Prevalence of delayed puberty and low bone density in patients with epidermolysis bullosa: Insight from a large single center's experience.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare genetic skin conditions that result in skin fragility. EB can be quite severe with chronic inflammation and malnutrition impairing growth and pubertal development. These factors have potential consequences for skeletal health. We aimed to determine the prevalence of delayed puberty and low bone mineral density (BMD) for age in children and young adults with EB. METHODS: Electronic medical records (EMR) of patients with confirmed EB <30 years of age at time of initial encounter at Cincinnati Children's Hospital Medical Center between January 1, 2010 and September 30, 2020 were reviewed. Natural language processing software was used to categorize pubertal status of patients with EB as early, normal or delayed. BMD was measured by dual energy x-ray absorptiometry and categorized as low if height adjusted Z-score was <-2.0 using age, sex and race specific reference ranges. RESULTS: 29% of individuals with EB had low BMD with most cases occurring prior to 10 years of age. Of patients who reached adolescence, 23% failed to develop any signs of puberty in the normal range (before age 13 in females or 14 in males) and BMD Z-scores further declined in these individuals. CONCLUSION: Delayed puberty is an under-recognized comorbidity of individuals with EB, especially in those with recessive dystrophic EB, and can have a significant impact on BMD.

Growth hormone deficiency and other endocrinopathies after childhood brain tumors: results from a close follow-up in a cohort of 242 patients.

PURPOSE: Brain tumors are the most common solid tumor in children. The prevalence of survivors from these cancers has been increasing, presenting endocrine sequelae in more than 40% of the cases. Our aim was to characterize the endocrinopathies diagnosed in this population, exploring the outcomes of growth hormone treatment. METHODS: We have performed a retrospective analysis of the survivors that were followed-up through a close protocol at our endocrine late-effects clinic. RESULTS: 242 survivors, followed during 6.4 (0-23.4) years, were considered. The median age at tumor diagnosis was 6.7 (0-18) years and pilocytic astrocytoma was the most frequent neoplasm (33.5%). The prevalence of endocrinopathies was of 71.5%, with growth hormone deficiency being the most frequent (52.9%). An indirect correlation between the age at the beginning of somatropin and growth velocity in the first year of treatment was observed. Those treated with craniospinal radiotherapy presented a smaller final upper/lower segments ratio comparing with those that only received cranial radiotherapy. However, their final height was not compromised when compared to their family height target. We found pubertal delay in 12%; accelerated/precocious puberty in 13.2%; central and primary hypogonadism in 21.9% and 3.3%, respectively; primary and central hypothyroidism in 23.6% and 14.5%, respectively; thyroid nodules in 7.4%; ACTH deficiency in 10.3% and diabetes insipidus in 12%. CONCLUSION: This study reveals a higher prevalence of endocrinopathies in brain tumors survivors and explores the influence of craniospinal irradiation in the adult body proportions. It reinforces the importance of routine follow-up among survivors.

Long-term implications of structured transition of adolescents with inflammatory bowel disease into adult health care: a retrospective study.

BACKGROUND: We aimed to evaluate the long-term clinical and socioeconomic outcome of structured transition care in adolescents with inflammatory bowel disease (IBD). METHODS: We compared the clinical long-term course of 24 patients with and 11 patients without structured transition care within 24 months before and 24 months after transfer from paediatric to adult health care. Socio-economic parameters and quality of life were assessed by IBD Questionnaire (IBDQ-32) and additional items. Treatment costs were calculated for medication, surgery and hospitalisation. RESULTS: The percentage of transfer group patients with an IBD-related intestinal complication was higher compared to the transition group (64% vs. 21%, p = 0.022). We also found a tendency towards a higher number of IBD-related surgery in the transfer group compared to the transition group (46% vs. 13%, p = 0.077). Transfer group patients received higher mean cumulated doses of radiation compared with the transition group (4.2 ± 5.3 mSv vs. 0.01 ± 0.01 mSv, p = 0.036). Delayed puberty was only noted in the transfer group (27%, p = 0.025). Mean expenditures for surgeries and hospitalisation tended to be lower in the transition group compared to transfer group patients (744 ± 630€ vs. 2,691 ± 4,150€, p = 0.050). Sexual life satisfaction was significantly higher (p = 0.023) and rates of loose bowel movements tended to be lower (p = 0.053) in the transition group. CONCLUSIONS: Structured transition of adolescents with IBD from paediatric into adult health care can lead to important clinical and economic benefits.

