Search

Objective The safety and impact of the advanced hybrid closed-loop (AHCL) system on glycemic outcome in 2-6-year-old children with type 1 diabetes and the diabetes distress of caregivers were evaluated. Research Design and Methods This was an open-label prospective study (n=35) with historical controls matched by treatment unit, diabetes duration, age, gender, and baseline treatment modality. The inclusion criteria were 1) type 1 diabetes diagnosis6 months, 2) total daily dose of insulin ≥ 8 units/day, 3) HbA1c10% (85 mmol/mol), and 4) capability to use insulin pump and continuous glucose monitoring (CGM). The MiniMed 780G™ AHCL in SmartGuard™ Mode was used for 12 weeks. Parental diabetes distress was evaluated with a validated PAID-PR (Problem Areas In Diabetes - Parent, revised) survey. Results No events of diabetic ketoacidosis (DKA) or severe hypoglycemia occurred. Between 0 and 12 weeks, Hba1c (mean change= -2.7 mmol/mol [SD 5.7], p=0.010), mean sensor glucose value (SG) (-0.8 mmol/l [1.0], p0.001), and time above range (TAR) (-8.6% [9.5], p0.001) decreased and time in range (TIR) (8.3% [9.3], p0.001) increased significantly, whereas no significant change in time below range (TBR) was observed. At the same time, PAID-PR score decreased from 37.5 (18.2) to 27.5 (14.8) (p=0.006). Conclusions MiniMed 780G™ AHCL is a safe system and 12-week use was associated with improvements in glycaemic control in 2-6-year-old children with type 1 diabetes. Additionally, AHCL is associated with a reduction in parental diabetes distress after 12-week use.

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.

Background Paternally inherited loss-of-function mutations in MKRN3 underlie central precocious puberty (CPP). We describe clinical and genetic features of CPP patients with paternally inherited MKRN3 mutations in two independent families. Methods The single coding exon of MKRN3 was analyzed in three patients with CPP and their family members, followed by segregation analyses. Additionally, we report the patients' responses to GnRH analog treatment. Results A paternally inherited novel heterozygous c.939C>G, p.(Ile313Met) missense mutation affecting the RING finger domain of MKRN3 was found in a Finnish girl with CPP (age at presentation 6 years). Two Polish siblings (a girl presenting with B2 at the age of 4 years and a boy with adult size testes at the age of 9 years) had inherited a novel heterozygous MKRN3 mutation c.1237_1252delGGAGACACATGCTTTT p.(Gly413Thrfs*63) from their father. The girls were treated with GnRH analogs, which exhibited suppression of the hypothalamic-pituitary-gonadal axis. In contrast, the male patient was not treated, yet he reached his target height. Conclusions We describe two novel MKRN3 mutations in three CPP patients. The first long-term data on a boy with CPP due to an MKRN3 mutation questions the role of GnRH analog treatment in augmenting adult height in males with this condition. Impact We describe the genetic cause for central precocious puberty (CPP) in two families. This report adds two novel mutations to the existing literature. One of the mutations, p.(Ile313Met) affects the RING finger domain of MKRN3, which has been shown to be important for repressing the promoter activity of and . MKRN3KISS1TAC3We describe the first long-term observation of a male patient with CPP due to a paternally inherited MKRN3 loss-of-function mutation. Without GnRH analog treatment, he achieved an adult height that was in accordance with his mid-parental target height.

Objective It has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term. Design The ESTER Preterm Birth Study participants were born in Northern Finland and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm ( Methods We measured serum total testosterone and sex hormone-binding globulin (SHBG) and calculated the free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire) or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/L). Results Women born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (−2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject’s birth weight s.d. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70). Conclusions Women born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.

A multicenter randomized controlled pilot trial investigated whether motivational interviewing (MI) by diabetes physicians improves glycemic control and variability in the context of follow-up for adolescent patients with poorly controlled type 1 diabetes. Patients (n = 47) aged 12 to 15.9 years who showed poor glycemic control (HbA1c >75 mmol/mol/9.0%) were randomized to standard education (SE) only or MI+SE, with study physicians randomized to employ MI+SE (N = 24 patients) or SE only (N = 23). For one year of follow-up, the main outcome measurements were obtained at three-month visits (HbA1c) or six-monthly: time in range (TIR) and glycemic variability (CV). Mean adjusted 12-month change in HbA1c was similar between the MI+SE and SE-only group (-3.6 vs. -1.0 mmol/mol), and no inter-group differences were visible in the mean adjusted 12-month change in TIR (-0.8 vs. 2.6%; P = 0.53) or CV (-0.5 vs. -6.2; P = 0.26). However, the order of entering the study correlated significantly with the 12-month change in HbA1c in the MI+SE group (r = -0.5; P = 0.006) and not in the SE-only group (r = 0.2; P = 0.4). No link was evident between MI and changes in quality of life. The authors conclude that MI’s short-term use by diabetes physicians managing adolescents with poorly controlled type 1 diabetes was not superior to SE alone; however, improved skills in applying the MI method at the outpatient clinic may produce greater benefits in glycemic control.

