Salivary microbiome differences in prepubertal children with and without adrenal androgen excess.

BACKGROUND: Premature adrenarche is a condition of childhood adrenal androgen excess (AAE) in the absence of gonadotropin-dependent puberty, and has been linked to insulin resistance and progression to metabolic syndrome. Microbial dysbiosis is associated with progression of inflammatory states and chronic diseases. Here, we aimed to examine the salivary microbiomes of children with AAE and assess the relationship with adrenal androgens and metabolic parameters. METHODS: In a prospective cross-sectional study of children with AAE and healthy controls, adrenal and metabolic parameters were characterized and salivary microbiome was profiled using V3-V4 16S rDNA gene amplicon sequencing. RESULTS: There was increased α-diversity in AAE (5 M, 15 F) compared to controls (3 M, 8 F), with positive correlation of 11OHA4, 11KA4, testosterone, androstenedione, DHEA, and DHEAS. Subanalyses showed increased α-diversity in both overweight/obese AAE and normal weight AAE compared to normal weight controls. Genus Peptostreptococcus, Veillonella, and Streptococcus salivarius were increased in normal weight AAE. Genus Prevotella, Abiotrophia, and Neisseria were increased in overweight/obese AAE. CONCLUSION: These pilot data demonstrate differences in salivary microbiome profiles of children with and without AAE. Further studies are needed to assess the causal relationships between adrenal androgens, metabolic dysfunction, and salivary microbiome composition. IMPACT: This study is the first to report the salivary microbiome of prepubertal children with adrenal androgen excess (AAE). α-Diversity is increased in the salivary microbiome of children with AAE independent of weight status, and in this study cohort several serum androgens are positively associated with α-diversity. Several taxa that have been associated with periodontal disease and inflammation are found to be significantly increased in AAE.

Adolescent polycystic ovary syndrome according to the international evidence-based guideline.

BACKGROUND: Diagnosing polycystic ovary syndrome (PCOS) during adolescence is challenging because features of normal pubertal development overlap with adult diagnostic criteria. The international evidence-based PCOS Guideline aimed to promote accurate and timely diagnosis, to optimise consistent care, and to improve health outcomes for adolescents and women with PCOS. METHODS: International healthcare professionals, evidence synthesis teams and consumers informed the priorities, reviewed published data and synthesised the recommendations for the Guideline. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied to appraise the evidence quality and the feasibility, acceptability, cost, implementation and strength of the recommendations. RESULTS: This paper focuses on the specific adolescent PCOS Guideline recommendations. Specific criteria to improve diagnostic accuracy and avoid over diagnosis include: (1) irregular menstrual cycles defined according to years post-menarche; > 90 days for any one cycle (> 1 year post-menarche), cycles< 21 or > 45 days (> 1 to < 3 years post-menarche); cycles < 21 or > 35 days (> 3 years post-menarche) and primary amenorrhea by age 15 or > 3 years post-thelarche. Irregular menstrual cycles (< 1 year post-menarche) represent normal pubertal transition. (2) Hyperandrogenism defined as hirsutism, severe acne and/or biochemical hyperandrogenaemia confirmed using validated high-quality assays. (3) Pelvic ultrasound not recommended for diagnosis of PCOS within 8 years post menarche. (4) Anti-Müllerian hormone levels not recommended for PCOS diagnosis; and (5) exclusion of other disorders that mimic PCOS. For adolescents who have features of PCOS but do not meet diagnostic criteria an 'at risk' label can be considered with appropriate symptomatic treatment and regular re-evaluations. Menstrual cycle re-evaluation can occur over 3 years post menarche and where only menstrual irregularity or hyperandrogenism are present initially, evaluation with ultrasound can occur after 8 years post menarche. Screening for anxiety and depression is required and assessment of eating disorders warrants consideration. Available data endorse the benefits of healthy lifestyle interventions to prevent excess weight gain and should be recommended. For symptom management, the combined oral contraceptive pill and/or metformin may be beneficial. CONCLUSIONS: Extensive international engagement accompanied by rigorous processes honed both diagnostic criteria and treatment recommendations for PCOS during adolescence.

Update on adrenarche.

