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JAMA Network Open Oct 2020There has been a worldwide secular trend toward earlier onset of puberty in the general population. However, it remains uncertain if these changes are paralleled with... (Comparative Study)
Comparative Study
IMPORTANCE
There has been a worldwide secular trend toward earlier onset of puberty in the general population. However, it remains uncertain if these changes are paralleled with increased incidence of central precocious puberty (CPP) and normal variant puberty (ie, premature thelarche [PT] and premature adrenarche [PA]) because epidemiological evidence on the time trends in the incidence of these puberty disorders is scarce.
OBJECTIVE
To provide valid epidemiological data on the 20-year secular trend in the incidence rates of CPP and normal variant puberty.
DESIGN, SETTING, AND PARTICIPANTS
This population-based, 20-year cohort study used national registry data for all youth in Denmark registered with an incident diagnosis of CPP, PT, or PA in the Danish National Patient Registry from 1998 to 2017 (N = 8596) using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). We applied the maximum diagnostic age limit for precocious puberty (ie, onset of puberty before age 8 years for girls and age 9 years for boys) with and without a 12-month lag to address time from first contact to final registration in the Danish National Patient Registry. Data analysis was conducted in 2019.
EXPOSURES
Diagnosis of CPP, PT, or PA.
MAIN OUTCOMES AND MEASURES
The age-specific and sex-specific incidence rates of first-time diagnosis of CPP, PT, and PA were estimated using data from the Danish National Patient Registry from 1998 to 2017, and information about the total number of children at risk within the same age groups and sex from Statistics Denmark. Incidences were stratified according to immigration group (Danish origin, first-generation immigrant, second-generation immigrant).
RESULTS
Overall a total 8596 children (7770 [90.4%] girls; median [interquartile] age at diagnosis for boys, 8.0 [7.1-9.0] years; for girls, 8.0 [7.6-8.5] years) were registered with an incident diagnosis of CPP, PT, or PA, of whom 7391 (86.0%) had Danish origin (6671 [90.3%] girls), corresponding to 370 new cases in children with Danish origin per year. The 20-year mean annual incidence rates of CPP, PT, PA, and all 3 conditions per 10 000 girls with Danish origin were 9.2 (95% CI, 8.0 to 10.3), 1.1 (95% CI, 0.7 to 1.5), 1.3 (95% CI, 0.9 to 1.7), and 11.5 (95% CI, 10.3 to 12.8), respectively. For boys with Danish origin, the 20-year mean annual incidence rates per 10 000 boys were lower: 0.9 (95% CI, 0.6 to 1.2), 0.2 (95% CI, 0.1 to 0.4), and 1.1 (95% CI, 0.7 to 1.4) for CPP, PA, and the sum, respectively. There was a 6-fold increase in incidence for girls with Danish origin (from 2.6 per 10 000 to 14.6 per 10 000) and a 15-fold increase for boys with Danish origin (from 0.1 per 10 000 to 2.1 per 10 000). The 20-year mean incidence of CPP and PA among girls in the first-generation and second-generation immigrant groups were greater than that of girls with Danish origin. The incidence rate for CPP per 10 000 girls in the first-generation and second-generation groups were 13.7 (95% CI, 9.3 to 18.2) and 14.2 (95% CI, 4.6 to 23.9), respectively; the incidence rate for PA per 10 000 girls in the first-generation and second-generation groups were 2.0 (95% CI, 0.3 to 3.6) and 1.5 (95% CI, -1.6 to 4.7), respectively. No differences associated with immigration status were observed among boys.
CONCLUSIONS AND RELEVANCE
Our findings suggest that the annual incidence of CPP and normal variant puberty has substantially increased in Denmark during the last 20 years. These findings have implications for short-term and long-term health and potentially for the international classification of the reference age of puberty.
Topics: Adolescent; Age Factors; Child; Cohort Studies; Denmark; Female; Humans; Incidence; Male; Puberty; Puberty, Precocious
PubMed: 33044548
DOI: 10.1001/jamanetworkopen.2020.15665 -
AACE Clinical Case Reports 2019Prader-Willi syndrome (PWS) is a rare genetic neuroendocrine disorder characterized by hypotonia, obesity, short stature, and mental retardation. Incomplete or delayed...
