocognitive profile was within the average range in both groups, but children with persistent CHI showed significant but restricted deficits in attention, memory, visual, and sensorimotor functions compared with the general population. The transient CHI group did not differ from the standardization samples. INTERPRETATION: Besides the more apparent broader neurological deficits, children with persistent CHI have an increased risk for milder specific neurocognitive problems, which should be considered in the follow-up. WHAT THIS PAPER ADDS: Children with persistent congenital hyperinsulinism showed deficits in attention, memory, visual, and sensorimotor functions. The deficits were potentially of hypoglycaemic origin. Children with transient hyperinsulinism did not differ from the general population.

EL EFECTO DE LA HIPOGLUCEMIA SOBRE EL RESULTADO NEUROCOGNITIVO EN NIÑOS Y ADOLESCENTES CON HIPERINSULINISMO CONGÉNITO TRANSITORIO O PERSISTENTE: OBJETIVO: Examinar el efecto hipoglucémico sobre el resultado del neurodesarrollo en pacientes nacidos en el siglo XXI con hiperinsulinismo congénito (HIC) transitorio y persistente. MÉTODO: Una cohorte de 117 pacientes (66 varones, 51 mujeres) con HIC de 5 a 16 años de edad (media de 8 años 11 meses, DS 2 años 7 meses) fueron seleccionados de un registro nacional finlandés para examinar a todos los pacientes con métodos similares. El neurodesarrollo se evaluó por primera vez de forma retrospectiva. Los 83 pacientes sin factores de riesgo para el deterioro neurológico distintos de la hipoglucemia fueron reclutados y 44 de ellos participaron (24 varones, 20 mujeres; edad media 9 años 7 meses, DS 3 años 1mes) en la evaluación neuropsicológica con la Escala de Inteligencia de Wechsler y la versión finlandesa de la Evaluación Neuropsicológica del desarrollo, segunda edición, incluyendo los dominios de atención, lenguaje, memoria, sensoriomotor y funcionamiento visual. RESULTADOS: En el análisis retrospectivo, los grupos de HIC transitorios y persistentes tuvieron prevalencias similares de dificultades del neurodesarrollo leves (22% y 18% respectivamente) o graves (5% y 7% respectivamente). En la evaluación clínica, el perfil neurocognitivo estuvo dentro del rango promedio en ambos grupos, pero los niños con HIC persistente mostraron déficits significativos pero restringidos en la atención, memoria, funciones visuales y sensomotrices en comparación con la población general. El grupo de HIC transitorio no difirió de las muestras de estandarización. INTERPRETACIÓN: Además de los déficits neurológicos más aparentes generalizados, los niños con HIC persistente tienen un mayor riesgo de presentar problemas neurocognitivos específicos más leves, que deben ser considerados en el seguimiento.

O EFEITO DA HIPOGLICEMIA NO RESULTADO NEUROCOGNITIVO EM CRIANÇAS E ADOLESCENTES COM HIPERINSULINEMIA CONGÊNITA TRANSITÓRIA OU PERSISTENTE: OBJETIVO: Examinar o efeito hipoglicêmico no resultado neurodesenvolvimental em pacientes com hyperinsulinemia congênita (HIC) transitória ou persistente nascidas no século 21. MÉTODO: Uma coorte de 117 pacientes (66 do sexo masculino, 51 do sexo feminino) com HIC e idades de 5 a 16 anos (média de idade 8a 11m, DP 2a 7m) foram selecionados de um registro nacional finlandês para exame com métodos similares. Primeiramente, o neurodesenvolvimento foi avaliado retrospectivamente. Os 83 pacientes sem risco para deficiência neurológica além da hipoglicemia foram recrutados, e 44 participaram (24 do sexo masculino, 20 do sexo feminino; média de idade 9a 7m, DP 3a 1m) na avaliação neuropsicológica com a escala Wechsler de Inteligência, e a versão finlandesa da Avaliação Neuropsicológica Desenvolvimental, segunda edição, nos domínios de atenção, linguagem, memória, sensório-motor, e funcionamento visual. RESULTADOS: Na análise retrospective, os grupos com HIC transitória e persistente tiveram prevalências similares de dificuldades neurodesenvolvimentais leves (22% e 18% respectivamente) ou severa (5% e 7% respectivamente). Na avaliação clínica, o perfil neurocognitivo estava dentro da média para ambos os grupos, mas crianças com HIC persistente mostraram deficits significantes, mas restritos, nas funções de atenção, de memória, visuais e sensório-motoras comparado com a população em geral. O grupo com HIC transitória não diferiu das amostras padronizadas. INTERPRETAÇÃO: Além dos deficits neurológicos mais amplos e aparentes, crianças com HIC persistente têm risco aumentado de problemas neurocognitivos específicos leves, o que deve ser considerado no acompanhamento.