Elite athletes and pubertal delay.

Intensive physical training and participation in competitive sports during childhood and early adolescence may affect athletes' pubertal development. On the other hand, pubertal timing, early or late, may impact on an athlete selection for a particular sport. Genetic predisposition, training load, nutritional status and psychological stress determine athletes' pubertal timing. Athletes that practice esthetic sports, especially gymnasts, are predisposed to a delay in pubertal development. The growing evidence indicates that energy deficiency, not a systemic training per se, plays a crucial role in the pathogenesis of functional hypothalamic hypogonadism in female athletes. Metabolic and psychologic stress activate hypothalamic-pituitary-adrenal axis and suppress hypothalamic-pituitary-ovarian axis. Female athletes who do not begin secondary sexual development by the age of 14 or menstruation by the age of 16 warrant a comprehensive evaluation and a targeted treatment. Somatic growth and sexual maturation of elite female athletes are largely sport-specific since each sport favors a particular somatotype and requires a specific training. Chronic negative energy balance resulting from a systemic physical training and inadequate energy intake may delay pubertal development in elite athletes. Youth athletes, especially those engaged in competitive sports that emphasize prepubertal or lean appearance, are at risk of developing relative energy deficiency in sport associated with disordered eating or eating disorders. Management strategies should address the complex conditions underlying functional hypothalamic hypogonadism.

Maternal fish oil supplementation during lactation is associated with reduced height at 13 years of age and higher blood pressure in boys only.

Dietary long-chain n-3 PUFA (n-3 LCPUFA) in infancy may have long-term effects on lifestyle disease risk. The present follow-up study investigated whether maternal fish oil (FO) supplementation during lactation affected growth and blood pressure in adolescents and whether the effects differed between boys and girls. Mother-infant pairs (n 103) completed a randomised controlled trial with FO (1·5 g/d n-3 LCPUFA) or olive oil (OO) supplements during the first 4 months of lactation; forty-seven mother-infant pairs with high fish intake were followed-up for 4 months as the reference group. We also followed-up 100 children with assessment of growth, blood pressure, diet by FFQ and physical activity by 7-d accelerometry at 13·5 (sd 0·4) years of age. Dried whole-blood fatty acid composition was analysed in a subgroup (n 49). At 13 years of age, whole-blood n-3 LCPUFA, diet, physical activity and body composition did not differ between the three groups. The children from the FO group were 3·4 (95 % CI 0·2, 6·6) cm shorter (P=0·035) than those from the OO group, and tended to have less advanced puberty (P=0·068), which explained the difference in height. There was a sex-specific effect on diastolic blood pressure (P sex×group=0·020), which was driven by a 3·9 (95 % CI 0·2, 7·5) mmHg higher diastolic blood pressure in the FO compared with the OO group among boys only (P=0·041). Our results indicate that early n-3 LCPUFA intake may reduce height in early adolescence due to a delay in pubertal maturation and increase blood pressure specifically in boys, thereby tending to counteract existing sex differences.

Delayed puberty in the female patient.

PURPOSE OF REVIEW: The purpose is to review current recommendations for the evaluation and management of delayed puberty in the female patient. RECENT FINDINGS: Kisspeptin activation has emerged as an important factor for initiation of pubertal development. Causes of delayed puberty can be considered in four main categories: constitutional delay of growth and puberty, hypergonadotropic hypogonadism, permanent hypogonadotropic hypogonadism, and transient/functional hypogonadism. The most common cause of delayed puberty is constitutional delay of growth and puberty; however, consistent differentiation from idiopathic hypogonadotropic hypogonadism remains challenging. Initial assessment with broad spectrum testing in an otherwise healthy adolescent is often of low clinical value. Treatment is aimed at the underlying cause of delayed puberty whenever possible and individualized to the patient. SUMMARY: Understanding the factors that contribute to delayed puberty and a thoughtful evaluation, structured to the patient, is important to identify the cause of delayed puberty and prevent unnecessary and often expensive investigations. Insuring appropriate pubertal progression, optimizing height and bone health, as well as preservation of psychosocial well-being are the ultimate goals of management of delayed puberty.

