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EClinicalMedicine Dec 2021Extremely tall children (defined as height SDS (HSDS) ≥+3) are frequently referred to specialized healthcare for diagnostic work-up. However, no systematic studies...
BACKGROUND
Extremely tall children (defined as height SDS (HSDS) ≥+3) are frequently referred to specialized healthcare for diagnostic work-up. However, no systematic studies focusing on such children currently exist. We investigated the aetiology, clinical features, and auxological clues indicative of syndromic tall stature in extremely tall children subject to population-wide growth monitoring and screening rules.
METHODS
Subjects with HSDS ≥+3 after three years of age born between 1990 and 2010 were identified from the Helsinki University Hospital district growth database. We comprehensively reviewed their medical records up to December 2020 and recorded underlying diagnoses, auxological data, and clinical features.
FINDINGS
We identified 424 subjects (214 girls and 210 boys) who fulfilled the inclusion criteria. Underlying growth disorder was diagnosed in 61 (14%) patients, in 36 (17%) girls and 25 (12%) boys, respectively (P=0•15). Secondary causes were diagnosed in 42 (10%) patients and the two most frequent secondary diagnoses, premature adrenarche, and central precocious puberty were more frequent in girls. Primary disorder, mainly Marfan or Sotos syndrome, was diagnosed in 19 (4%) patients. Molecular genetic studies were used as a part of diagnostic work-up in 120 subjects. However, array CGH or next-generation sequencing studies were seldom used. Idiopathic tall stature (ITS) was diagnosed in 363 (86%) subjects, and it was considered familial in two-thirds. Dysmorphic features or a neurodevelopmental disorder were recorded in 104 (29%) children with ITS. The probability of a monogenic primary growth disorder increased with the degree of tall stature and deviation from target height.
INTERPRETATION
A considerable proportion of extremely tall children have an underlying primary or secondary growth disorder, and their risk is associated with auxological parameters. Clinical features related to syndromic tall stature were surprisingly frequent in subjects with ITS, supporting the view that syndromic growth disorders with mild phenotypes may be underdiagnosed in extremely tall children. Our results lend support to comprehensive diagnostic work-up of extremely tall children.
FUNDING
Päivikki and Sakari Sohlberg Foundation, Foundation for Pediatric Research, and Helsinki University Hospital research grants.
PubMed: 34849478
DOI: 10.1016/j.eclinm.2021.101208 -
Journal of the Endocrine Society Mar 2023Premature adrenarche (PA) may predispose to some adverse long-term health outcomes. Cardiorespiratory fitness (CRF) is one of the strongest factors known to predict...
CONTEXT
Premature adrenarche (PA) may predispose to some adverse long-term health outcomes. Cardiorespiratory fitness (CRF) is one of the strongest factors known to predict overall health, but no data exist on the CRF of women with a history of PA.
OBJECTIVE
To study if hyperandrogenism in childhood resulting from PA leads to a measurable difference in CRF between young adult PA and control women.
METHODS
A total of 25 women with PA and 36 age-matched controls were followed from prepubertal age until adulthood. Anthropometric measurements, body composition, biochemical, and lifestyle factors were assessed. The main outcome measure was maximal cycle ergometer test result at the mean age of 18.5 years. We also assessed prepubertal predicting factors for CRF with different linear regression models.
RESULTS
Though prepubertal children with PA were taller and heavier than their non-PA peers, there were no significant differences in height, body mass index, body composition, or physical activity in young adulthood. We observed no significant differences in any of the parameters of the maximal cycle ergometer test, including maximal load ( = .194) or peak oxygen consumption ( = .340). Hemodynamic responses of the groups were similar. None of the examined models or prepubertal factors significantly predicted CRF at adult age.
CONCLUSION
This study suggests that hyperandrogenism in childhood/adolescence resulting from PA does not have a significant impact on adulthood CRF.
PubMed: 37077523
DOI: 10.1210/jendso/bvad041 -
Congenital adrenal hyperplasia caused by compound heterozygosity of two novel CYP11B1 gene variants.Hormones (Athens, Greece) Mar 2022Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by pathogenic variants in seven genes involved in the cortisol and aldosterone... (Review)
Review
BACKGROUND
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by pathogenic variants in seven genes involved in the cortisol and aldosterone biosynthetic pathway. The second most common cause, 11β-hydroxylase deficiency (11βOHD), is attributed to pathogenic variants in the CYP11B1 gene encoding for the enzyme 11β-hydroxylase (11βOH).