Associations of lifestyle factors with serum dehydroepiandrosterone sulphate and insulin-like growth factor-1 concentration in prepubertal children.

OBJECTIVE: Little is known about the relationships of dietary factors, physical activity and sedentary behaviour to dehydroepiandrosterone sulphate (DHEAS) and insulin-like growth factor-1 (IGF-1) concentrations among prepubertal children. Therefore, we studied the associations of these lifestyle factors with serum DHEAS and IGF-1 in children. DESIGN AND SUBJECTS: Cross-sectional analysis of a population sample of 431 prepubertal children aged 6-9 years. MEASUREMENTS: Assessment of dietary factors by food records and physical activity and sedentary behaviour by a combined heart rate and movement monitor and a questionnaire. Measurement of serum DHEAS and IGF-1. RESULTS: Consumption of low-fibre grain products (standardized regression coefficient ß = .118, P = .017) and intake of vegetable protein (ß = .100, P = .045) was positively and consumption of sugar-sweetened beverages (ß = -.117, P = .018) was inversely associated with DHEAS after adjustment for sex, age and body fat percentage. Energy intake (ß = .160, P = .001) was positively associated with IGF-1 adjusting for sex, age and body fat percentage. Vigorous physical activity was inversely associated with DHEAS after adjustment for sex and age (ß = -.120, P = .027), and total (ß = -.137, P = .007), moderate (ß = -.130, P = .012), vigorous (ß = -.136, P = .011) and moderate to vigorous physical activity (ß = -.160, P = .003) were inversely and total sedentary behaviour (ß = .151, P = .003) was positively associated with IGF-1 adjusting for sex and age. None of physical activity measures was associated with DHEAS or IGF-1 after additional adjustment for body fat percentage. CONCLUSIONS: Lifestyle factors have weak and moderate associations with biochemical markers of adrenarche in prepubertal children. These associations indicate body fat independent and dependent influences of diet and physical activity, respectively.

Birth size, body composition, and adrenal androgens as determinants of bone mineral density in mid-childhood.

BackgroundBirth weight has an impact on adult bone mass. Higher birth weight is associated with greater bone mineral content (BMC) and children born small for gestational age (SGA) are at an increased risk for impaired accrual of bone mass. Our aim was to study whether the impact of birth size or early childhood growth on bone mass is visible already in mid-childhood.MethodsWe studied 49 children born large for gestational age (LGA), 56 children born appropriate for gestational age (AGA), and 23 children born SGA at 5.0-8.7 years of age. Body composition was assessed by whole-body dual-energy X-ray absorptiometry. Fasting blood samples and anthropometric data were collected.ResultsThe children born SGA had lower bone mineral density (BMD) Z-score (P<0.001) and age- and sex-adjusted BMD (P<0.005) than the LGA and AGA children. Adjusted BMC, muscle mass, and body fat percentage (%BF) did not differ between the study groups. Muscle mass, BMI SD score (SDS), %BF, and serum dehydroepiandrosterone sulfate (DHEAS) concentration were the strongest predictors of high BMD in mid-childhood.ConclusionSGA-born children had lower BMD in mid-childhood compared with AGA- and LGA-born ones. Muscle mass or BMI SDS, %BF, and DHEAS were significant predictors of childhood BMD.

Birth weight is associated with dietary factors at the age of 6-8 years: the Physical Activity and Nutrition in Children (PANIC) study.