Evaluation of Delayed Puberty in Adolescents With Cleft Lip/Palate.

OBJECTIVE: To assess the frequency of delayed puberty in adolescents with cleft lip and/or cleft palate (CL/P). DESIGN: This was a cross-sectional study of 203 patients with CL/P and no associated syndromes treated at the Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil. We evaluated boys aged 14-19 years and girls aged 13-18 years. The patients were classified according to Tanner stages of sexual development. The age of menarche was recorded. Patients were assigned to three groups according to cleft type: isolated cleft lip (CL), cleft lip and palate (CLP), and isolated cleft palate (CP). The results were expressed as frequencies and averages and compared with pubertal changes described for typically developing adolescents as reported in the literature. RESULTS: Subjects were 115 boys and 88 girls. All boys in the CL group and the CP group had already started puberty, and two boys in the CLP group (2.3%) had delayed puberty. All girls had started puberty. The average age at menarche was 12.3 years in the CL group, 12.1 years in the CLP group, and 12.5 years in the CP group. CONCLUSIONS: The frequency of delayed puberty and the average age at menarche in adolescents with CL/P and no associated genetic syndromes or anomalies were within the expected range for typically developing adolescents (i.e., those without CL/P) in the same age group.

Pathological fractures in paediatric patients with inflammatory bowel disease.

UNLABELLED: Paediatric inflammatory bowel disease (IBD), especially Crohn's disease (CD), is commonly associated with poor skeletal health, related to the direct effects of chronic inflammation, prolonged use of glucocorticoid (GC), poor nutrition, delayed puberty and low muscle mass. Low bone mineral density is commonly reported, although the prevalence of long bone fractures may not be increased in these patients. Emerging evidence however suggests that there may be an increased risk of vertebral fractures (VFs) in this group. VFs presenting at diagnosis of paediatric CD, prior to any GC exposure, have been reported, highlighting the deleterious effect of inflammation on skeletal health. This paper reviews the published literature on pathophysiology of skeletal morbidity and fractures in paediatric IBD, illustrated with a new case report of multiple VFs in a prepubertal girl with CD, soon after diagnosis, who received minimal amounts of oral GC. Optimising control of disease, addressing vitamin D deficiency, encouraging physical activity and ensuring normal growth and pubertal progression are paramount to management of bone health in these patients. Despite the lack of evidence, there may be a place for bisphosphonate treatment, especially in the presence of symptomatic pathological fractures, but this requires close monitoring by clinicians with expertise in paediatric bone health. CONCLUSION: Chronic inflammation mediated by pro-inflammatory cytokines may have adverse effects on skeletal health in paediatric patients with IBD. The risk of vertebral fractures may be increased, even without exposure to glucocorticoid. Clinical monitoring of these patients requires careful attention to the various factors that impact on bone health.

Sexual maturation in Moroccan patients with juvenile idiopathic arthritis.

