Prevalence and Factors Associated With Delayed Puberty Among Adolescents on Boosted Protease Inhibitor-based Second-line Antiretroviral Therapy: A Cross-sectional Study at a Pediatric Infectious Diseases Clinic in Uganda.

BACKGROUND: Delayed puberty is a recognized phenomenon among children living with HIV type 1 infection but has not been widely reported among adolescents on second-line or newer treatments in high burden settings. The study aimed to determine the prevalence of, and factors associated with delayed puberty among adolescents on boosted protease inhibitor-based second-line antiretroviral therapy (ART) in Uganda. METHODS: Between December 2017 and May 2018, we conducted a cross-sectional study among adolescents living with HIV (ALWHIV) 10-19 years of age on atazanavir- and lopinavir-based regimens at the Paediatric Infectious Diseases Clinic, Kampala. Participants were on ART for at least 3 months and had a recent viral load. Sociodemographics, clinical measurements: body mass index for age Z score, height for age Z score, Tanner staging were collected. ART history was extracted from medical records. The outcome was delayed puberty defined as absence of signs of breast development in a girl 13 years of age or a testicular volume of less than 4 mL in a boy 14 years of age by Tanner staging, or an age for Tanner staging which was at least 2 standard deviations above the expected mean. RESULTS: Among 230 perinatally infected ALWHIV participants, 14.7 ± 3.1 years of age were included, 54.9% were female, 5.2% were wasted and the median duration on ART was 9.5 years (interquartile range 7.3-11.7). The prevalence of delayed puberty was 8.7% (10.4% females, 6.7% males). Overall mean age estimates at different Tanner stages by sex were significantly higher than reference populations. Age at ART initiation (adjusted odds ratio 1.37, 95% confidence interval: 1.06-1.77) and body mass index for age Z score (adjusted odds ratio: 7.63, 95% confidence interval: 1.80-32.38) were associated with delayed puberty. CONCLUSIONS: Timely initiation of ART and nutritional monitoring could optimize body weight and consequently, normal puberty for ALWHIV. Longitudinal studies could establish biological diagnoses and guide treatment of delayed puberty in this population.

A single-centre study on predictors and determinants of pubertal delay and growth impairment in Epidermolysis Bullosa.

BACKGROUND: Delayed puberty is a possible complication of Epidermolysis Bullosa (EB), though the actual incidence is still unknown. In chronic illnesses delayed puberty should be correctly managed since, if untreated, can have detrimental effects on adult height attainment, peak bone mass achievement and psychological health. AIMS AND METHODS: This is a single-centre study on pubertal development, growth and bone status in EB. Auxological, densitometric (areal Bone Mineral Density-aBMD Z-score, Bone Mineral Apparent Density-BMAD Z-score, Trabecular Bone Score-TBS and Bone Strain Index-BSI at Lumbar spine) and body composition data (Total Body DXA scans) were collected. Disease severity was defined according to Birmingham Epidermolysis Bullosa Severity (BEBS) score. RESULTS: Twenty-one patients (12 Recessive Dystrophic EB-RDEB, 3 Dominant Dystrophic EB, 3 Junctional EB-JEB, 2 EB Simplex and one Kindler EB) aged 13 years (females) or 14 years (males) and above were enrolled (age 16.2±2.5 years, M/F 11/10). Short stature was highly prevalent (57%, mean height -2.12±2.05 SDS) with 55% patients with height <-2SD their mid-parental height. 7/21 patients (33%, 6 RDEB and 1 JEB) had delayed puberty with a median BEBS of 50 (range 29 to 63), a height SDS of -2.59 SDS (range -5.95 to -2.22) and a median lumbar BMAD Z-score of -4.0 SDS (range -5.42 to -0.63 SDS). Pubertal status was negatively associated with BEBS, skin involvement, inflammatory state and positively with height SDS and BMI SDS. CONCLUSIONS: Pubertal delay is highly prevalent in EB, especially in patients with RDEB and JEB, high severity score and inflammatory state. Moreover, pubertal delay worsens growth impairment and bone health. A study on pubertal induction is ongoing to enlighten possible beneficial effects on adult height attainment and peak bone mass accrual.

