We investigated pubertal development of 4019 boys and 3562 girls Ͼ8 y of age participating in a cross-sectional survey in The Netherlands and compared the results with those of two previous surveys. Reference curves for all pubertal stages were constructed. The 50th percentile of Tanner breast stage 2 was 10.7 y, and 50% of the boys had reached a testicular volume of 4 mL at 11.5 y of age. Median age at menarche was 13.15 y. The median age at which the various stages of pubertal development were observed has stabilized since 1980. The increase of the age at stage G2 between 1965 and 1997 is probably owing to different interpretations of its definition. The current age limits for the definition of precocious are close to the third percentile of these references. A high agreement was found between the pubic hair stages and stages of pubertal (genital and breast) development, but slightly more in boys than in girls. Menarcheal age was dependent on height, weight, and body mass index. At a given age tall or heavy girls have a higher probability of having menarche compared with short or thin girls. A body weight exceeding 60 kg (ϩ1 SDS), or a body mass index of Ͼ20 (ϩ1 SDS), has no or little effect on the chance of having menarche, whereas for height such a ceiling effect was not observed. In conclusion, in The Netherlands the age at onset of puberty or menarche has stabilized since 1980. Height, weight, and body mass index have a strong influence on the chance of menarche. The development and first appearance of secondary sexual characteristics can be regarded as a reflection of the overall physiologic development in adolescence (1). The continuous process of pubertal development is usually subdivided into discrete numerical stages, as proposed by Marshall and Tanner (2, 3).The assessment of pubertal stages in the individual child or adolescent in the clinic is only useful if recent and reliable reference data from the same population are available for comparison. As in many European countries a positive secular trend with regard to height, accompanied by a decrease of the age at onset of puberty (1, 4, 5), has been observed, nationwide reference data should be collected at 10-to 20-y intervals. If the age at onset of puberty would indeed decrease, the definition of precocious and delayed puberty should be adjusted. In fact, in the United States it was recently proposed to revise the guidelines for the evaluation of girls with precocious puberty (6, 7).Besides clinical reasons, there are also scientific reasons to study pubertal development in a large population-based sample of healthy children and adolescents. First, it is unclear whether the secular trend with regard to body stature is invariably associated with a trend toward earlier pubertal development. Second, there are few data on the association between the markers of the maturation process of the hypothalamopituitary-gonadal axis (breast development in girls and genital stage in boys) and the occurrence of pubic hair. One would suspect that the agreement be...

SummaryBackgroundKCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.MethodsIn this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.Findings90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol [55·2–77·1]) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol [35·5–47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol [41·0–56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2–10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5–24·0] vs 4·1 years [1·3–10·2]; p=0·0005). Initial improvement was noted following transfer to sulfo...

The secular changes in growth and maturation can be seen as indicators of socio-economic and health status. In most European countries the age of onset of puberty and of menarcheal age has been decreasing during the past few decades. The duration of puberty seems also to decrease, though few studies provide sufficient data to support this postulation. The four Dutch nationwide growth surveys are useful examples assessing the secular trend in pubertal development over the past 45 years. Genetic and environmental factors contribute to the secular changes. Environmental factors seem to be the most important. Recently, attention has been given to substances with oestrogen-like actions that are present in nutrients. The possible role of these substances in growth and maturation is discussed.

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