Abnormal puberty is often reported in children suffering from many chronic diseases. Juvenile idiopathic arthritis (JIA) is the most common joint disorder in developing children. The aim of this study was to assess sexual maturation of Moroccan children with JIA and to compare the development of secondary sexual characteristics in children with JIA to children in the general population. Forty children with JIA and 74 healthy controls were included in a cross-sectional study. The diagnosis of JIA was made according to the criteria of the International League of Association of Rheumatology. Every child was examined for the development of genitalia as per criteria given by Tanner. The children with JIA were also divided into 3 groups: pre-puberty (stage 1), puberty (stages 2-3) and post-puberty (stage 4-5), and the association between puberty and cumulative dose of steroids, disease duration, disease activity, height, weight and age was investigated. Forty children with JIA were included (22 male, 18 female); the mean of age of the patients was 11 ± 4.23 years. Puberty in the patients (mean of tanner 2.43 ± 1.36) was lower than controls (2.55 ± 1.36). The prevalence of the children in prepuberty was of 15 (37.5 %) and 8 (20 %) in postpuberty. The prevalence of the children having a delayed puberty was of 6 (15 %) versus 1(1.4 %) in healthy controls (p = 0.005). There was an association between dose of corticosteroids, age at the administration of corticosteroids and the delayed puberty in boys (p = 0.009). In addition, there was no significant association in both sex between this poor puberty and duration of JIA (p = 0.45 in boys and p = 1.99 in girls) and its activity calculated by the DAS28 (p = 0.73 in boys and p = 1). Our study suggests that the puberty is retarded in Moroccan patients with JIA comparing to healthy children and that the dose of corticosteroid and the age at its administration may contribute to delayed puberty in boys.

Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.

CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Accelerated pubertal onset in short children with delayed bone age.

OBJECTIVES: Constitutional delay of growth (CDG) is usually associated with a delay in pubertal onset (CDGP) and a catch-up growth after puberty. Some individuals, however, have earlier-than-expected pubertal onset resulting in a shorter adult height. We investigated the current incidence of such individuals and that of 30 years ago. METHODS: The study subjects are 1,312 consecutive Japanese children referred to Osaka City General Hospital (OCGH) for short stature during 2010-2018, and a cohort of 11,256 individuals in the Ogi Growth Research (OGR, 1979-1992). Individuals with the height standard deviation score <-1.0, the bone age (BA)/chronological age (CA) ratio <0.8 at first visits, and without other identifiable causes of short stature were extracted from the record of OCGH. Similarly, individuals meeting the height and bone age criteria were extracted from the OGR record. The pubertal growth onset was auxologically determined as the upward shift from the prepubertal growth curve fitted to a quadratic function. Earlier-than-expected onset was defined as the onset earlier than the population average +1 year. RESULTS: From the OCGH cohort, 55 children (38 boys, 17 girls) met the criteria, and earlier-than-expected onset was observed in 34.2% of boys and 29.4% of girls. In the 73 short individuals with delayed bone age in the OGR cohort, earlier-than-expected onset was less common (13.0% for boys and 14.8% for girls). There was no significant association between the timing of pubertal growth onset and the BA/CA ratio, IGF-1, and midparental height. CONCLUSIONS: Earlier-than-expected pubertal growth onset is common in CDG and possibly increasing.

Increased androgen-related comorbidity in adolescents and adults born with hypospadias: A population-based study.

BACKGROUND: Hypospadias is a common congenital malformation often related to the effect of androgens in utero. While hypogonadism is associated with many potential health risks including metabolic and cardiovascular disease, the risk of clinical hypogonadism and comorbidities in men with hypospadias later in life has not been studied. OBJECTIVES: Investigate the risk of hypogonadism and somatic comorbidities in adolescents and men born with hypospadias. MATERIALS AND METHODS: We conducted a population-based cohort study using Swedish registers. Associations between hypospadias and hypogonadism, delayed puberty, metabolic, and cardiovascular disease respectively were estimated using Cox proportional hazards regression. Body measurements from military conscription were analysed in a subpopulation as indicators of growth and cardiometabolic risk. We used sibling comparison analyses to control for familial confounding. RESULTS: Using register data, a total of 2,165,255 men including 9,714 men born with hypospadias were followed from the age of 10 to a maximum of 60 years. We found an association between hypospadias and hypogonadism (Hazard ratio (HR) 3.27, 95% confidence interval (CI) 2.33-4.59) which was more pronounced in proximal hypospadias. Men with hypospadias had shorter average height than their brothers and the general population. We further found an increased risk of delayed puberty (HR 1.49, 95% CI 1.08-2.07), diabetes mellitus type 2 (HR 1.57, 95% CI 1.18-2.09) and cardiovascular disease (HR 1.47, 95% CI 1.27-1.71). DISCUSSION: We found an increased risk of hypogonadism, metabolic and cardiovascular disease in men born with hypospadias, increasing with severity of phenotype, as well as impacted growth. These results indicate discruptions in androgen function past childhood, although some of the associations may be due to other underlying aetiologies. CONCLUSION: Hypospadias is associated with an increased risk of androgen-related comorbidity in adolescence and adulthood. We suggest that this can be considered clinically, while further research is needed, especially in older populations.