OBJECTIVE: Low and high birth weight have been associated with increased risk of type 2 diabetes and CVD. Diet could partly mediate this association, e.g. by intra-uterine programming of unhealthy food preferences. We examined the association of birth weight with diet in Finnish children. DESIGN: Birth weight standard deviation score (SDS) was calculated using national birth register data and Finnish references. Dietary factors were assessed using 4 d food records. Diet quality was defined by the Finnish Children Healthy Eating Index (FCHEI). SETTING: The Physical Activity and Nutrition in Children (PANIC) study. SUBJECTS: Singleton, full-term children (179 girls, 188 boys) aged 6-8 years. RESULTS: Birth weight was inversely associated (standardized regression coefficient ß; 95 % CI) with FCHEI (-0·15; -0·28, -0·03) in all children and in boys (-0·27; -0·45, -0·09) but not in girls (-0·01; -0·21, 0·18) after adjusting for potential confounders (P=0·044 for interaction). Moreover, higher birth weight was associated with lower fruit and berries consumption (-0·13; -0·25, 0·00), higher energy intake (0·17; 0·05, 0·29), higher sucrose intake (0·19; 0·06, 0·32) and lower fibre intake (-0·14; -0·26, -0·01). These associations were statistically non-significant after correction for multiple testing. Children with birth weight >1 SDS had higher sucrose intake (mean; 95 % CI) as a percentage of energy intake (14·3 E%; 12·6, 16·0 E%) than children with birth weight of -1 to 1 SDS (12·8 E%; 11·6, 14·0 E%) or <-1 SDS (12·4 E%; 10·8, 13·9 E%; P=0·036). CONCLUSIONS: Higher birth weight may be associated with unhealthy diet in childhood.

Prepubertal children born large for gestational age have lower serum DHEAS concentrations than those with a lower birth weight.

BackgroundChildren born small for gestational age (SGA) have higher serum dehydroepiandrosterone sulfate (DHEAS) concentrations than children born appropriate for gestational age (AGA). The overall metabolic risk associated with birth weight is U-shaped, but it is not known whether children born large for gestational age (LGA) have elevated serum DHEAS levels.MethodsA cohort of 49 children born LGA, 56 children born AGA, and 23 children born SGA were studied at 5-8 years of age. Anthropometric data at birth, at the age of 2 years, and at examination were recorded. Fasting blood samples were collected for serum analyses of DHEAS, insulin-like growth factor 1 (IGF-1), and insulin concentrations.ResultsThe children born LGA had lower serum DHEAS levels adjusted for body mass index (BMI) standard deviation score (SDS) and age than the rest of the children. Lower birth weight SDS and higher weight gain during the first 2 years of life predicted higher serum DHEAS levels. Higher serum IGF-1 levels were also associated with higher prevalence of adrenarchal DHEAS levels.ConclusionBeing born LGA was associated with lower DHEAS levels, whereas small birth size and early catch-up growth predicted higher levels. This suggests that genetic or early epigenetic factors have an impact on adrenarche. IGF-1 may be a mediator in this process.

Paediatric obesity treatment had better outcomes when children were younger, well motivated and did not have acanthosis nigricans.

AIM: This study evaluated the efficacy of a paediatric obesity treatment programme and explored the factors that contributed to the outcome. METHODS: We recorded the body mass index standard deviation scores (BMI SDS) of 654 children aged 2-18 years who were treated for obesity in 2005-2012 in three Finnish hospitals, one year before treatment and up to three years after treatment. The family-based multidisciplinary treatment included nutritional advice, exercise and behavioural counselling. The BMI SDS changes, and their contributors, were explored with mixed-model and logistic regression analyses. RESULTS: BMI SDS increased before baseline and decreased at six, 12 and 24 months (all p < 0.001) and 36 months (p = 0.005). Younger age (p < 0.001), higher BMI SDS at baseline (p = 0.001), motivation (p = 0.013), adherence to the protocol (p = 0.033) and lack of acanthosis nigricans (p < 0.001) improved the outcome. The BMI SDS of children aged 2-6 decreased best from baseline to 12 (-0.35), 24 (-0.58) and 36 months (-0.64) (all p < 0.001). CONCLUSION: Paediatric obesity treatment was most effective at a younger age. Good motivation and adherence contributed to favourable outcomes, while acanthosis nigricans was associated with a poor outcome.

Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly.

BACKGROUND: Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. OBJECTIVE: To characterise the genotypic and phenotypic findings in individuals with GLI2 variants and clarify clinical findings in individuals with loss-of-function mutations. METHODS: Through the National Institutes of Health and collaborating centres, ∼400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies were screened for GLI2 mutations. Results were combined with all published cases. We compared the clinical and molecular features of individuals with truncating mutations to individuals with variants of unknown significance (defined as not resulting in protein truncation, reported in normal controls and/or deemed unlikely to be pathogenic by functional prediction software). RESULTS: 112 individuals with variants in GLI2 were identified, with 43 having truncating mutations. Individuals with truncating mutations were more likely to have both pituitary anomalies and polydactyly versus those with variants of unknown significance (p<0.0001 by Fisher's exact test); only 1 of 43 had frank HPE. These individuals were more likely to have recognised penetrance (polydactyly or pituitary anomalies or both) than those without truncating mutations (p=0.0036 by Fisher's exact test). A common facial phenotype was seen in individuals (with midface hypoplasia, cleft lip/palate and hypotelorism) with truncating mutations. CONCLUSIONS: Individuals with truncating mutations in GLI2 typically present with pituitary anomalies, polydactyly and subtle facial features rather than HPE. This will be helpful in screening populations for GLI2 mutations and for counselling affected patients. TRIAL REGISTRATION: 98-HG-0249/04-HG-0093.

Serum androgen bioactivity is low in children with premature adrenarche.

BACKGROUND: Clinical findings in children with premature adrenarche (PA) correlate only partly with circulating levels of adrenal androgens. It is not known whether the prepubertal low circulating concentrations of testosterone (T) and dihydrotestosterone, together with those of adrenal androgens, are capable of activating the androgen receptor. METHODS: This cross-sectional study was performed at a university hospital. Circulating androgen bioactivity was measured in 67 prepubertal children with clinical signs of PA and 94 control children using a novel androgen bioassay. RESULTS: Circulating androgen bioactivity was low in the PA and control children. In the subgroup of children (n = 28) with serum T concentration over the assay sensitivity (0.35 nmol/l) and a signal in the androgen bioassay, we found a positive correlation between androgen bioactivity and serum T (r = 0.50; P < 0.01) and the free androgen index (r = 0.61; P < 0.01) and a negative correlation with serum sex hormone-binding globulin concentration (r = -0.41; P < 0.05). CONCLUSION: Peripheral metabolism of adrenal androgen precursors may be required for any androgenic effects in PA. However, the limitations in the sensitivity of the bioassay developed herein may hide some differences between the PA and control children.

Health-related quality of life of young adult women with a history of premature adrenarche.

INTRODUCTION: Children with premature adrenarche (PA) have increased adrenal androgen concentrations and earlier pubertal development than their peers. Early sexual maturation and exposure to androgens have both been associated with an increased risk for neuropsychological adversities in adulthood. Such adversities would presumably influence the experienced health-related quality of life (HRQoL) of those affected. METHODS: A longitudinal case-control cohort study, in which 30 PA girls and 40 age-matched controls were followed from childhood to young adult age. The main outcome measure was the total 15D HRQoL score. In addition, we assessed specific dimensions of the questionnaire, the subjects' relationship statuses and living arrangements. RESULTS: There were no differences between the groups in the overall 15D scores (PA, 0.956 (0.052); control, 0.947 (0.055); p 0.482), or on any dimension of this instrument. CONCLUSION: The study suggests that a history of PA does not lead to impaired HRQoL in adult age.

Multiple androgen pathways contribute to the steroid signature of adrenarche.