CASE PRESENTATION
A 13-year-old girl was referred to the pediatric endocrinologist due to a syncopal episode. She is the third child of non-consanguineous parents. She presented with premature adrenarche at the age of 6 years and menarche at the age of 12 years. On physical examination, her height was 154.5 cm and weight 50 kg, while she presented with acne, hirsutism, clitoromegaly, and normal blood pressure. Laboratory investigation revealed increased androgen levels and poor cortisol response to the ACTH stimulation test. From the family history, the mother was diagnosed with CAH at the age of 10 years and was under treatment with methylprednisolone. Previous molecular investigation of the CYP21A2 gene was negative. Due to the increased androstenedione levels in the index patient, the suspicion of 11βOH was raised, and she was investigated for 11-deoxycortisol, 11-deoxycorticosterone, and CYP11B1 gene pathogenic variants. The patient and her mother were found to be compound heterozygous for two novel variants of the CYP11B1 gene.
CONCLUSION
We present a case of CAH due to compound heterozygosity of two novel pathogenic variants of the CYP11B1 gene, emphasizing the importance of molecular investigation in order to confirm clinical diagnosis and allow proper genetic counseling of the family.
Topics: Adolescent; Adrenal Hyperplasia, Congenital; Aldosterone; Child; Female; Humans; Hydrocortisone; Mutation; Steroid 11-beta-Hydroxylase; Steroid 21-Hydroxylase
PubMed: 34697763
DOI: 10.1007/s42000-021-00322-1 -
Journal of Ovarian Research Nov 2023Existing studies have investigated the relationship between the levels of serum inhibin B (INHB), anti-müllerian hormone (AMH) and precocious puberty in girls, but the... (Meta-Analysis)
Meta-Analysis
BACKGROUNDS
Existing studies have investigated the relationship between the levels of serum inhibin B (INHB), anti-müllerian hormone (AMH) and precocious puberty in girls, but the results are inconsistent.
OBJECTIVE
The aim of this meta-analysis was to assess whether the INHB and AMH levels changed in girls with precocious puberty relative to healthy controls.
METHODS
PubMed, Embase, Cochrane Library and Web of Science were searched through June 2022. We included observational clinical studies reporting the serum levels INHB and AMH in girls with precocious puberty. Conference articles and observational study abstracts were included if they contained enough information regarding study design and outcome data. Case series and reports were excluded. An overall standard mean difference (SMD) between precocious puberty and healthy controls was estimated using a DerSimonian-Laird random-effects model.
RESULTS
A total of 11 studies featuring 552 girls with precocious puberty and 405 healthy girls were selected for analysis. The meta-analysis showed that the INHB level of precocious puberty [including central precocious puberty (CPP) and premature the larche (PT)] were significantly increased. While there was no significant association between precocious puberty [including CPP, PT, premature pubarche (PP) and premature adrenarche (PA)] and the level of serum AMH.
CONCLUSION
Scientific evidence suggested that the INHB level, but not the AMH level, altered in girls with precocious puberty compared with healthy controls. Through our results we think that INHB level might be a marker for the auxiliary diagnosis of precocious puberty (especially CPP and PT). Therefore, it is important to evaluate and thoroughly investigate the clinical indicators (e.g., INHB) in order to ensure early diagnosis and medical intervention, and the risk of physical, psychological and social disorders in immature girls with precocious puberty is minimized.
Topics: Female; Humans; Anti-Mullerian Hormone; Follicle Stimulating Hormone; Inhibins; Observational Studies as Topic; Puberty, Precocious
PubMed: 37996919
DOI: 10.1186/s13048-023-01302-2 -
Practical Laboratory Medicine Aug 2022Androstenedione (ASD) is a biomarker used in the diagnostic workup of hyperandrogenism, congenital adrenal hyperplasia, premature adrenarche, and polycystic ovary...
UNLABELLED
Androstenedione (ASD) is a biomarker used in the diagnostic workup of hyperandrogenism, congenital adrenal hyperplasia, premature adrenarche, and polycystic ovary syndrome (PCOS). The Elecsys ASD competitive electrochemiluminescence immunoassay (Roche Diagnostics, Indianapolis, IN) is a new assay recently available in the US.
OBJECTIVE
This study evaluated the analytical and clinical performance of the Elecsys ASD assay.
DESIGN & METHODS
We evaluated the linearity/analytical measuring range (AMR), precision, and accuracy of the Elecsys ASD assay on the cobas e601 analyzer. ASD was measured in serum/plasma in the Elecsys ASD, Immulite (Siemens Medical Solutions USA, Inc. Malvern, PA), and LC-MS/MS assays. Reference intervals (RI) were evaluated across genders, menopausal status, and in children. Statistical analysis was performed using EP evaluator and R program.
