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BACKGROUND: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. METHODS: In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. FINDINGS: Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. INTERPRETATION: We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.

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Introducción. La pubertad se manifiesta inicialmente por la aparición de los caracteres sexuales secundarios, como consecuencia de cambios hormonales que progresivamente conducen a la madurez sexual completa. En Argentina y el mundo, la pandemia ocasionada por el coronavirus SARS-CoV-2 generó un confinamiento que pudo haber interferido en el inicio y tempo del desarrollo puberal. Objetivo. Describir la percepción de los endocrinólogos pediatras del país sobre las consultas por sospecha de pubertad precoz y/o pubertad de rápida progresión durante la pandemia. Materiales y métodos. Estudio descriptivo, observacional, transversal. Encuesta anónima a endocrinólogos pediatras pertenecientes a la Sociedad Argentina de Pediatría y/o a la Asociación de Endocrinología Pediátrica Argentina, en diciembre de 2021. Resultados. Respondieron la encuesta 83 de 144 endocrinólogos pediátricos (tasa de respuesta 58 %). Todos consideraron que aumentó la consulta por desarrollo precoz o temprano, ya sea en sus variantes telarca precoz (84 %), pubarca precoz (26 %) y/o pubertad precoz (95 %). El 99 % acuerda con que se ha dado en mayor medida en niñas. La totalidad de los encuestados también considera que aumentó el diagnóstico de pubertad precoz central. El 96,4 % considera que ha aumentado el número de pacientes tratados con análogos de GnRH. Conclusión. Nuestros resultados sobre la percepción de endocrinólogos pediatras coinciden con datos publicados en otras regiones sobre el aumento del diagnóstico de pubertad precoz durante la pandemia por COVID-19. Se reafirma la necesidad de generar registros nacionales de pubertad precoz central, difundir las evidencias para su detección y abordaje oportuno.

Introduction. Puberty is manifested initially by the onset of secondary sexual characteristics as a result of hormonal changes that progressively lead to complete sexual maturity. In Argentina and worldwide, the lockdown resulting from the SARS-CoV-2 pandemic may have interfered in the onset and timing of pubertal development. Objective. To describe the perception of pediatric endocrinologists in Argentina regarding consultations for suspected precocious and/or rapidly progressive puberty during the pandemic. Materials and methods. Descriptive, observational, cross-sectional study. Anonymous survey among pediatric endocrinologists members of the Sociedad Argentina de Pediatría and/or the Asociación de Endocrinología Pediátrica Argentina administered in December 2021. Results. Out of 144 pediatric endocrinologists, 83 completed the survey (rate of response: 58%). All of them considered that consultation for precocious or early puberty increased, either in terms of early thelarche (84%), early pubarche (26%), and/or precocious puberty (95%). Ninety-nine percent agreed that this has occurred to a greater extent in girls. All survey respondents also consider that the diagnosis of central precocious puberty has increased. In total, 96.4% of respondents consider that the number of patients treated with GnRH analogs has increased. Conclusion. Our results about the perception of pediatric endocrinologists are consistent with data published in other regions on the increase in the diagnosis of precocious puberty during the COVID-19 pandemic. We underscore the need to develop national registries of central precocious puberty, and to disseminate the evidence for a timely detection and management

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Introducción. Durante la pandemia por COVID-19, observamos un aumento de consultas por pubertad precoz (PP). Nuestro objetivo fue determinar la frecuencia de PP y su progresión antes y durante la pandemia. Métodos. Estudio retrospectivo, observacional y analítico. Se evaluaron las historias clínicas de los pacientes que consultaron en Endocrinología Infantil entre abril de 2018 y marzo de 2021. Se analizaron las consultas por sospecha de PP durante la pandemia (período 3) y se compararon con 2 años previos (períodos 1 y 2). Se recolectaron datos clínicos y estudios complementarios de la evaluación inicial y su progresión. Resultados. Se analizaron 5151 consultas. Se observó un aumento de consultas por sospecha de PP durante el período 3 (21 % vs.10 % y 11 %, p <0,001). Los pacientes que consultaron por sospecha de PP durante el período 3 aumentaron 2,3 veces (80 vs. 29 y 31, p <0,001). El 95 % fueron niñas; esa población fue analizada. Se incluyeron 132 pacientes que fueron similares en edad, peso, talla, edad ósea y determinaciones hormonales en los 3 períodos. En el período 3, se observó un menor índice de masa corporal, mayor porcentaje de estadio mamario Tanner 3-4 y mayor longitud uterina. Se indicó tratamiento al diagnóstico en el 26 % de los casos. En el resto, se controló su evolución. Durante el seguimiento, se observó una evolución rápidamente progresiva con mayor frecuencia durante el período 3 (47 % vs. 8 % vs. 13 %; p: 0,02). Conclusiones. Evidenciamos un aumento de la PP y una evolución rápidamente progresiva en niñas durante la pandemia.