Clinical profile and aetiologies of delayed puberty: a 15 years' experience from a tertiary centre in Sudan.

OBJECTIVES: Delayed puberty is a common presentation to endocrine clinics, with adult height, sexual capability and fertility being the main concerns for the child and his/her family. Presentation is variable including short stature and/or absence of secondary sexual characteristics. The aetiology can either be constitutional, functional or permanent hypogonadotropic hypogonadism, permanent hypergonadotropic hypogonadism or unclassified. Despite the importance of this subject, there are no publications from Sudan. METHODS: A retrospective hospital-based study. Records of all patients who were seen in the endocrinology unit at Gaffar Ibn Auf Children's Hospital and were diagnosed as having delayed puberty were reviewed and demographic, clinical, and investigations data were obtained. RESULTS: A total of 136 patients were included in this study. Presentation includes short stature in 52.2%, both short stature and delayed puberty in 27.2%, and delayed puberty in 20.6%. The most common aetiologies were permanent hypogonadotropic hypogonadism and functional hypogonadotropic hypogonadism presented in 37.5% and 36% respectively, while constitutional delay of growth and puberty was found in only 14.7%. Type 1 diabetes mellitus (T1DM) was the most frequent chronic illness followed by coeliac disease. Hypergonadotropic hypogonadism was diagnosed in 11.7%, the majority of which were females. CONCLUSIONS: The aetiological pattern reported in this series highlights the role of nutrition and general well-being in pubertal development, as well as the major impact of genetics and consanguinity on disease patterns. Data from African countries are limited and this is the first reported cohort on delayed puberty from Sudan.

Menarche delay and menstrual irregularities persist in adolescents with type 1 diabetes.

BACKGROUND: Menarche delay has been reported in adolescent females with type 1 diabetes (T1DM), perhaps due to poor glycemic control. We sought to compare age at menarche between adolescent females with T1DM and national data, and to identify factors associated with delayed menarche and menstrual irregularity in T1DM. METHODS: This was a cross-sectional study and females ages 12- 24 years (n = 228) with at least one menstrual period were recruited during their outpatient diabetes clinic appointment. The National Health and Nutrition Examination Survey (NHANES) 2001-2006 data (n = 3690) for females 12-24 years were used as a control group. RESULTS: Age at menarche was later in adolescent females with T1DM diagnosed prior to menarche (12.81 +/- 0.09 years) (mean+/- SE) (n = 185) than for adolescent females diagnosed after menarche (12.17 0.19 years, p = 0.0015) (n = 43). Average age of menarche in NHANES was 12.27 +/- 0.038 years, which was significantly earlier than adolescent females with T1DM prior to menarche (p < 0.0001) and similar to adolescent females diagnosed after menarche (p = 0.77). Older age at menarche was negatively correlated with BMI z-score (r = -0.23 p = 0.0029) but not hemoglobin A1c (A1c) at menarche (r = 0.01, p = 0.91). Among 181 adolescent females who were at least 2 years post menarche, 63 (35%) reported usually or always irregular cycles. CONCLUSION: Adolescent females with T1DM had a later onset of menarche than both adolescent females who developed T1DM after menarche and NHANES data. Menarche age was negatively associated with BMI z-score, but not A1c. Despite improved treatment in recent decades, menarche delay and high prevalence of menstrual irregularity is still observed among adolescent females with T1DM.

Development and linear growth in diabetic children receiving insulin pigment.