RESULTS
The Elecsys ASD assay had a linear response across the AMR. The intra- and inter-assay coefficients of variation at various concentrations were ≤4.5%. The Elecsys ASD assay had a mean difference of -0.04 ng/mL (-1.7%) with the LC-MS/MS assay, whereas the Immulite assay had a mean difference of 1.17 ng/mL (66%) and -1.22 ng/mL (-38%) compared to the LC-MS/MS and Elecsys ASD assays, respectively. The Roche recommended RIs for healthy men (0.280-1.52 ng/mL) and postmenopausal women (0.187-1.07 ng/mL) were successfully verified. The RIs for children were adopted from published data. For pre-menopausal women, a RI of <1.60 ng/mL was established. The ASD concentrations in women with and without PCOS overlapped.
CONCLUSIONS
The Elecsys ASD assay has superior comparability to the LC-MS/MS assay than the Immulite assay.
PubMed: 35620064
DOI: 10.1016/j.plabm.2022.e00279 -
Journal of the Endocrine Society Feb 2021
PubMed: 33381669
DOI: 10.1210/jendso/bvaa166 -
Hormone Research in Paediatrics 2021Central precocious puberty (CPP) in females is characterized by thelarche before 8 years of age. Evidence of reproductive axis activation confirms the diagnosis (basal...
BACKGROUND
Central precocious puberty (CPP) in females is characterized by thelarche before 8 years of age. Evidence of reproductive axis activation confirms the diagnosis (basal serum luteinizing hormone (LH) ≥0.3 IU/L or LH-releasing hormone (LHRH)-stimulated LH ≥5 IU/L). Stimulation testing is the diagnostic gold standard but is time-consuming and costly. Serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are increased in girls with CPP.
OBJECTIVE
The aim of the study was to assess the utility of serum IGF-1 and IGFBP-3 in identifying CPP in girls aged 6-8 years.
METHODS
The study was a single-center retrospective study. Girls with confirmed CPP (n = 44) and isolated premature precocious adrenarche/ precocious thelarche (PA/PT, n = 16) had baseline biochemical profiling and LHRH stimulation testing. Serum IGF-1 and IGFBP-3 results were converted to standard deviation scores (SDS). Correlations were calculated and receiver operating characteristic curves were plotted.
RESULTS
Girls with CPP had higher basal and peak LH, IGF-1 SDS, and growth velocity (p < 0.05). IGF-1 SDS correlated positively with basal and peak LH (p < 0.05). IGF-1 SDS (1.75-2.15) differentiated CPP and PA/PT with 89% sensitivity and 56% specificity (basal LH) and 94% specificity and 55% sensitivity (peak LH). IGFBP-3 SDS did not differ between groups or by CPP parameters.
CONCLUSIONS
In clinical practice, IGF-1 SDS may be an additional tool for identifying CPP in girls aged 6 to 8 years when baseline clinical and laboratory diagnostic criteria are inconclusive, possibly avoiding more time-consuming and costly procedures.
Topics: Child; Female; Follicle Stimulating Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Luteinizing Hormone; Puberty, Precocious; Retrospective Studies; Sensitivity and Specificity
PubMed: 34098553
DOI: 10.1159/000516361 -
The Journal of Adolescent Health :... May 2020This project investigated internal consistency and test-retest reliability of the frequently used Pubertal Development Scale (PDS) and compared parent and child reports...
PURPOSE
This project investigated internal consistency and test-retest reliability of the frequently used Pubertal Development Scale (PDS) and compared parent and child reports with clinician-rated Tanner staging.
METHODS
Using a repository of data collected from 1995 to 2016, 252 participants (aged 7.8-17.7 years) provided self- and parent-reported PDS and received Tanner staging by a certified health care professional within 30 days. Internal consistency and test-retest reliability statistics were evaluated for 56 children across two assessments occurring within 6 months. Comparisons with Tanner staging involved examining concurrent validity and calibration analysis using data from 233 child and 252 parental ratings.
RESULTS
Self- and parent-reported PDS demonstrated good internal consistency, with Cronbach's alpha .91-.96; high test-retest reliability was confirmed with intraclass correlation coefficient .81-.92. The association of Tanner stage with self- and parent-reported PDS was moderate to high; Kendall's Tau ranged from .67 to .76, and intraclass correlation coefficient ranged from .73 to 83. The absolute agreement of Tanner stage with self- and parent-reported PDS was low; Cohen's Kappa ranged from .20 to .37. However, combining pubertal scores into three stages of development (pre/early-, mid-, and late/post-pubertal) improved interrater agreement across measures (κ = .65, 95% confidence interval = .57-.73).