The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/β-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/β-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/β-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype., SCOPUS: ar.j, info:eu-repo/semantics/published

Paternally inherited loss-of-function mutations in MKRN3 underlie central precocious puberty (CPP). We describe clinical and genetic features of CPP patients with paternally inherited MKRN3 mutations in two independent families.The single coding exon of MKRN3 was analyzed in three patients with CPP and their family members, followed by segregation analyses. Additionally, we report the patients' responses to GnRH analog treatment.A paternally inherited novel heterozygous c.939CG, p.(Ile313Met) missense mutation affecting the RING finger domain of MKRN3 was found in a Finnish girl with CPP (age at presentation 6 years). Two Polish siblings (a girl presenting with B2 at the age of 4 years and a boy with adult size testes at the age of 9 years) had inherited a novel heterozygous MKRN3 mutation c.1237_1252delGGAGACACATGCTTTT p.(Gly413Thrfs*63) from their father. The girls were treated with GnRH analogs, which exhibited suppression of the hypothalamic-pituitary-gonadal axis. In contrast, the male patient was not treated, yet he reached his target height.We describe two novel MKRN3 mutations in three CPP patients. The first long-term data on a boy with CPP due to an MKRN3 mutation questions the role of GnRH analog treatment in augmenting adult height in males with this condition.We describe the genetic cause for central precocious puberty (CPP) in two families. This report adds two novel MKRN3 mutations to the existing literature. One of the mutations, p.(Ile313Met) affects the RING finger domain of MKRN3, which has been shown to be important for repressing the promoter activity of KISS1 and TAC3. We describe the first long-term observation of a male patient with CPP due to a paternally inherited MKRN3 loss-of-function mutation. Without GnRH analog treatment, he achieved an adult height that was in accordance with his mid-parental target height.

Objective: Previous studies have suggested that people born preterm have increased rates of eating disorders (ED). However, a recent study suggested lower levels of ED-related symptoms in the extreme group of adults born preterm with very low birth weight (

Context: Maternal gestational diabetes mellitus (GDM) and prepregnancy overweight/obesity [body mass index (BMI) ≥25 kg/m²] might adversely affect offspring cardiometabolic health. Objective: To assess the associations between maternal GDM and prepregnancy overweight/obesity with adult offspring cardiometabolic risk factors. Design: Longitudinal cohort study (ESTER Maternal Pregnancy Disorders Study and the Arvo Ylppö Longitudinal Study). Setting: Province of Uusimaa and Northern Finland. Participants: At a mean age of 24.1 ± 1.3 years, we classified offspring as offspring of mothers with GDM regardless of the prepregnancy BMI (OGDM; n = 193); normoglycemic mothers with prepregnancy overweight/obesity (ONO; n = 157); and normoglycemic mothers with prepregnancy BMI

Context Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified. Objective To assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP. Design, Patients, and Setting We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo. Results A potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 × 10−5). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1+/− and Hs6st1+/+ mice, but vaginal opening was delayed in Hs6st1+/− mice despite normal postnatal growth. Conclusions We have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene., A damaging mutation in HS6ST1 was found to cause familial self-limited delayed puberty (DP), and heterozygous Hs6st1 loss produced DP in mice. Mutations in other GnRH deficiency genes were not seen.

BACKGROUND AND OBJECTIVES: Lung function attained in young adulthood is 1 of the strongest predictors of obstructive airways disease in later life. Adults born preterm at very low birth weight (VLBW; METHODS: We performed spirometry for 160 VLBW subjects (29 with BPD according to Northway criteria) aged 18 to 27 years and 162 term control subjects group-matched for gender, age, and birth hospital. Lung function was expressed as z scores according to the Global Lung Function Initiative standards. RESULTS: Forced expiratory volume in 1 second z score was 1.41 units (95% confidence interval [CI]: 0.89 to 1.94) lower in BPD-VLBW subjects and 0.39 units (95% CI: 0.08 to 0.69) in non–BPD VLBW subjects compared with control subjects. Corresponding differences for forced expiratory volume in 1 second/forced vital capacity were 1.52 (95% CI: 0.99 to 2.05) and 0.51 (95% CI: 0.21 to 0.81), respectively. Maternal smoking in pregnancy predicted poorer airflow in all groups; this finding was strongest in the BPD-VLBW group. Lung function was unrelated to fetal or postnatal growth or to neonatal respiratory distress syndrome. CONCLUSIONS: Young adults born at VLBW have reduced airflow. The outcome is stronger in those who have a history of BPD but is present among those with no such history. This finding suggests an increased risk of later obstructive airways disease in adults born at VLBW.