OBJECTIVE
Prader-Willi syndrome (PWS) is a rare genetic neuroendocrine disorder characterized by hypotonia, obesity, short stature, and mental retardation. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty is rarely seen.
METHODS
This study reports the clinical, biochemical, and histologic findings in 2 boys with PWS who developed central precocious puberty.
RESULTS
Both boys were started on growth hormone therapy during the first years of life according to the PWS indication. They had both bilateral cryptorchidism at birth and had orchidopexy in early childhood. Retrospective histologic analysis of testicular biopsies demonstrated largely normal tissue architecture and germ cell maturation, but severely decreased number of prespermatogonia in one of the patients. Both boys had premature adrenarche around the age of 6. Precocious puberty was diagnosed in both boys with enlargement of testicular volume (>3 mL), signs of virilization and a pubertal response to a gonadotropin-releasing hormone (GnRH) test and they were both treated with GnRH analog.
CONCLUSION
The cases described here displayed typical characteristics for PWS, a considerable heterogeneity of the hypothalamic-pituitary function, as well as testicular histology. Central precocious puberty is extremely rare in PWS boys, but growth hormone treatment may play a role in the pubertal timing.
PubMed: 31967069
DOI: 10.4158/ACCR-2019-0245 -
Clinical Endocrinology Jun 2024Children with Prader-Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS.
OBJECTIVES
Children with Prader-Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS.
DESIGN, PATIENTS AND MEASUREMENTS
A chart review of children with PWS treated at our institution between 1990 and 2021 was performed. PP was defined as Tanner stage 2 (TS2) pubic hair in girls <8 and boys <9 years old. Demographic, anthropometric, and laboratory data were collected to assess predisposing factors and consequences of PP in comparison to patients with PWS who had normal pubarche (NP).
RESULTS
Analysis included 43 children with PWS, 23 (53.5%) with PP and 20 (46.5%) with NP. Median age at pubarche was 7.0 years in PP group and 10.0 years in NP group. Age at pubarche was not correlated with age of recombinant human growth hormone (rhGH) initiation, body mass index (BMI) z-score, or homeostasis model assessment of insulin resistance (HOMA-IR) at pubarche. BMI z-score at pubarche was modestly correlated with degree of pubarchal BA advancement (p = 0.033). Those with PP were more likely to have a lower high-density lipoprotein (HDL) (1.05 mmol/L vs. 1.41 mmol/L in the NP group, p = 0.041). The difference between target and final height did not differ between groups (p = 0.507).
CONCLUSION
PP is common in PWS but does not compromise final height in comparison to the NP group. Obesity and insulin resistance were not associated with PP in children with PWS, contrary to what has been seen in obese children without PWS.
PubMed: 38935853
DOI: 10.1111/cen.15108 -
Journal of Chromatography. B,... Apr 2023The measurement of dehydroepiandrosterone-sulphate (DHEAs) is an important second-line test to aid in the diagnosis of premature adrenarche, peripubertal gynaecomastia...
A liquid chromatography-tandem mass spectrometry method for the analysis of dehydroepiandrosterone sulphate (DHEAs) in serum and plasma with comparison to an immunoassay method in a neonatal population.