Introduction. During the COVID-19 pandemic, an increase in consultations for precocious puberty (PP) was observed. Our objective was to determine the frequency of PP and its progression before and during the pandemic. Methods. Retrospective, observational, analytical study. The medical records of patients who consulted with the Department of Pediatric Endocrinology between April 2018 and March 2021 were assessed. Consultations for suspected PP during the pandemic (period 3) were analyzed and compared to the 2 previous years (periods 1 and 2). Clinical data and ancillary tests done in the initial assessment and PP progression information were collected. Results. Data from 5151 consultations were analyzed. An increase in consultations for suspected PP was observed during period 3 (21% versus 10% and 11%, p < 0.001). Patients who consulted for suspected PP during period 3 increased 2.3-fold (80 versus 29 and 31, p < 0.001). In total, 95% were female; this was the population analyzed. We included 132 patients with similar age, weight, height, bone age, and hormonal characteristics in the 3 periods. During period 3, a lower body mass index, a higher percentage of Tanner breast stage 3­4, and a greater uterine length were observed. Treatment was indicated upon diagnosis in 26% of the cases. In the rest, their evolution was monitored. During follow-up, a rapidly progressive course was observed more frequently in period 3 (47% versus 8% versus 13%, p: 0.02). Conclusions. We observed an increase in PP and a rapidly progressive evolution in girls during the pandemic.

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Introducción. Desde inicios de la pandemia por coronavirus 2019 (COVID-19), fue comunicado en varios países un incremento de las consultas de niñas con pubertad precoz central idiopática (PPCI), sin que contáramos con datos argentinos. Este aumento estaría vinculado con los cambios en el estilo de vida y los niveles de estrés resultantes del aislamiento que afectó particularmente a la población infantil. Objetivos. 1) Describir la evolución de la incidencia de PPCI con requerimiento de inhibición del eje hipotálamo-hipófiso-gonadal (EHHG) en niñas entre 2010 y 2021 en una cohorte del Área Metropolitana de Buenos Aires. 2) Comparar las características de las niñas, con dicho diagnóstico realizado durante la pandemia, con las de un grupo control. Métodos. Serie de tiempo interrumpida y estudio de casos y controles. Resultados. La incidencia anual fue estable entre 2010 y 2017. Desde 2017 hubo un ascenso anual que promedió el 59,9 % (IC95 % 18,6-115,5) y pareciera haberse acelerado durante la pandemia. Constatamos asociación entre haber desarrollado PPCI y haber requerido tratamiento inhibitorio entre el 01 de junio de 2020 y el 31 de mayo de 2021, y dos variables: edad de menarca materna (OR 0,46; IC95 % 0,28-0,77) y antecedente familiar de PPCI (OR 4,42; IC95 % 1,16-16,86). Conclusión. Evidenciamos desde 2017 un aumento significativo en la incidencia de PPCI con requerimiento de inhibición del EHHG. El incremento en la exposición a diversos desencadenantes ambientales durante la pandemia por COVID-19 podría haber ejercido mayor influencia en las niñas con alguna predisposición genética.