Adults who were born preterm with a very low birth weight have higher blood pressure and impaired glucose regulation later in life compared with those born at term. We investigated cardiometabolic risk factors in young adults who were born at any degree of prematurity in the Preterm Birth and Early Life Programming of Adult Health and Disease (ESTER) Study, a population-based cohort study of individuals born in 1985–1989 in Northern Finland. In 2009–2011, 3 groups underwent clinical examination: 134 participants born at less than 34 gestational weeks (early preterm), 242 born at 34–36 weeks (late preterm), and 344 born at 37 weeks or later (controls). Compared with controls, adults who were born preterm had higher body fat percentages (after adjustment for sex, age, and cohort (1985–1986 or 1987–1989), for those born early preterm, difference = 6.2%, 95% confidence interval (CI): 0.4, 13.2; for those born late preterm, difference = 8.0%, 95% CI: 2.4, 13.8), waist circumferences, blood pressure (for those born early preterm, difference = 3.0 mm Hg, 95% CI: 0.9, 5.1; for those born late preterm, difference = 1.7, 95% CI: −0.1, 3.4), plasma uric acid levels (for those born early preterm, difference = 20.1%, 95% CI: 7.9, 32.3; for those born late preterm, difference = 20.2%, 95% CI: 10.7, 30.5), alanine aminotransferase levels, and aspartate transaminase levels. They were also more likely to have metabolic syndrome (for those born early preterm, odds ratio = 3.7, 95% CI: 1.6, 8.2; for those born late preterm, odds ratio = 2.5, 95% CI: 1.2, 5.3). Elevated levels of conventional and emerging risk factors suggest a higher risk of cardiometabolic disease later in life. These risk factors are also present in the large group of adults born late preterm.

Earlier puberty, especially in girls, is associated with physical and mental disorders. Prenatal glucocorticoid exposure influences the timing of puberty in animal models, but the human relevance of those findings is unknown. We studied whether voluntary consumption of licorice, which contains glycyrrhizin (a potent inhibitor of placental 11β-hydroxysteroid dehydrogenase type 2, the "barrier" to maternal glucocorticoids), by pregnant women was associated with pubertal maturation (height, weight, body mass index for age, difference between current and expected adult height, Tanner staging, score on the Pubertal Development Scale), neuroendocrine function (diurnal salivary cortisol, dexamethasone suppression), cognition (neuropsychological tests), and psychiatric problems (as measured by the Child Behavior Checklist) in their offspring. The children were born in 1998 in Helsinki, Finland, and examined during 2009-2011 (mean age = 12.5 (standard deviation (SD), 0.4) years; n = 378). Girls exposed to high maternal glycyrrhizin consumption (≥500 mg/week) were taller (mean difference (MD) = 0.4 SD, 95% confidence interval (CI): 0.1, 0.8), were heavier (MD = 0.6 SD, 95% CI: 0.2, 1.9), and had higher body mass index for age (MD = 0.6 SD, 95% CI: 0.2, 0.9). They were also 0.5 standard deviations (95% CI: 0.2, 0.8) closer to adult height and reported more advanced pubertal development (P < 0.04). Girls and boys exposed to high maternal glycyrrhizin consumption scored 7 (95% CI: 3.1, 11.2) points lower on tests of intelligence quotient, had poorer memory (P < 0.04), and had 3.3-fold (95% CI: 1.4, 7.7) higher odds of attention deficit/hyperactivity disorder problems compared with children whose mothers consumed little to no glycyrrhizin (≤249 mg/week). No differences in cortisol levels were found. Licorice consumption during pregnancy may be associated with harm for the developing offspring.

Information on the associations between objectively measured sleep and hypothalamic-pituitary-adrenal axis function in early adolescence is scarce. We examined associations between average sleep duration and quality (sleep efficiency and wake after sleep onset) over 8 days with actigraphs and (1) diurnal cortisol patterns and (2) cortisol reactivity to a low-dose (3 μg/kg) overnight dexamethasone suppression test (DST) in a birth cohort born in 1998 (N=265 participants, mean age 12.3 years, SD=0.5). We also explored (3) if sleep duration and quality were affected the nights after the DST exposure. Cortisol was measured during 2 days, and participants were exposed to dexamethasone in the evening of first day. In boys, short sleep duration was associated with higher cortisol upon awakening and lower cortisol awakening response (CAR; P0.05 and P0.01). Long sleep duration in boys associated with higher CAR (P0.02). Lower sleep quality in boys associated with lower CAR, but fell slightly short of significance (P0.06). In girls, no significant associations were detected. Sleep quantity and quality were not associated with responses to the DST. There were no effects of DST on sleep (P0.15 in between-subject analyses). The average sleep patterns showed associations with diurnal cortisol patterns during early adolescence, but only in boys. Sleep was not associated with cortisol reactivity to DST and the exogenous corticosteroid exposure did not affect sleep significantly.