CONCLUSIONS
The present study shows that the PDS is reliable and generally tracks with Tanner staging (for both self and parent report). Low absolute agreement indicates that PDS categories do not map directly to specific Tanner stages, partly because a premature adrenarche is often misinterpreted by parents and pediatricians alike. However, three broad categories showed better agreement and are generally adequate for most applications in child and adolescent research.
Topics: Adolescent; Child; Family; Humans; Puberty; Reproducibility of Results; Surveys and Questionnaires
PubMed: 31974011
DOI: 10.1016/j.jadohealth.2019.11.308 -
Frontiers in Endocrinology 2022Wiedemann-Steiner Syndrome (WSS) is a genetic disorder associated with an array of clinical phenotypes, including advanced bone age and short stature....
CONTEXT
Wiedemann-Steiner Syndrome (WSS) is a genetic disorder associated with an array of clinical phenotypes, including advanced bone age and short stature. 11-ketotestosterone (11KT) is a member of the group known as 11-oxygenated C19 androgens that are implicated in premature adrenarche.
CASE DESCRIPTION
Case 1: The patient is a 3 year and 11-month-old female diagnosed with WSS due to deletion of detected on CGH microarray. At two years and 11 months, imaging revealed an advanced bone age. We obtained an 11KT level on this patient. 11KT in case 1 was elevated at 26.3 ng/dL, while the normal reference range is 7.3-10.9 ng/dL and the reference interval for premature adrenarche is 12.3-22.9 ng/dL, The repeat 11KT at follow up (chronological age 4 years and 6 months) was still elevated at 33.8 ng/dL Case 2: A second child with WSS and a 5kb intragenic deletion was evaluated at 11 months of age; his 11KT was 4.5 ng/dL.
CONCLUSIONS
The elevated 11KT may indicate maturational changes related to increasing adrenal gland androgenic activation and may explain the advanced bone age seen in some patients with WSS. To our knowledge, this is the first case report that describes 11KT as a bioactive androgen potentially causing bone age advancement in WSS. Lack of elevation of 11KT in the second child who is an infant suggests increasing androgenic precursors and metabolites related to premature adrenarche may need to be longitudinally followed.
Topics: Female; Humans; Androgens; Abnormalities, Multiple; Intellectual Disability
PubMed: 36263329
DOI: 10.3389/fendo.2022.1004114 -
Journal of Pediatric Endocrinology &... Jun 2023Premature adrenarche is often linked to a cluster of endocrine-metabolic risk factors. Our objective was to explore the association of dehydroepiandrosterone sulfate...
OBJECTIVES
Premature adrenarche is often linked to a cluster of endocrine-metabolic risk factors. Our objective was to explore the association of dehydroepiandrosterone sulfate (DHEAS) levels at age 7 with cardio-metabolic traits at ages 10 and 13, independently of adiposity and pubertal stage.
METHODS
Longitudinal study of 603 individuals (301 girls/302 boys) from the Generation XXI birth cohort. DHEAS at age 7 was measured by immunoassay. Anthropometrics, pubertal staging, blood pressure, and metabolic outcomes were evaluated at ages 7, 10, and 13. Pearson correlations between DHEAS and cardio-metabolic traits (insulin, HOMA-IR, triglycerides, LDL-cholesterol, high-sensitivity C-reactive protein, and systolic and diastolic blood pressure) were computed. Path analysis was used to estimate the effect of DHEAS at age 7 on cardiometabolic traits at ages 10 and 13, adjusted for body mass index (BMI) z-score and Tanner stage.
RESULTS
DHEAS at age 7 correlated positively with insulin and HOMA-IR at ages 7 and 10 in both sexes, and at age 13 in girls, but not in boys. In girls, DHEAS levels at age 7 directly influenced HOMA-IR at age 13, controlling for BMI and Tanner stage. In boys, DHEAS at age 7 did not influence HOMA-IR at ages 10 and 13. DHEAS at age 7 did not influence the other cardio-metabolic outcomes analyzed.
CONCLUSIONS
DHEAS levels in mid-childhood have a positive longitudinal association with on insulin-resistance that persists, in girls, but not in boys, at least until age 13. No association was found regarding dyslipidemia, hypertension, or low-grade inflammation.
Topics: Male; Female; Humans; Child; Adolescent; Dehydroepiandrosterone Sulfate; Longitudinal Studies; Birth Cohort; Insulin Resistance; Insulin; Body Mass Index
PubMed: 37141272
DOI: 10.1515/jpem-2022-0593