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.

Long-Term Outcomes of Paediatric-Onset Craniopharyngioma: A Retrospective Analysis from a Tertiary Care Centre in North India.

Background: Craniopharyngiomas are associated with long-term morbidity in the form of hormone deficiencies, visual deficits, and hypothalamic obesity. Objective: To study the long-term outcomes, including cure rates, endocrine dysfunction, visual dysfunction, hypothalamic obesity, and mortality in pediatric-onset craniopharyngiomas. Methods: A retrospective data analysis of pediatric (onset <18 years) craniopharyngioma diagnosed between 2003 and 2018. Data were collected from electronic hospital records, case files, and direct patient interviews. Results: The mean age at presentation was 10.4 ± 4.5 years (n = 62). The median duration of symptoms at diagnosis was 6 months (3-13 months). At presentation, central diabetes insipidus was present in four (6.5%), central hypothyroidism in 27 (43.5%), secondary adrenal insufficiency in 20 (32%) and delayed puberty in 15 (24%) patients. Hypothalamus was involved in 59/60 patients (98%). At last visit, 22.6% were obese in comparison to 4.6% at presentation, and anterior pituitary deficiency was present in 90% of the patients. Sixty-one percent patients (n = 62) had delayed puberty and 67% (n = 53) had short-stature. Out of 35 short children, nine (14%) children who received growth hormone had significant increase in height SD score (-3.8 (1.4) at start vs. -2.9 (1.2) at last follow-up; P = 0.008). Tumor progression was significantly less in the group that received RT compared to those who did not (8% vs. 39%; P = 0.002). Conclusion: Childhood-onset craniopharyngioma results in significant morbidity. The prevalence of pituitary hormones deficiency, visual deficits, and obesity are high at long-term follow-up. Incomplete tumor removal is also frequent. Thus, long-term monitoring is necessary for the timely management of the morbidities associated with craniopharyngioma.

Disorders of Puberty in Girls.

Puberty is the process through which reproductive competence is achieved and comprises gonadarche and adrenarche. Breast development is the initial physical finding of pubertal onset in girls and typically occurs between 8 and 13 years. Menarche normally occurs 2 to 3 years after the onset of breast development. Pubertal onset is controlled by the gonadotropin-releasing hormone pulse generator in the hypothalamus; however, environmental factors such as alterations in energy balance and exposure to endocrine-disrupting chemicals can alter the timing of pubertal onset. Improvement in nutritional and socioeconomic conditions over the past two centuries has been associated with a secular trend in earlier pubertal onset. Precocious puberty is defined as onset of breast development prior to 8 years and can be central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic and is defined as lack of breast development by 13 years or lack of menarche by 16 years. Both precocious and delayed puberty may have negative effects on self-esteem, potentially leading to psychosocial stress. Patients who present with pubertal differences require a comprehensive assessment to determine the underlying etiology and to devise an effective treatment plan.

Endocrinal Complications in Children and Adolescents with Thalassemia Major in Central India: An Observational Study.

OBJECTIVE: To determine the prevalence of short stature, delayed puberty, hypothyroidism, and diabetes mellitus in multiply transfused patients of beta thalassemia major and their correlation with serum ferritin. METHODS: A descriptive observational study was conducted in a tertiary care center in Indore, Madhya Pradesh from 2014 to 2016. All children with thalassemia major of the age group 8 to 18 y attending outpatient department or admitted in ward were included in the study. Detailed clinical history, demographic data, compliance to transfusion and chelation therapy, and growth parameters were recorded. Blood samples to look for endocrinopathies and serum ferritin were assessed. Tanner staging was done to assess for delayed puberty. RESULTS: Mean age of study participants (n = 50) was 15.98 ± 3.4 y. Short stature (n = 44; 88%), delayed puberty (n = 33; 71.7%), hypothyroidism (n = 6; 16%), and diabetes mellitus (n = 5; 10%) were the endocrinal abnormalities found. Mean serum ferritin level was 3122 ± 2117 ng/mL. Serum ferritin had significant positive correlation with serum TSH (thyroid stimulating hormone), fasting blood sugars, postprandial blood sugar, and delayed puberty. CONCLUSION: Evaluation of endocrinopatines must be carried out in thalassemia major patients regularly by pediatricians to detect and treat endocrinal complications. Importance of chelation therapy must be emphasized frequently to parents and patients.