OBJECTIVE: The aim of this study was to ascertain if there are differences in the development and linear growth between a group of diabetic children who had been receiving insulin pigment and healthy children. METHODS: A total of 57 Chinese children with type 1 diabetes diagnosed at the age from 6 to 10 years old (26 boys and 31 girls) were included in the study. Their height and weight and development conditions were recorded until they reached their 18th birthday. RESULTS: Diabetic children were taller than healthy children at the onset of diabetes, even though there was no significant difference between them [male height standard deviation score (SDS): 0.34 +/- 0.93, female height SDS: 0.38 +/- 0.50]. When they reached their final height, they were slightly shorter than the healthy group. However, there were still no significant differences between these two groups (male height SDS: -0.42 +/- 0.95, female height SDS: -0.60 +/- 0.98). The median age at onset of puberty, 12.62 years in boys and 11.13 years in girls, was significantly delayed in diabetic boys compared to 10.55 years in healthy boys and 9.2 years in healthy girls. The median age at menarche in diabetic girls (14.15 years) was also delayed compared with 12.27 years in healthy girls. The majority of these diabetic children were thinner than the healthy children when they were diagnosed [male body mass index (BMI): 14.45 +/- 1.35 kg/m2 vs. 16.08 +/- 0.59 kg/m2, t = -0.63, p < 0.05; female BMI: 13.50 +/- 1.87 kg/m2 vs. 15.46 +/- 0.45 kg/m2, t = -6.67, p < 0.05]; however, as they reached their final height, they became fatter, especially the girls (male BMI: 21.43 +/- 1.62 kg/m2 vs. 20.8 +/- 0.00 kg/m2, t = 1.97, p > 0.05; female BMI: 23.95 +/- 2.37 kg/m2 vs. 20.3 +/- 0.00 kg/m2, t = 8.60, p < 0.05). CONCLUSION: Even with well-controlled glucose levels, the development of children with diabetes who had been receiving insulin pigment were still adversely affected. However, linear growth had only been slightly affected. All patients, especially girls, became fatter when they reached their final height.

Exposure to non-persistent pesticides and puberty timing: a systematic review of the epidemiological evidence.

BACKGROUND: Numerous modern non-persistent pesticides have demonstrated estrogenic/anti-androgenic activity and have been classified as endocrine-disrupting chemicals (EDCs). Processes involved in puberty development are vulnerable to EDCs, such as compounds that interfere with the metabolism or activity of sex steroids. OBJECTIVE: To conduct a systematic review of epidemiological studies on the relationship between early-life exposure to non-persistent pesticides and puberty timing and/or sexual maturation in girls and boys. METHODS: A systematic search was carried out using MEDLINE and SCOPUS databases, including original articles published up to November 2020. RESULTS: Thirteen studies were selected after excluding non-original and non-human studies. Exposure to different types of pesticides has been associated with altered puberty timing in girls and/or boys in eight studies. In utero exposure to atrazine has been related to earlier age of menarche in girls; exposure to organophosphate (OP) pesticides has been related to delayed sexual development in boys and girls; childhood pyrethroid exposure has been associated with pubertal delay in girls and pubertal advancement in boys; and prenatal/childhood exposure to multiple pesticides has been linked to earlier puberty onset in girls and pubertal delay in boys. CONCLUSIONS: Most of the reviewed studies describe a relationship between pesticide exposure and changes in the age of puberty onset or sex hormone levels, although the quality of the evidence is generally low. Further well-designed longitudinal studies are warranted on specific classes of pesticides and on possible interactions between different types of compounds.

Timing of Pubertal Onset in Girls and Boys With Constitutional Delay.

CONTEXT: The decision whether to treat a child with delayed puberty with sex steroids is primarily based on patient, family, and provider preference. Knowing when children with constitutional delay eventually enter puberty would inform this decision. OBJECTIVE, DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: To estimate and compare rates of pubertal entry, we conducted a retrospective cohort study by reviewing medical records of children evaluated for delayed puberty at a large academic medical center between 2000 and 2015, extracting data on pubertal status for all clinical visits, then conducting time-to-event analyses. RESULTS: Of 392 girls and 683 boys with delayed puberty, constitutional delay was the most common cause, found in 32% of girls and 70% of boys. In a subcohort of 97 girls and 243 boys who were prepubertal at one or more visits, we observed a broad age range for pubertal entry, up to >16 years for girls and >17 years for boys. The probability of entering puberty within the next year for 12- to 15.5-year-old girls and 13.5- to 16.5-year-old boys with delayed puberty ranged between 38% and 74%. No differences in the rates of pubertal entry were seen between girls and boys after data harmonization. CONCLUSION: The broad range of ages at pubertal entry for children with constitutional delay challenges the concept that constitutional delay is merely an extreme of normal variation. Discussions with patients and families about management should consider the possibility that some children may need to wait years after presentation until puberty starts.