The measurement of dehydroepiandrosterone-sulphate (DHEAs) is an important second-line test to aid in the diagnosis of premature adrenarche, peripubertal gynaecomastia in males and in identifying the source of elevated androgens in females. Historically, DHEAs has been measured by immunoassay platforms which are prone to poor sensitivity and more importantly poor specificity. The aim was to develop an LC-MSMS method for the measurement of DHEAs in human plasma and serum, develop an in-house paediatric (<6 year old) reference limit and compare the performance against the Abbott Alinity DHEAs immunoassay method. Following pre-treatment with an internal standard, samples were loaded onto EVOLUTE® EXPRESS ABN plate. Analytes were separated with reverse-phase chromatography using ACQUITY® UPLC® HSS T3 2.1 mm × 50 mm, 1.8 μm column. Mass spectrometry detection was performed using a Waters® Xevo TQ-XS in electrospray negative mode. For the paediatric reference range, samples were collected from an inpatient setting (age ≤ 6 years old) with no evidence of adrenal dysfunction or history of/current steroid use. The method comparison was performed using samples from this cohort aged between 0 and 52 weeks. The assay demonstrated linearity up to 15 µmol/L (r > 0.99) with a functional sensitivity of 0.1 µmol/L. Accuracy results revealed a mean bias of 0.7% (-14% to 15%) when compared against the NEQAS EQA LC-MSMS consensus mean (n = 48). The paediatric reference limit was calculated as ≤ 2.3 µmol/L (95% C.I. 1.4 to 3.8 µmol/L) for ≤ 6 year olds (n = 38). Comparison of neonatal (<52 weeks) DHEAs with the Abbott Alinity revealed that the immunoassay ran at a 166% positive bias (n = 24) which appeared to lessen with increasing age. Described is a robust LC-MSMS method for the measurement of plasma or serum DHEAs validated against internationally recognised protocols. Comparison of paediatric samples of <52 weeks against an immunoassay platform demonstrated that in the immediate new-born period results generated from the LC-MSMS method offer superior specificity than an immunoassay platform.
Topics: Male; Infant, Newborn; Female; Humans; Child; Infant; Dehydroepiandrosterone Sulfate; Tandem Mass Spectrometry; Chromatography, Liquid; Plasma; Immunoassay
PubMed: 36906955
DOI: 10.1016/j.jchromb.2023.123615 -
Journal of Clinical Research in... Jun 2020Loss-of-function mutations of are an X-linked cause of central hypothyroidism (CeH) and hypoprolactinemia. A boy who is now 15.2 years old presented at the age of 7.69...
Loss-of-function mutations of are an X-linked cause of central hypothyroidism (CeH) and hypoprolactinemia. A boy who is now 15.2 years old presented at the age of 7.69 years for evaluation of obesity. Previous thyroid function evaluation suggested CeH [FT4 0.6 ng/mL, thyroid-stimulating hormone (TSH) 2.2 mIU/L] but his physician took no action. At presentation he was clinically and biochemically euthyroid, prepubertal and obese. Serum prolactin (PRL) was undetectable. Biochemistry was normal except for mild hypercholesterolemia, total cholesterol 198 mg/dL. Subsequently FT4 and TSH levels fluctuated between 0.72-0.95 ng/dL (normal 0.8-2.0) and 1.94-5.77 mIU/L (normal 0.3-5.0), respectively. Sequencing of gene revealed a novel genetic change c.3805C>T in exon 19; substitution of amino acid Arginine at position 1269 with a premature «stop» codon resulting in an altered protein product. The patient additionally presented delayed adrenarche, low height velocity that resolved spontaneously and normal pubertal onset associated with increased FSH levels. At 14 years-of-age, while the patient was at Tanner stage 4, PRL levels became detectable, rising gradually to 2.3 ng/mL at last examination. Thyroxine replacement therapy resulted in decrease in total cholesterol 103 mg/dL. A high index of suspicion for the disorder is needed since several measurements of thyroid function may be required for CeH to be disclosed. The patient’s normal FT4 levels and normal intelligence would have resulted in a missed diagnosis if the serum PRL levels had not been measured. This case highlights the importance of measuring PRL in a boy with low normal FT4 and normal TSH levels.
Topics: Adolescent; Humans; Hypothyroidism; Immunoglobulins; Male; Membrane Proteins; Prolactin
PubMed: 31448769
DOI: 10.4274/jcrpe.galenos.2019.2019.0085 -
Journal of Pediatric Genetics Mar 2020Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency...
Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency of the and genes. Cornelia de Lange's syndrome (CdLS) is a genetically heterogeneous dysmorphic syndrome where heterozygous mutations of gene have been associated with a mild clinical presentation (CDLS type 4; MIM: 614701). We report a female patient with a 2.3-Mb interstitial deletion at 8q23.3-q24.1 encompassing and genes but not . Clinical findings in this patient are correlated with a mixed phenotype of LGS and CdLS type 4.
PubMed: 31976145
DOI: 10.1055/s-0039-1694779