Circulating miR-30b levels increase during male puberty.

OBJECTIVE: The role of miRNA as endocrine regulators is emerging, and microRNA mir-30b has been reported to repress Mkrn3. However, the expression of miR-30b during male puberty has not been studied. DESIGN AND METHODS: Circulating relative miR-30b expression was assessed in sera of 26 boys with constitutional delay of growth and puberty (CDGP), treated with low-dose testosterone (T) (n =11) or aromatase inhibitor letrozole (Lz) (n =15) for 6 months and followed up to 12 months (NCT01797718). The associations between the relative expression of miR-30b and hormonal markers of puberty were evaluated. RESULTS: During the 12 months of the study, circulating miR-30b expression increased 2.4 ± 2.5 (s.d.) fold (P = 0.008) in all boys, but this change did not correlate with corresponding changes in LH, testosterone, inhibin B, FSH, or testicular volume (P = 0.25-0.96). Lz-induced activation of the hypothalamic-pituitary-gonadal (HPG) axis was associated with more variable miR-30b responses at 3 months (P < 0.05), whereas those treated with T exhibited significant changes in relative miR-30b levels in the course the study (P < 0.01-0.05). CONCLUSIONS: Circulating miR-30b expression in boys with CDGP increases in the course of puberty, and appears to be related to the activity of the HPG axis.

Expanding the phenotype of biallelic RNPC3 variants associated with growth hormone deficiency.

Pathogenic variants in components of the minor spliceosome have been associated with several human diseases. Recently, it was reported that biallelic RNPC3 variants lead to severe isolated growth hormone deficiency and pituitary hypoplasia. The RNPC3 gene codes for the U11/U12-65K protein, a component of the minor spliceosome. The minor spliceosome plays a role in the splicing of minor (U12-type) introns, which are present in ~700-800 genes in humans and represent about 0.35% of all introns. Here, we report a second family with biallelic RNPC3 variants in three siblings with a growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. These cases further confirm the association between biallelic RNPC3 variants and severe postnatal growth retardation due to growth hormone deficiency. Furthermore, these cases show that the phenotype of this minor spliceosome-related disease might be broader than previously described.

Long-Term Follow-Up and Treatment of a Female With Complete Estrogen Insensitivity.

CONTEXT: We previously reported the first female with a causative ESR1 gene variant, who exhibited absent puberty and high estrogens. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown. OBJECTIVE: The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment. DESIGN: We have characterized gonadotropin pulsatility and followed this patient's endocrine profile and bone density over 8 years. Seventy-five different compounds were tested for transactivation of the variant receptor. A personalized medicine approach was tailored to our patient. SETTING: Academic medical center. PATIENT OR OTHER PARTICIPANTS: A 24-year-old adopted white female with CEI. INTERVENTION(S): The patient was treated with diethylstilbestrol (DES) for approximately 2.5 years. MAIN OUTCOME MEASURE(S): Induction of secondary sexual characteristics. RESULTS: Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH, and mildly elevated mean follicle-stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the variant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient. CONCLUSIONS: Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.

Blue Rubber Bleb Nevus Syndrome: A Possible Cause for Growth Retardation and Pubertal Delay.

OBJECTIVE: The aim of this paper was to describe a rare case of blue rubber bleb nevus (BRBNS) with growth retardation and pubertal delay. CLINICAL PRESENTATION AND INTERVENTION: A 16-year-old boy with severe iron deficiency anemia was diagnosed with BRBNS, showing growth retardation and pubertal delay simultaneously. The patient was treated conservatively with intravenous iron therapy, and his puberty advanced gradually. CONCLUSION: Given that growth retardation and pubertal delay are rare in BRBNS patients, this case reminds us to include BRBNS in the differential diagnosis of growth retardation.

Delayed puberty and abnormal anthropometry and its associations with quality of life in young Fontan survivors: A multicenter cross-sectional study.