BACKGROUND Shorter leucocyte telomere length (LTL) is a promising marker of biological ageing. It is predicted by cumulative adverse conditions throughout life course, but few studies have data from the prenatal period when most developmental processes and cell replication take place. We studied whether body size at birth and underlying factors including severely preterm birth predict LTL in adult life. METHODS We used data from following three cohorts: (i) 1894 subjects (age: 56-69 years) from the Helsinki Birth Cohort Study (HBCS), representing normal variation in fetal growth; (ii) the Helsinki Study of Very Low Birth Weight Adults encompassing 164 subjects born preterm at very low birthweight (

Background Immunologic pathways are primed in early life. Preterm birth can influence this process and thereby affect whether a person will have atopy later in life. Previous studies on the effects of preterm birth on atopy in adulthood have been inconclusive and limited to children or subjects born moderately preterm. Objective Our aim was to compare the incidence of atopy among young adults who were born preterm and at very low birth weight (≤1500 g) with that of term-born young adults (control subjects). Methods The study comprised 166 adults who were born preterm and at very low birth weight and 172 control subjects, all of whom were from the Helsinki Study of Very Low Birth Weight Adults. We assessed atopic predisposition at ages 18 to 27 years using skin prick tests for 6 common aeroallergens and measurements of serum concentrations of total IgE and 3 types of allergen-specific (cat, birch, and timothy) IgE. We asked the subjects whether they had been given a diagnosis of asthma or allergic rhinitis or had atopic eczema and analyzed data by using logistic or linear regression, adjusting for potential confounding factors. Results The risk for having at least 1 positive reaction on a skin prick test was reduced (adjusted odds ratio, 0.43; 95% CI, 0.23-0.79, P = .007), and the concentration of cat-specific IgE was less (25% less; 95% CI, 43% to 2.3% less; P = .033) in sera from very-low-birth-weight subjects compared with that seen in sera from control subjects. Within the very-low-birth-weight group, those born at an earlier gestational age were less likely to have positive skin prick test reactions (adjusted odds ratio for 1 week, 0.82; 95% CI, 0.68-0.98, P = .029) and less likely to have high levels of allergen-specific IgE. Cumulative incidences of atopic disease were similar between adults of very low birth weight and control subjects. Conclusions Young adults born prematurely and at very low birth weight have a lower incidence of atopy than adults who were born full term. This finding supports the hypothesis that the risk for atopy is determined during early stages of development.

Background/Aims: Boys with constitutional delay of growth and puberty (CDGP) with early reduction in relative height before the onset of puberty will have adult height (AH) clearly below their target height (TH). Characteristics of growth in girls with CDGP are poorly known. We examined whether girls with CDGP attain their TH and whether early reduction in height SDS influences their AH. We also investigated effects of low-dose estrogen on AH. Methods: We investigated growth of 39 women (7 treated with low-dose estrogen) with CDGP history. We compared AH between estrogen-treated and untreated subjects, and used multiple linear regression to investigate the influence of various growth characteristics, e.g. height SDS changes between different ages in childhood, on AH. Results: AH was similar in estrogen-treated and untreated subjects. Reduction of height SDS between 3 and 8 years was significantly associated with the difference between AH and TH (regression coefficient 0.8, 95% confidence interval 0.1–1.5). Overall, 49% of subjects had AH >0.50 SDS below TH. Conclusion: A proportion of CDGP girls do not attain AH consistent with their TH. Reduction in height SDS in childhood predicts smaller AH. Low-dose estrogen treatment does not seem to influence AH in girls with CDGP.

Background: Recently variation in LIN28B, a human ortholog of the gene-regulating processing of micro-RNAs (miRNAs) controlling the timing of major developmental events in the nematode Caenorhabtidis elegans, was reported to be associated with timing of puberty in humans. In C. elegans, a gain-of-function allele of lin-28 causes a retarded phenotype. Objective: The objective of the study was to evaluate the variation in the LIN28B gene in 145 subjects with constitutional delay of growth and puberty (CDGP). Patients and Methods: For this study, 115 males and 30 females with CDGP were included. CDGP was defined by Tanner genital or breast stage II and pubertal growth spurt taking place 2 sd later than average. The four coding exons (exons 1–4) and exon-intron boundaries, as well as the fragment of 3′ untranslated region containing miRNA recognition elements A and B, of LIN28B were PCR amplified from genomic DNA obtained from peripheral blood leukocytes of the subjects and bidirectionally sequenced. Results: No variation in the coding region of LIN28B in the 145 subjects with CDGP was found. However, 16 of 145 subjects carried a 2-nucleotide deletion immediately 5′ from miRNA recognition element A. These patients did not differ in phenotypic features as compared with noncarriers, and this variant was present in 100 controls with the same frequency. Conclusions: Our results show that mutations in the coding region or 3′ untranslated region miRNA recognition elements A and B of LIN28B do not underlie CDGP. Lack of any variation in the coding region of the gene suggests that LIN28B in developmental timing is so crucial that any changes in the conserved protein would probably be lethal.

Secular trends towards earlier puberty, possibly caused by new environmental triggers, provide a basis for periodic evaluation of the influence and interaction of genetic and environmental effects on pubertal timing. In such studies, a practical marker that reflects timing of puberty in both genders needs to be used. We investigated genetic and environmental influences on pubertal timing by using change in the relative height between early and late adolescence (HD:SDS, height difference in standard deviations) as a new marker of pubertal timing. HD:SDS correlated well with age at peak height velocity in a population of men and women with longitudinal growth data. In 2,309 twin girls and 1,828 twin boys, HD:SDS was calculated between height SDs at age 11.5 and 17.5, and 14.0 and 17.5 years, respectively. Quantitative genetic models for twin data were fitted to estimate the genetic contribution to HD:SDS. We also investigated whether the same genetic factors influenced individual differences between HD:SDS and development of secondary sex characteristics prospectively collected by pubertal development scale (PDS). Genetic effects contributed to 86 and 82% of the variance in HD:SDS in girls and boys, respectively, when using the same model including additive genetic and specific environmental factors. In girls, 30% and in boys, 49% of the genetic factors affecting PDS and HD:SDS were the same. Future comparison of the results of periodic evaluations allows estimation of possible changes in the effects of environment on timing of puberty. In such studies, HD:SDS can be used as a practical marker of pubertal timing peerReviewed