PURPOSE OF REVIEW: Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when dehydroepiandrosterone sulfate (DHEAS) concentrations increase. This review provides an update on adrenal steroidogenesis and the differential diagnosis of premature development of pubic hair. RECENT FINDINGS: The complexity of adrenal steroidogenesis has increased with recognition of the alternative 'backdoor pathway' and the 11-oxo-androgens pathways. Traditionally, sulfated steroids such as DHEAS have been considered to be inactive metabolites. Recent data suggest that intracellular sulfated steroids may function as tissue-specific intracrine hormones particularly in the tissues expressing steroid sulfatases such as ovaries, testes, and placenta. SUMMARY: The physiologic mechanisms governing the onset of adrenarche remain unclear. To date, no validated regulatory feedback mechanism has been identified for adrenal C19 steroid secretion. Available data indicate that for most children, premature adrenarche is a benign variation of development and a diagnosis of exclusion. Patients with premature adrenarche tend to have higher BMI values. Yet, despite greater knowledge about C19 steroids and zona reticularis function, much remains to be learned about adrenarche.

The diagnosis and treatment of PCOS in adolescents: an update.

PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is often difficult to diagnose in adolescents. Recent recommendations and concepts regarding the diagnosis and treatment of PCOS in the adolescent girl are considered. RECENT FINDINGS: The diagnosis of PCOS in adolescents should be primarily based on clinical and biochemical signs of hyperandrogenism and presentation with irregular menses. Because of the similarity of normal pubertal development and features of PCOS, the diagnosis should be deferred until at least 2 years following menarche. For girls who do not fulfill the diagnostic criteria, the focus should be on treatment of symptoms. SUMMARY: PCOS is a complex, multifaceted disorder, and should be diagnosed and treated in adolescents after taking into consideration the patient's full diagnostic picture, metabolic risks, and individual concerns, to both avoid overdiagnosis but yet be able to provide early and meaningful interventions.

Present Knowledge on the Etiology and Treatment of Adrenarche.

Premature adrenarche (PA) has been assumed to be a benign variant of normal pubertal development. Yet, current collective information suggests associations between PA and potential risks for development of polycystic ovary syndrome and adult diseases such as the metabolic syndrome. Adrenarche refers to the increased secretion of the adrenal androgen precursors DHEA, DHEAS, and androstenedione, which normally occurs in children at age 6-8 years. PA may be identified clinically by early pubarche, which is defined as the development of pubic or axillary hair before 8 years in girls or 9 years in boys. This paper will consider adrenal steroidogenesis, genetic markers, neurobiological changes, skeletal maturation, and associations with adult disorders. The differential diagnosis will be reviewed because PA remains a diagnosis of exclusion. Finally, synthesis of current knowledge regarding PA, suggestions for evaluation, management, and treatment are offered.

A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius.

Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures, we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD (aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P < 5 × 10(-6) for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10(-11), ß =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10(-8), ß = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex.

BMD Loci Contribute to Ethnic and Developmental Differences in Skeletal Fragility across Populations: Assessment of Evolutionary Selection Pressures.

Bone mineral density (BMD) is a highly heritable trait used both for the diagnosis of osteoporosis in adults and to assess bone health in children. Ethnic differences in BMD have been documented, with markedly higher levels in individuals of African descent, which partially explain disparity in osteoporosis risk across populations. To date, 63 independent genetic variants have been associated with BMD in adults of Northern-European ancestry. Here, we demonstrate that at least 61 of these variants are predictive of BMD early in life by studying their compound effect within two multiethnic pediatric cohorts. Furthermore, we show that within these cohorts and across populations worldwide the frequency of those alleles associated with increased BMD is systematically elevated in individuals of Sub-Saharan African ancestry. The amount of differentiation in the BMD genetic scores among Sub-Saharan and non-Sub-Saharan populations together with neutrality tests, suggest that these allelic differences are compatible with the hypothesis of selective pressures acting on the genetic determinants of BMD. These findings constitute an explorative contribution to the role of selection on ethnic BMD differences and likely a new example of polygenic adaptation acting on a human trait.

Childhood acromegaly due to X-linked acrogigantism: long term follow-up.