Introduction. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, consultations of girls with idiopathic central precocious puberty (ICPP) increased in several countries, but there were no data from Argentina. This increase may be related to changes in lifestyle and stress levels resulting from the lockdown, which particularly affected the child population. Objectives. 1) To describe the progression of the incidence of ICPP requiring inhibition of the hypothalamic- pituitary-gonadal (HPG) axis in girls between 2010 and 2021 in a cohort from the Metropolitan Area of Buenos Aires. 2) To compare the characteristics of girls diagnosed with ICPP during the pandemic with those of a control group. Methods. Interrupted time-series and case-control study. Results. The annual incidence remained stable between 2010 and 2017. Since 2017, it increased to an average of 59.9% (95% CI: 18.6­115.5) and appears to have accelerated during the pandemic. We found an association between ICPP and requiring inhibitory treatment between June 1 st, 2020 andMay 31 st, 2021 and 2 variables: maternal age at menarche (OR: 0.46, 95% CI: 0.28­0.77) and family history of ICPP (OR: 4.42, 95% CI: 1.16­16.86). Conclusion. We evidenced a significant increase in the incidence of ICPP with requirement of HPG axis inhibition since 2017. Increased exposure to various environmental triggers during the COVID-19 pandemic may have had a greater influence in girls with some genetic predisposition.

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Introduction. Puberty is manifested initially by the onset of secondary sexual characteristics as a result of hormonal changes that progressively lead to complete sexual maturity. In Argentina and worldwide, the lockdown resulting from the SARS-CoV-2 pandemic may have interfered in the onset and timing of pubertal development. Objective. To describe the perception of pediatric endocrinologists in Argentina regarding consultations for suspected precocious and/or rapidly progressive puberty during the pandemic. Materials and methods. Descriptive, observational, cross-sectional study. Anonymous survey among pediatric endocrinologists members of the Sociedad Argentina de Pediatría and/or the Asociación de Endocrinología Pediátrica Argentina administered in December 2021. Results. Out of 144 pediatric endocrinologists, 83 completed the survey (rate of response: 58%). All of them considered that consultation for precocious or early puberty increased, either in terms of early thelarche (84%), early pubarche (26%), and/or precocious puberty (95%). Ninety-nine percent agreed that this has occurred to a greater extent in girls. All survey respondents also consider that the diagnosis of central precocious puberty has increased. In total, 96.4% of respondents consider that the number of patients treated with GnRH analogs has increased. Conclusion. Our results about the perception of pediatric endocrinologists are consistent with data published in other regions on the increase in the diagnosis of precocious puberty during the COVID-19 pandemic. We underscore the need to develop national registries of central precocious puberty, and to disseminate the evidence for a timely detection and management.

Introducción. La pubertad se manifiesta inicialmente por la aparición de los caracteres sexuales secundarios, como consecuencia de cambios hormonales que progresivamente conducen a la madurez sexual completa. En Argentina y el mundo, la pandemia ocasionada por el coronavirus SARS-CoV-2 generó un confinamiento que pudo haber interferido en el inicio y tempo del desarrollo puberal. Objetivo. Describir la percepción de los endocrinólogos pediatras del país sobre las consultas por sospecha de pubertad precoz y/o pubertad de rápida progresión durante la pandemia. Materiales y métodos. Estudio descriptivo, observacional, transversal. Encuesta anónima a endocrinólogos pediatras pertenecientes a la Sociedad Argentina de Pediatría y/o a la Asociación de Endocrinología Pediátrica Argentina, en diciembre de 2021. Resultados. Respondieron la encuesta 83 de 144 endocrinólogos pediátricos (tasa de respuesta 58 %). Todos consideraron que aumentó la consulta por desarrollo precoz o temprano, ya sea en sus variantes telarca precoz (84 %), pubarca precoz (26 %) y/o pubertad precoz (95 %). El 99 % acuerda con que se ha dado en mayor medida en niñas. La totalidad de los encuestados también considera que aumentó el diagnóstico de pubertad precoz central. El 96,4 % considera que ha aumentado el número de pacientes tratados con análogos de GnRH. Conclusión. Nuestros resultados sobre la percepción de endocrinólogos pediatras coinciden con datos publicados en otras regiones sobre el aumento del diagnóstico de pubertad precoz durante la pandemia por COVID-19. Se reafirma la necesidad de generar registros nacionales de pubertad precoz central, difundir las evidencias para su detección y abordaje oportuno.