Context and Objective: Constitutional delay of growth and puberty (CDGP), more commonly observed in boys than girls, often has a familial background. We characterized the occurrence of CDGP in relatives of CDGP patients to elucidate the mechanisms influencing timing of puberty.Participants and Design: We identified 492 subjects with CDGP from hospital records of two pediatric clinics in Finland; 95 male and 29 female subjects and their first-degree relatives participated. In family members, CDGP was defined by use of growth charts (growth spurt taking place 2 sd beyond the mean). One third of the families was expanded to include also second-degree relatives with an interview-based assessment of pubertal timing.Results: Of males, 80%, and of female probands, 75% had first-degree relatives with CDGP. Of all probands, 45% had one parent (unilineal families) and 32% had two parents affected. In 2% of the families, only siblings were affected. The prevalence of CDGP in male first-degree relatives was only slightly higher than in female relatives: 79 of 148 (53%) vs. 64 of 164 (39%), respectively (P = 0.01); male to female ratio was 1.2:1. In 74% of extended unilineal pedigrees (17 of 23), the inheritance pattern of CDGP was consistent with autosomal dominant inheritance.Conclusions: CDGP clusters in families. Although its inheritance likely is complex, some predisposing genetic factors may have a dominant effect. CDGP was almost as common in male and female relatives of the CDGP subjects seen at specialist care, challenging the view of a marked overall male preponderance of CDGP.

Objective:\ud Previous studies have suggested that people born preterm have increased rates of eating disorders (ED). However, a recent study suggested lower levels of ED-related symptoms in the extreme group of adults born preterm with very low birth weight (

Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79-124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (

The immunoglobulin superfamily member 1 (IGSF1) gene encodes a plasma membrane glycoprotein mainly expressed in pituitary and testes. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism (CeH), macroorchidism, and delayed puberty (delayed rise of testosterone, but normal timing of testicular growth). As this syndrome was discovered in patients with CeH, it is unknown whether IGSF1 mutations might also cause delayed puberty without CeH. We therefore determined the prevalence of IGSF1 sequence variants in 30 patients with an apparent X-linked form of constitutional delay of growth and puberty (CDGP). In four families, we discovered three novel variants of unknown clinical significance (VUCSs), with possible pathogenicity predicted by in silico analysis. However, the genotype did not fully cosegregate with CDGP, all three VUCSs showed normal plasma membrane expression in transfected HEK293 cells, and no other features of the IGSF1 deficiency syndrome were observed in family members carrying the VUCSs. The observation of hyperprolactinemia in two carriers remains unexplained. Conclusion: There is insufficient evidence to conclude that the three observed VUCSs in IGSF1 are associated with CDGP, making it unlikely that IGSF1 mutations are a prevalent cause of CDGP.

Preterm birth is associated with an increased risk of type 2 diabetes in adult life. The mechanisms are poorly known.We studied insulin sensitivity and secretion in adults born preterm at very low birth weight (VLBW;1500 g).Longitudinal Birth Cohort Study (Helsinki Study of Very Low Birth Weight Adults).The study was conducted at Uusimaa, Finland.One hundred seven adults born at VLBW and 100 controls born at term not small for gestational age (SGA), group-matched for sex, age, and birth hospital. The mean age was 25.0 years.We performed a 14-sample intravenous glucose tolerance test and calculated insulin sensitivity (Si), insulin secretory response (AIR), and disposition index, by Minimal Model (Minmod Millennium®).Compared with controls, VLBW adults had lower Si (mean difference -11.9%, 95% CI -22.1 to -0.4%, adjusted for sex, age, and body mass index) and higher AIR (19.9%; 4.4-37.7%). The association with Si attenuated when further adjusted for height, parental diabetes, parental education, smoking, maternal smoking, hormonal contraception, and physical activity, but the association with AIR remained. Disposition index was similar. There was no difference between the 40 VLBW adults born SGA and the remaining VLBW adults.Adults born preterm at VLBW have lower insulin sensitivity than their term-born peers with a similar body size. In young adulthood, this remains compensated by higher insulin secretion. We suggest that this represents an early stage in the pathway leading to type 2 diabetes. Our results underline the importance of a healthy lifestyle and prompt vigilance in the screening of type 2 diabetes and impaired glucose tolerance in adults born preterm.