INTRODUCTION: We sought to evaluate the prevalence of delayed puberty and abnormal anthropometry and its association with quality of life (QoL) in young Fontan survivors. METHODS: This was a cross-sectional study at 11 Pediatric Heart Network centers. Demographic and clinical data, anthropomety, and Tanner stage were collected. Anthropometric measurements and pubertal stage were compared to US norms. QoL was assessed using Pediatric Quality of Life inventory (PedsQL). Mixed effects regression modeling adjusting for clustering by center was used to evaluate factors associated with abnormal anthropometry and delayed puberty and associations with QoL. RESULTS: Of the 299 subjects, 42% were female. The median enrollment age was 13.9 years, and the median age at Fontan was 3 years. Fontan survivors had a higher prevalence of short stature relative to normative data (20% vs 5%, P < .0001) and an increased prevalence of abnormal BMI (16% vs 10%, P < .0001) (low [43%] and high [57%]). Fontan subjects, both males (58%) and females (58%), had a delay of 1.5-2 years in ≥1 Tanner stage parameter compared to normal population. There was no association between delayed puberty and QoL. Abnormal anthropometry was associated with lower overall (62.3 ± 17.3 vs 72.5 ± 16.6; P < .001) and physical appearance scores (72.2 ± 27.4 vs 79.8 ± 21.5; P < .01). Lower exercise capacity was associated with abnormal anthropometry and >2 surgeries before Fontan was associated with delayed puberty. Lower family income (<$25 000) and hypoplastic left heart syndrome were associated with lower QoL. CONCLUSION: Compared to the normal population, Fontan survivors have high prevalence of short stature, abnormal BMI and delayed puberty. Abnormal anthropometry, but not delayed puberty, was associated with lower overall QoL and perceived physical appearance scores. Routine screening for abnormal anthropometry, especially in HLHS and in lower socioeconomic status families, should be considered to allow interventions, which might ameliorate the negative psychosocial impact.

Ultrasonographic assessment of pubertal breast development in obese children: compliance with the clinic.

BACKGROUND: The aim of the study was to determine the compliance with the clinical and ultrasonographic staging of pubertal breast development in obese children. METHODS: Fifty-two obese children with Tanner stage 2 and stage 3 breast development accompanied by at least one pubertal clinical finding were included in the study. The staging of breast development was also performed according to the ultrasonographic morphostructural appearance. The subjects were then divided into subgroups according to their clinical and ultrasonographic breast stages. The stages given by both methods were compared for consistency with the hormonal values and other radiological (uterus long diameter, ovary sizes) findings. RESULTS: The correlation between the clinical and ultrasonographic staging of pubertal breast development was determined to be weak (r=0.19). Estradiol levels, uterus long diameter and ovary sizes were significantly increased when the ultrasonographic stage increased among the subjects with clinically similar breast development stage. However, no statistical difference was determined in these parameters among the subjects with ultrasonographically similar but clinically different breast development. CONCLUSIONS: It was shown that the ultrasonographic staging of breast development could provide more accurate and objective data due to the possible mistakes caused in the breast development staging of obese children by their adipose tissue.

Etiologies of short stature in a pediatric endocrine clinic in Southern Thailand.

BACKGROUND: Short stature is one of the common disorders referred for investigation of an endocrine disorder. The etiologies of short stature vary and are commonly grouped into pathological and non-pathological disorders. The objective of the study was to determine the etiologies and describe the characteristics of short stature patients who attended the Pediatric Endocrinology Clinic and to compare factors between normal variant short stature (NVSS) and growth hormone deficiency (GHD). METHODS: This was a retrospective review of 572 patients referred for evaluation of short stature between January 2004 and December 2015. Short stature was defined as height below -2 standard deviation score (SDS) by gender and age based on population data of Thai children. RESULTS: In total, 521 patients were identified as having short stature. NVSS was the most common etiology (44.9%) and pathological short stature was found in 35.3% of the cases, of which 21.2% had GHD. The median age at presentation of NVSS patients was 8.6 years while that of pathological short stature patients was 2.1 years (p<0.001). Patients with NVSS had significantly higher median height SDS (HSDS) than patients with pathological diseases. The common etiologies in severe short patients, defined by HSDS ≤-3, were syndromic short stature (16.2%) and GHD (14.1%). In the moderate short stature group (HSDS between -2 and -3), constitutional delay of growth and puberty (CDGP) was the most common etiology (34.1%). CONCLUSIONS: NVSS was the most common etiology of short stature, followed by syndromic short stature and GHD. Physical examination is crucial to identify GHD from syndromic short patients.