CONTEXT: Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been well described in adrenarche, but the role of newer active androgens and additional androgen pathways is less clear. OBJECTIVE: To study the contribution of novel androgens and related steroid biosynthesis pathways to the development of adrenarche, and to identify additional steroid biomarkers of adrenarche. DESIGN: A longitudinal study of children aged 6-8 years at baseline, followed up at ages 8-10 and 14-16 years. A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche (cases) and 24 children (11 girls) without these signs (controls) at age 8-10 years were included. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry. MAIN OUTCOME MEASURES: Thirty-two steroids compartmentalized in progestagens, gluco- and mineralocorticoid pathways, and four androgen related pathways, including the classic, backdoor, 11-oxy, and 11-oxy backdoor pathways. RESULTS: The classic and 11-oxy androgen pathways were more active, and serum concentrations of main androgens in the classic (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione and androsterone) and 11-oxy (11ß-hydroxyandrostenedione, 11ß-hydroxytestosterone, 11-ketoandrostenedione, and 11-ketotestosterone) pathways were higher in cases at ages 6-8 and 8-10 years. Pregnenolone concentrations at adrenarchal age (8-10 years) and cortisol concentrations at adolescence (14-16 years) were higher in cases. 11ß-hydroxyandrosterone and 11-ketoandrosterone tended to be higher in cases with clinical signs compared to cases who had only biochemical evidence of adrenarche, albeit they were detected at low levels. In biomarker analyses, calculated steroid ratios with cortisol, cortisone, or 11-deoxycortisone as dividers were better classifiers for adrenarche than single steroids. Among these ratios, androstenedione/cortisone was the best. CONCLUSIONS: The classic and 11-oxy androgen pathways are active in adrenarche. Children with earlier timing of adrenarche have higher serum cortisol levels at late pubertal age, suggesting that early adrenarche might have long-term effects on adrenal steroidogenesis by increasing the activity of the glucocorticoid pathway. Future studies should employ comprehensive steroid profiling to define novel classifiers and biomarkers for adrenarche and premature adrenarche.

Accelerated Early Childhood Growth Is Associated With the Development of Earlier Adrenarche and Puberty.

Context: Small birth size and increased postnatal growth have been associated with earlier timing of adrenarche and puberty, but it is not well known whether these factors alone or together lead to earlier maturation. Objective: This work aimed to search for different growth trajectories using a clustering approach to analyze the effects of birth size and postnatal growth on adrenarchal and pubertal development. Methods: Altogether 351 children (48% girls) were examined prospectively at ages 6 to 9 and 9 to 11 years. Birth and early-growth data were collected retrospectively. Main outcome measures included clinical signs of adrenarche and puberty, and serum androgen concentrations (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, testosterone). Results: We detected 4 clusters with different birth sizes and postnatal growth trajectories: 1) children with average birth size and increased postnatal growth (AI), 2) children with small birth size and increased postnatal growth (SI), 3) children with average birth size and postnatal growth (AA), and 4) children with small birth size and average postnatal growth (SA). Thelarche at age 9 to 11 was most common and serum androgens at ages 6 to 9 and 9 to 11 years were highest in girls belonging to the AI and SI groups. Similar patterns in the onset of puberty and in androgen levels were not seen in the SA group. Conclusion: Increased early growth and weight gain predict higher serum androgen concentrations and earlier onset of puberty in girls. Adrenarche and puberty do not appear to be shifted earlier in children with small birth size who do not have catch-up growth.

Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.

The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.

Metabolic risk factors are associated with stiffness index, reflection index and finger skin temperature in children--Physical Activity and Nutrition in Children (PANIC) study.