Unimpaired adults born preterm at very low birth weight (

Study objectives We examined associations between pubertal maturation and sleep in early adolescence, at age 12 y, and continuity and change in actigraphy-based sleep and parent-reported sleep disorders from age 8 to 12 y. We also explored longitudinal associations between actigraph estimates of sleep and sleep disorders. Design A cohort study of children born in 1998 and tested at ages 8 y (standard deviation [SD] = 0.3) and 12 y (SD = 0.5). Participants A total of 348 children participated in cross-sectional analyses. We had longitudinal actigraphy data for 188 children and repeated parent reports of sleep disorders for 229 children. Measurements and results At age 8 y, participants wore actigraphs for 7.1 nights (SD = 1.2, range 3-14) on average and at age 12 y for 8.4 nights (SD = 1.7, range 3-11). Sleep disorders were parent-rated based on the Sleep Disturbance Scale for Children. Pubertal maturity was self-reported at age 12 y using the continuous Pubertal Development Scale and the picture-assisted categorical Tanner scales. Results Significant mean-level changes toward shorter but higher quality sleep occurred over time. Sleep variables had low to high rank-order stability over time. Sleep disorders were highly stable from age 8 to 12 y. Actigraphy-based sleep and parent-rated sleep disorders showed no association either in cross-section or longitudinally. Pubertal maturation was not associated with worse sleep. Conclusions Sleep in early adolescence can be anticipated from childhood sleep patterns and disorders, but is not associated with pubertal maturity. Although sleep duration becomes shorter, sleep quality may improve during early adolescence. Parent-rated sleep disorders are distinct from actigraph estimates of sleep.

SummaryObjective Adults born preterm at very low birthweight (VLBW; ≤1500 g) have high levels of cardiovascular risk factors and altered responses to psychosocial stress including higher blood pressure and lower cortisol. Our aim was to investigate adrenalin (A), noradrenalin (NA) and heart rate (HR) responses to psychosocial stress in adults born preterm at VLBW. Design and participants We studied 50 young adults, aged 19–27 years, born at VLBW and 39 term-born controls, group-matched for age, sex and birth hospital. They underwent a standardized psychosocial stress test, the Trier Social Stress Test (TSST). Measurements During TSST, A, NA (baseline and 0, 10 and 90 min after stress) and HR were measured. Data were analysed with mixed-effects and linear regression models, adjusted for age, sex, body mass index, hormonal contraception, time of day and highest parental educational attainment. Results Baseline concentrations, peak after stress, increments and area under the curve for A and NA were similar in VLBW and control groups. In women, NA concentrations were 27·7% lower (95% CI; 3·1–52·2) in VLBW compared with control women; in men, there was no significant difference. A concentrations were similar for VLBW and control groups in both sexes. Mean HR at baseline, task and HR reactivity was also similar in VLBW and control groups. Conclusions Very low-birthweight women seem to have a lower NA response to stress compared with term-born peers. If replicated, this could be a protective characteristic for cardiovascular diseases.

Introduction People born preterm at very low birth weight (VLBW, ≤1500g) have higher rates of risk factors for adult-onset diseases, including cardiovascular diseases and type 2 diabetes. These risks may be mediated through epigenetic modification of genes that are critical to normal growth and development. Methods We measured the methylation level of an imprinted insulin-like-growth-factor 2 (IGF2) locus (IGF2/H19) in young adults born preterm at VLBW and in their peers born at term. We studied 158 VLBW and 161 control subjects aged 18 to 27 years from the Helsinki Study of Very Low Birth Weight Adults. Methylation fraction at two IGF2 differentially methylated regions (DMRs) – IGF2 antisense transcript (IGF2AS, also known as IGF2 DMR0) and last exon of IGF2 (IGF2_05, also known as IGF2 DMR2) – were measured with Sequenom Epityper. We used linear regression and adjustment for covariates to compare methylation fractions at these DMRs between VLBW and control subjects. Results At one IGF2AS CpG site, methylation was significantly lower in VLBW than in control subjects, mean difference −0.017 (95% CI; −0.028, −0.005), P = 0.004. Methylation at IGF2_05 was not different between the groups. Conclusions Methylation of IGF2AS is altered 20 years after preterm birth at VLBW. Altered methylation may be a mechanism of later increased disease risk but more data are needed to indicate causality.

Background Adults born preterm at very low birth weight (VLBW ≤ 1500g) have increased risk factors for cardiovascular diseases including high blood pressure and impaired glucose regulation. Non-optimal lipoprotein profile is generally also likely to affect the increased cardiovascular risk, but lipoprotein subclass level data on adults born at VLBW are sparse. Subjects and methods We studied 162 subjects born at VLBW and 169 term-born controls, aged 19 to 27 years. Total lipid, triglyceride and cholesterol concentrations of 14 lipoprotein subclasses were determined by proton nuclear magnetic resonance spectroscopy in the fasting state and in 2-hour serum samples from an oral glucose tolerance test. Findings In comparison to controls, VLBW subjects had significantly higher fasting concentration of triglycerides in chylomicrons and largest very-low-density lipoprotein particles [XXL-VLDL-TG, difference 0.026 (95% CI: 0.004 to 0.049), P = 0.024], and of triglycerides in small high-density lipoprotein particles [S-HDL-TG, 0.026 (95% CI: 0.002 to 0.051), P = 0.037]. The seemingly important role of triglycerides was further supported by principal component analysis in which the first component was characterized by multiple lipoprotein triglyceride measures. Conclusions Young adults born at VLBW and their peers born at term had triglyceride-related differences in both VLDL and HDL subclasses. These differences suggest that the increased risk factors for cardiovascular diseases among the VLBW individuals in adulthood may partly relate to impaired triglyceride metabolism.