Adult Consequences of Self-Limited Delayed Puberty.

Delayed puberty is a common condition defined as the lack of sexual maturation by an age ≥2 SD above the population mean. In the absence of an identified underlying cause, the condition is usually self-limited. Although self-limited delayed puberty is largely believed to be a benign developmental variant with no long-term consequences, several studies have suggested that delayed puberty may in fact have both harmful and protective effects on various adult health outcomes. In particular, height and bone mineral density have been shown to be compromised in some studies of adults with a history of delayed puberty. Delayed puberty may also negatively affect adult psychosocial functioning and educational achievement, and individuals with a history of delayed puberty carry a higher risk for metabolic and cardiovascular disorders. In contrast, a history of delayed puberty appears to be protective for breast and endometrial cancer in women and for testicular cancer in men. Most studies on adult outcomes of self-limited delayed puberty have been in small series with significant variability in outcome measures and study criteria. In this article, we review potential medical and psychosocial issues for adults with a history of self-limited delayed puberty, discuss potential mechanisms underlying these issues, and identify gaps in knowledge and directions for future research.

TRANSITION IN ENDOCRINOLOGY: Hypogonadism in adolescence.

Puberty is a remarkable developmental process with the activation of the hypothalamic-pituitary-gonadal axis culminating in reproductive capacity. It is accompanied by cognitive, psychological, emotional, and sociocultural changes. There is wide variation in the timing of pubertal onset, and this process is affected by genetic and environmental influences. Disrupted puberty (delayed or absent) leading to hypogonadism may be caused by congenital or acquired etiologies and can have significant impact on both physical and psychosocial well-being. While adolescence is a time of growing autonomy and independence, it is also a time of vulnerability and thus, the impact of hypogonadism can have lasting effects. This review highlights the various forms of hypogonadism in adolescence and the clinical challenges in differentiating normal variants of puberty from pathological states. In addition, hormonal treatment, concerns regarding fertility, emotional support, and effective transition to adult care are discussed.

Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay.

OBJECTIVE: To analyze the GNRHR in patients with normosmic isolated hypogonadotropic hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP). DESIGN: Molecular analysis and in vitro experiments correlated with phenotype. SETTING: Academic medical center. PATIENT(S): A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP. INTERVENTION(S): GNRHR coding region was amplified and sequenced. MAIN OUTCOME MEASURE(S): Novel variants were submitted to in vitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect. RESULT(S): Eleven IHH patients (10%) carried biallelic GNRHR mutations. In vitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic. CONCLUSION(S): GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP.

Growth hormone treatment in a patient with Hurler-Scheie syndrome.

A female patient with known Hurler-Scheie syndrome, who underwent hematopoietic cell transplantation, presented with growth retardation and delayed puberty. She started growth hormone (GH) treatment at age 12.33 years, resulting in significantly improved linear growth and predicted adult height. We describe details of her clinical course and literature review of growth pattern as well as GH use in patients with mucopolysaccharidosis I.

A longitudinal study of body dissatisfaction and pubertal timing in an ethnically diverse adolescent sample.

In a 7-year study, adolescents' body dissatisfaction (N=1370) was examined across four high school years as a function of pubertal development (perceived timing relative to peers and self-reported physical changes measured during Grades 6-10) in the context of the high school transition. Boys and girls who, during early high school, perceived themselves to be late relative to peers were at risk for body dissatisfaction across the high school years. Boys who were late in pubertal development reported more body dissatisfaction in early high school than on-time boys, but then decreased over time. African-American girls reported less body dissatisfaction across the high school years relative to other girls. Asian girls reported more dissatisfaction in early high school than African-American, Latina, and Multiethnic girls, and increased over time. Results highlight the importance of considering late development within context as a risk factor in body dissatisfaction research.