BACKGROUND: Childhood metabolic syndrome (MetS) has been found to predict adulthood MetS, type 2 diabetes and cardiovascular disease, emphasizing the early identification of children at increased risk of these diseases. Children with clustering of metabolic risk factors have been reported to have a mild arterial stiffness and endothelial dysfunction, but limited evidence is available from population-based samples of children. METHODS AND RESULTS: The associations of metabolic risk factors with arterial stiffness, tone and endothelial function were studied in 173 prepubertal children (90 girls) 6-8 years of age. MetS was assessed both by continuous MetScore and dichotomously. Stiffness index (SI), reflection index (RI) and finger skin temperature (FST) were measured before and after maximum exercise test, and percent change was calculated for RI (RI%Δ) and FST (FST%Δ). MetScore (r=0.26, P=0.001), fasting insulin (r=0.24, P=0.002), fasting triglycerides (r=0.20, P=0.009), systolic (SBP; r=0.24, P=0.002) and diastolic blood pressure (DBP; r=0.19, P=0.013) correlated with SI. MetScore (r=-0.17, P=0.024, r=0.21, P=0.006), waist circumference (r=-0.19, P=0.012, r=0.23, P=0.003) and SBP (r=-0.16, P=0.035, r=0.21, P=0.005) correlated with RI and FST. High-density lipoprotein cholesterol correlated with FST (r=-0.22, P=0.004) and FST%Δ (r=-0.24, P=0.002). RI decreased and FST increased with exercise (P<0.001). Waist circumference correlated inversely with RI%Δ in boys (r=-0.22, P=0.046) and directly with RI%Δ in girls (r=0.27, P=0.011). CONCLUSIONS: Metabolic risk factors are associated with arterial stiffness, tone and endothelial function in prepubertal children.

Cardiorespiratory Fitness in Young Adult Women With a History of Premature Adrenarche.

Context: Premature adrenarche (PA) may predispose to some adverse long-term health outcomes. Cardiorespiratory fitness (CRF) is one of the strongest factors known to predict overall health, but no data exist on the CRF of women with a history of PA. Objective: To study if hyperandrogenism in childhood resulting from PA leads to a measurable difference in CRF between young adult PA and control women. Methods: A total of 25 women with PA and 36 age-matched controls were followed from prepubertal age until adulthood. Anthropometric measurements, body composition, biochemical, and lifestyle factors were assessed. The main outcome measure was maximal cycle ergometer test result at the mean age of 18.5 years. We also assessed prepubertal predicting factors for CRF with different linear regression models. Results: Though prepubertal children with PA were taller and heavier than their non-PA peers, there were no significant differences in height, body mass index, body composition, or physical activity in young adulthood. We observed no significant differences in any of the parameters of the maximal cycle ergometer test, including maximal load (P = .194) or peak oxygen consumption (P = .340). Hemodynamic responses of the groups were similar. None of the examined models or prepubertal factors significantly predicted CRF at adult age. Conclusion: This study suggests that hyperandrogenism in childhood/adolescence resulting from PA does not have a significant impact on adulthood CRF.

Treatment of Congenital Hypothyroidism: Impact of Secular Changes in Levothyroxine Initial Dose on Early Growth.

INTRODUCTION: Newborn screening of congenital hypothyroidism (CH) has enabled early treatment with levothyroxine (LT4), ensuring normal growth and development. The initial LT4 dose recommendation has increased over decades. We evaluated whether the increased LT4 dosing influenced thyroid-stimulating hormone (TSH) and thyroxine (fT4) concentrations, growth, or treatment-related symptoms. METHODS: LT4 doses, TSH, fT4, anthropometrics, and treatment-related symptoms until age 2 years were evaluated in 172 Finnish CH patients born between 1980 and 2018. The patients were grouped according to birth decade: 1980s (n = 19, mean LT4 starting dose 6.8 µg/kg/day), 1990s (n = 50, 7.4 µg/kg/day), 2000s (n = 59, 9.7 µg/kg/day), and 2010s (n = 44, 10.8 µg/kg/day). RESULTS: TSH concentrations were higher during the first 2 years of life in children born in the 1980s compared to children born later. TSH concentrations were often subnormal in children receiving higher LT4 doses (children born in the 2000s and 2010s). However, symptoms of overtreatment were uncommon. Linear or head growth showed no differences between the groups during the first 2 years of life. Although growth was within the normal spectrum, children in all groups were shorter than their target length at 2 years and their weight-for-length was above the mean through the first 2 years of life. DISCUSSION: Current treatment practice with higher LT4 dose normalizes TSH rapidly without significant increase in side effects. However, irrespective of initial LT4 dose, children were shorter than expected at 2 years of age. Effects of different initial LT4 dose on cognitive development urges further investigation.