SummaryBackground Young adults born preterm at very low birth weight (VLBW, ≤1500 g) have higher levels of cardiovascular risk factors, including impaired glucose regulation, than their term-born peers. This could be mediated through altered hypothalamic-pituitary-adrenal axis (HPAA) response to stress. Objective To compare HPAA, glucose and insulin responses provoked by psychosocial stress in VLBW subjects versus a comparison group of term-born controls. Design and participants We studied 54 unimpaired young adults, aged 19–27 years, born at VLBW and a comparison group of 40 adults born at term, group-matched for age, sex and birth hospital, from one regional centre in southern Finland. The participants underwent a standardized psychosocial stress test (Trier Social Stress Test, TSST). Measurements In conjunction with TSST, we measured salivary cortisol, plasma ACTH, cortisol, glucose and insulin. Data were analysed with mixed-effects model and multiple linear regression analyses. Results Baseline concentrations for cortisol, ACTH, insulin and glucose were similar in VLBW and comparison groups. During TSST, analysed with mixed-effects model, overall concentrations of plasma cortisol were 17·2% lower (95% CI; 3·5 to 28·9) in the VLBW group. The VLBW group also had lower salivary (P = 0·04) and plasma cortisol (P = 0·02) responses to TSST. Insulin and glucose concentrations correlated with changes in cortisol concentrations. Accordingly, VLBW subjects had 26·5% lower increment in insulin (95% CI; 9·8–40·1). Analyses were adjusted for age, sex, body mass index, hormonal contraception, menstrual cycle phase, time of day and parental education. Conclusions VLBW adults have lower HPAA responses to psychosocial stress than term-born controls. This is accompanied by a lower insulin response.

Background Abnormal timing of puberty affects over 4% of adolescents and is associated with adverse health and psychosocial outcomes. Previous studies estimate that 60–80% of variation in the timing of pubertal onset is genetically determined. However, little is known about the genetic control of human puberty. Self-limited delayed puberty segregates in an autosomal dominant pattern; our study aimed to identify novel genetic regulators of disease in these patients. Methods We performed whole-exome sequencing in 18 families with self-limited delayed puberty from our cohort, followed by candidate gene sequencing in a further 42 families. The functional consequences of the identified mutations in one candidate gene were interrogated via expression of wild type and mutant proteins in mammalian cells. For this gene we defined tissue expression in human and mouse embryos. The effects of gene knockdown were assessed via in-vitro neuronal migration assays, and in vivo with a transgenic zebrafish model. Findings In ten unrelated families, we identified four rare mutations in IGSF10 in individuals with self-limited delayed puberty (adjusted p value after rare variant burden testing=3·4 × 10 –2 ). The identified mutations were in evolutionarily conserved positions, and two mutations resulted in intracellular retention with failure in secretion of the N-terminal fragment of the protein. IGSF10 mRNA was strongly expressed in the nasal mesenchyme in mouse and human embryos during migration of gonadotropin-releasing hormone (GnRH) neurons from their nasal origin towards the hypothalamus. IGSF10 knockdown caused reduced migration of immature GnRH neurons in the in-vitro analysis, and perturbed migration and extension of GnRH neurons in the zebrafish model. Interpretation Our findings strongly support the contention that mutations in IGSF10 cause delayed puberty in human beings, through misregulation of GnRH neuronal migration during embryonic development. Funding Wellcome Trust (102745), Rosetrees Trust (M222), and the Barts and the London Charity (417/1551) (SH); Biotechnology and Biological Sciences Research Council (BB/L002671/1) (LG and GB); LD is partly supported by the Academy of Finland (14135); National Institutes for Health Research (NIHR) (MB, HW, and CC); Medical Research Council (MR/K021613/1) (AD); Telethon Foundation (GP13142) (AC); VA is partly supported by a COST STSM (BM1105-16145) and a travel grant sponsored by Development (The Company of Biologists Ltd).

Objective To assess dietary intake in young adults born preterm at very low birth weight (VLBW) (≤1500 g). Study design We studied 151 young adults aged 19-27 years who were born at VLBW and 156 term-born controls, group-matched for age, sex, and birth hospital. Participants completed a 3-day food record, which was checked by a nutritionist. Food and nutrient intakes were calculated with use of a dietary analysis program. Data were analyzed by multiple linear regression, adjusted for age, sex, body mass index, height, living at parental home, daily smoking, and highest parental education. Results Compared with controls, VLBW subjects had lower mean (SD) daily intake of vegetables, fruits, and berries (183 [150] g vs 241 [168] g, P = .002] and milk products (343 [242] g vs 427 [316] g, P = .003). Energy intake from carbohydrates, protein, and fat was similar, as was salt intake. VLBW participants had lower daily intake of calcium (858 [389] mg vs 1080 [514] mg, P P = .02), and cholesterol (189 [74] mg vs 227 [105] mg, P = .002], whereas intake of essential fatty acids was higher (4.3 [1.5] mg vs 4.0 [1.5] mg, P = .01). Conclusions Lower consumption of vegetables, fruits, berries, and milk products combined with lower calcium and vitamin D intake in VLBW participants offers a target for reducing the risk of osteoporosis and cardiovascular diseases in persons of VLBW.