PURPOSE: Acromegaly in infancy is extremely rare. We describe a 32 year old woman who presented at 6 months of age with isolated macrocephaly, followed by accelerated linear growth. At 21 months of age, her head circumference was 55 cm (+5.5 SD), height was 97.6 cm (+4.4 SD) and weight was 20.6 kg (+6.2 SD). She had markedly elevated levels of growth hormone (GH) (135 ng/ml), IGF-1 (1540 ng/ml) and prolactin (370 ng/ml). A pituitary macroadenoma was surgically resected. Immunohistochemical staining was positive for GH. Post-operatively, she developed ACTH and TSH deficiency and diabetes insipidus. METHODS: Long term clinical follow-up and genetic testing with chromosomal microarray analysis. RESULTS: Despite GH deficiency, she grew well until 7 ½ years old, with subsequent decline in growth velocity, and received GH therapy for 5 years. Puberty was initiated with estrogen therapy. As an adult, she has no stigmata of acromegaly, with a height of 164.5 cm and non-acromegalic features. IGF-1 has remained in the low normal range. Prolactin has been mildly elevated. Serial MRIs have shown no evidence of tumor recurrence. She receives replacement therapy with hydrocortisone, levothyroxine and DDAVP. Chromosomal microarray analysis revealed that she has X-linked acrogigantism (X-LAG) due to a de novo duplication of Xq26.3 (516 kb). She recently became pregnant following ovarian stimulation and chorionic villus sampling revealed that she is carrying a male with the same duplication. CONCLUSION: This report provides detailed long term clinical follow-up of a patient with X-LAG syndrome.

Gestational weight gain and obesity, adiposity and body size in African-American and Dominican children in the Bronx and Northern Manhattan.

Gestational weight gain (GWG) is potentially modifiable and is associated with infant size and body composition; however, long-term effects on childhood obesity have not been reported among multi-ethnic urban populations. We examined the association between GWG and child anthropometric measures and body composition at 7 years [waist circumference (WC), body mass index z-score (BMIZ), obesity (BMIZ ≥95%ile) and bioelectrical impedance analysis estimates of percentage body fat (%fat)] in African-American and Dominican dyads (n = 323) in the Columbia Center for Children's Environmental Health prospective birth cohort study from 1998 to 2013. Linear and logistic regression evaluated associations between excessive GWG [>Institute of Medicine (IOM) 2009 guidelines] and outcomes, adjusting for pre-pregnancy BMI and covariates. Pre-pregnancy BMI (mean ± standard deviation, all such values) and total GWG were 25.8 ± 6.2 kg m(-2) (45% overweight/obese) and 16.4 ± 7.9 kg (64% > IOM guidelines), respectively. Excessive GWG was associated with higher BMIZ {0.44 [95% confidence interval (CI): 0.2, 0.7], P < 0.001}, WC [ß: 2.9 cm (95% CI: 1.1, 4.6), P = 0.002], %fat at 7 years [ß: 2.2% (95% CI: 1.0, 3.5), P = 0.001)] and obesity [odds ratio: 2.93 (95% CI: 1.5, 5.8), P = 0.002]. Pre-pregnancy BMI was positively associated with child size, adiposity and obesity (all P < 0.05). Excessive GWG was highly prevalent and was associated with child obesity, greater percentage body fat and abdominal adiposity. Strategies to support healthy GWG are warranted to promote healthy growth and prevent childhood obesity.

Postpartum Obesity Is Associated With Increases in Child Adiposity in Midchildhood in a Cohort of Black and Dominican Youth.

Background: Obesity disproportionately affects marginalized and low-income populations. Birth parent obesity from the prenatal period and childhood has been associated with child obesity. It is unknown whether prenatal or postnatal birth parent obesity has differential effects on subsequent changes in adiposity and metabolic health in children. Objectives: We evaluated how birth parent obesity 7 y after delivery was associated with child body composition changes and cardiometabolic health in midchildhood and further assessed the influence of the perinatal and postpartum period on associations. Methods: Black and Dominican pregnant individuals were enrolled, and dyads (n = 319) were followed up at child age 7 and 9 y. Measures included, height, weight, waist circumference (WC), and percent body fat (BF%). Multiple linear regression was used to relate postpartum weight status with child outcomes accounting for attrition, and a series of secondary analyses were conducted with additional adjustment for perinatal weight status, gestational weight gain (GWG), and/or long-term weight retention to evaluate how these factors influenced associations. Results: Almost one-quarter (23%) of birth parents and 24.1% children were classified with obesity at child age 7 y, while at 9 y, 30% of children had obesity. Birth parent obesity at child age 7 y was associated with greater changes, from ages 7 to 9 y, in child BMI z-score (ß: 0.13; 95% CI: 0.02, 0.24) and BF% (ß: 1.15; 95% CI: 0.22, 2.09) but not obesity at age 9 y. All observed associations crossed the null after additional adjustment for prenatal factors. Conclusions: Birth parent obesity at 7-y postpartum is associated with greater gains in child BMI z-score and BF% in midchildhood. These associations diminish after accounting for prenatal size, suggesting a lasting impact of the perinatal environment and that interventions supporting families from the prenatal period through childhood are needed.