Delayed puberty: experience of a tertiary care centre in India.

BACKGROUND: Pubertal delay can be a manifestation of a wide variety of diseases, the proportions of which may vary between developing and industrialised countries. OBJECTIVE: A retrospective study was undertaken to investigate the aetiology of delayed puberty in northern India. SUBJECTS AND METHODS: Follow-up records of patients with delayed puberty presenting to the endocrine clinic between 2003 and 2007 were analysed. RESULTS: Forty-two patients (19 boys, 23 girls, age range 14-27 y) of 46 who initially presented had complete evaluation. The main causes of pubertal delay were chronic systemic illnesses (16), e.g. malnutrition, anaemia and chronic infections, hormone deficiencies (11), hypergonadotrophic hypogonadism (7) and constitutional delay (6). While the majority of girls (11/23) were found to have underlying systemic disorders, endocrinopathies (6/19) were the major causes of pubertal delay in boys. CONCLUSION: Chronic systemic illnesses are the major cause of pubertal delay in developing countries. Social awareness and education leading to early detection and treatment can prevent pubertal delay in a large proportion of cases.

Influence of sexual maturation status on the relationship between body adiposity indicators and age: a cross-sectional study.

OBJECTIVES: To determine the influence of sexual maturation status on adiposity indicators of children and adolescents. RESULTS: 2412 individuals participated, 1285 (47.4%) males and 1408 (52.6%) females. There was moderate to weak correlation between age and adiposity indicators for both sexes. By analyzing the relationship between age and body fat indexes adjusted for Sexual Maturation Status, several changes were observed, mainly in girls. Precocious maturation was associated with increased adiposity indicators in girls, whereas late maturation was associated with decreased adiposity indicators in both sexes. Precocious maturation was associated with increased adiposity indicators in girls, whereas late maturation was associated with decreased adiposity indicators in both sexes.

Hypogonadotrophic hypogonadism, delayed puberty and risk for neurodevelopmental disorders.

Hypogonadotrophic hypogonadism (HH) is a rare disorder that manifests absent puberty and infertility. Genetic syndromes with hypogonadism, such as Klinefelter syndrome, are associated with an increased risk of neurodevelopmental disorders (NDDs). However, it is not clear whether patients with HH or transient delayed puberty in general, have an increased risk of NDDs. We performed a register-based study on a national cohort of 264 patients with HH and 7447 patients diagnosed with delayed puberty that was matched with 2640 and 74 470 controls, respectively. The outcome was defined as having any of the following NDD diagnoses: (i) autism spectrum disorder (ASD); (ii) attention deficit hyperactivity disorder (ADHD); or (iii) intellectual disability (ID). Additional sensitivity analyses were performed to control for different parental and birth variables, as well as diagnosed malformation syndromes and chromosomal anomalies (ie, Down's and Turner syndromes). Patients with HH had increased risk for being diagnosed with ASD (odds ratio [OR] = 5.7; 95% confidence interval [CI] = 2.6-12.6), ADHD (OR = 3.0; 95% CI = 1.8-5.1) and ID (OR = 18.0; 95% CI = 8.9-36.3) compared to controls. Patients with delayed puberty also had a significantly increased risk of being diagnosed with an NDD. These associations remained significant after adjustments. This is the first study to demonstrate a significant association between HH, delayed puberty and NDDs in a population-based cohort. Clinicians should be aware of the overlap between these disorders. Further studies should explore the mechanisms behind these associations.