BACKGROUND: Adults born at a very low birth weight (VLBW) (< 1500 g), compared with those born at term, bear risk factors for cardiovascular disease, including higher blood pressure and insulin resistance. OBJECTIVE: We studied, in young adults born at a VLBW, early signs of an accelerated atherosclerotic process and the relationship of these signs with postnatal growth. METHODS: We compared 92 with a VLBW with 68 who were born at term. At age 18 to 27, we measured stiffness and intima-media thickness (IMT) of the right carotid artery and flow-mediated dilatation (FMD) of the right brachial artery. RESULTS: Those with a VLBW had 1.1% units higher FMD (95% confidence interval [CI]: 0.0–2.2) (P = .06) and 0.5% units higher IMT relative to lumen size (95% CI: 0.1–0.9). IMT or FMD, when analyzed as the absolute change in millimeters, and carotid stiffness in the groups were similar. Among those with a VLBW, each 100-g-greater weight gain during the first 2 postnatal weeks predicted 1.1% units higher FMD (95% CI: 0.2–2.0) in adulthood. CONCLUSIONS: Although young adults born at VLBWs, compared with those born at term, have higher levels of risk factors for cardiovascular disease, we found no clear evidence for elevated early markers of atherosclerosis. However, in relation to artery lumen diameter, IMT in the participants who had a VLBW was higher than in those who were born at term. In our study, weight gain during the first postnatal weeks had no harmful effect on the arteries in young adulthood.

Context: Among people born at term, low birth weight is associated with early puberty. Early maturation may be on the pathway linking low birth weight with cardiovascular disease and type 2 diabetes. Subjects born preterm with very low birth weight (VLBW; Objective: The objective of the investigation was to study the timing of pubertal growth in subjects born preterm with VLBW as compared with controls. Design, Setting, and Participants: A follow-up study of subjects born preterm including 188 VLBW and 190 term-born control subjects. Growth data were available for 128 VLBW and 147 control subjects, of whom we excluded 15 and 1, respectively, because of neurological impairment. Main Outcome Measure: Timing of pubertal growth spurt was estimated by assessing the ages, corrected for gestational age at birth, at acceleration (take-off) and peak height velocity of pubertal growth, and age at attaining adult height. Results: All components of pubertal growth occurred earlier in VLBW subjects than in controls. Age at take-off was 0.8 yr earlier [95% confidence interval (CI) 0.4–1.3] in VLBW subjects born appropriate and 0.9 yr earlier (95% CI 0.4–1.5) in those born small for gestational age. VLBW subjects were more likely to have a pubertal growth spurt that was at least 2 yr earlier than population average [odds ratio 3.8 (95% CI: 1.5–9.6)]. Conclusions: Prematurity per se is associated with advanced pubertal growth. Advanced puberty may be among the factors mediating adult metabolic outcomes in subjects born preterm with VLBW.

Background Adults born preterm with very low birth weight (VLBW

Variation in FGFR1, GNRHR, TAC3, and TACR3 was evaluated in 146 Finnish subjects with constitutional delay of growth and puberty. Although one male subject carried a previously undescribed heterozygous deletion (Phe309del) in GNRHR, which segregated with delayed puberty in his family, mutations in the coding regions of FGFR1, GNRHR, TAC3, and TACR3 are not likely to underlie common constitutional delay of growth and puberty.

Context: Twin studies indicate that the timing of pubertal onset is under strong genetic control. However, genes controlling pubertal timing in the general population have not yet been identified. Objective: To facilitate the identification of genes influencing the timing of pubertal growth and maturation, we conducted linkage mapping of constitutional delay of growth and puberty (CDGP), an extreme variant of normal pubertal timing, in extended families. Participants and Methods: Fifty-two families multiply affected with CDGP were genotyped with 383 multiallelic markers. CDGP was defined based on growth charts (the age at onset of growth spurt, peak height velocity, or attaining adult height taking place at least 1.5 sd later than average). Chromosomal regions cosegregating with CDGP were identified with parametric affected-only linkage analysis using CDGP as a dichotomized trait. Results: The genome-wide scan detected linkage of CDGP to a region on chromosome 2p13-2q13. The two-point heterogeneity LOD (HLOD) score was 1.62 (α = 0.27), and the corresponding multipoint HLOD was 2.54 (α = 0.31). Fine-mapping the region at 1 cM resolution increased the multipoint HLOD score to 4.44 (α = 0.41). The linkage became weaker if family members diagnosed with CDGP without growth data were also included in the analyses. Conclusions: The pericentromeric region of chromosome 2 harbors a gene predisposing to pubertal delay in multiply affected pedigrees. Our data suggest that this locus may be a component of the internal clock controlling the timing of the onset of puberty.