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RESUMO

Introduction. During the COVID-19 pandemic, an increase in consultations for precocious puberty (PP) was observed. Our objective was to determine the frequency of PP and its progression before and during the pandemic. Methods. Retrospective, observational, analytical study. The medical records of patients who consulted with the Department of Pediatric Endocrinology between April 2018 and March 2021 were assessed. Consultations for suspected PP during the pandemic (period 3) were analyzed and compared to the 2 previous years (periods 1 and 2). Clinical data and ancillary tests done in the initial assessment and PP progression information were collected. Results. Data from 5151 consultations were analyzed. An increase in consultations for suspected PP was observed during period 3 (21% versus 10% and 11%, p < 0.001). Patients who consulted for suspected PP during period 3 increased 2.3-fold (80 versus 29 and 31, p < 0.001). In total, 95% were female; this was the population analyzed. We included 132 patients with similar age, weight, height, bone age, and hormonal characteristics in the 3 periods. During period 3, a lower body mass index, a higher percentage of Tanner breast stage 3-4, and a greater uterine length were observed. Treatment was indicated upon diagnosis in 26% of the cases. In the rest, their evolution was monitored. During follow-up, a rapidly progressive course was observed more frequently in period 3 (47% versus 8% versus 13%, p: 0.02). Conclusions. We observed an increase in PP and a rapidly progressive evolution in girls during the pandemic.

Introducción. Durante la pandemia por COVID-19, observamos un aumento de consultas por pubertad precoz (PP). Nuestro objetivo fue determinar la frecuencia de PP y su progresión antes y durante la pandemia. Métodos. Estudio retrospectivo, observacional y analítico. Se evaluaron las historias clínicas de los pacientes que consultaron en Endocrinología Infantil entre abril de 2018 y marzo de 2021. Se analizaron las consultas por sospecha de PP durante la pandemia (período 3) y se compararon con 2 años previos (períodos 1 y 2). Se recolectaron datos clínicos y estudios complementarios de la evaluación inicial y su progresión. Resultados. Se analizaron 5151 consultas. Se observó un aumento de consultas por sospecha de PP durante el período 3 (21 % vs.10 % y 11 %, p <0,001). Los pacientes que consultaron por sospecha de PP durante el período 3 aumentaron 2,3 veces (80 vs. 29 y 31, p <0,001). El 95 % fueron niñas; esa población fue analizada. Se incluyeron 132 pacientes que fueron similares en edad, peso, talla, edad ósea y determinaciones hormonales en los 3 períodos. En el período 3, se observó un menor índice de masa corporal, mayor porcentaje de estadio mamario Tanner 3-4 y mayor longitud uterina. Se indicó tratamiento al diagnóstico en el 26 % de los casos. En el resto, se controló su evolución. Durante el seguimiento, se observó una evolución rápidamente progresiva con mayor frecuencia durante el período 3 (47 % vs. 8 % vs. 13 %; p: 0,02). Conclusiones. Evidenciamos un aumento de la PP y una evolución rápidamente progresiva en niñas durante la pandemia.

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Introduction. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, consultations of girls with idiopathic central precocious puberty (ICPP) increased in several countries, but there were no data from Argentina. This increase may be related to changes in lifestyle and stress levels resulting from the lockdown, which particularly affected the child population. Objectives. 1) To describe the progression of the incidence of ICPP requiring inhibition of the hypothalamic-pituitary-gonadal (HPG) axis in girls between 2010 and 2021 in a cohort from the Metropolitan Area of Buenos Aires. 2) To compare the characteristics of girls diagnosed with ICPP during the pandemic with those of a control group. Methods. Interrupted time-series and case-control study. Results. The annual incidence remained stable between 2010 and 2017. Since 2017, it increased to an average of 59.9% (95% CI: 18.6-115.5) and appears to have accelerated during the pandemic. We found an association between ICPP and requiring inhibitory treatment between June 1st, 2020 and May 31st, 2021 and 2 variables: maternal age at menarche (OR: 0.46, 95% CI: 0.28-0.77) and family history of ICPP (OR: 4.42, 95% CI: 1.16-16.86). Conclusion. We evidenced a significant increase in the incidence of ICPP with requirement of HPG axis inhibition since 2017. Increased exposure to various environmental triggers during the COVID-19 pandemic may have had a greater influence in girls with some genetic predisposition.

Introducción. Desde inicios de la pandemia por coronavirus 2019 (COVID-19), fue comunicado en varios países un incremento de las consultas de niñas con pubertad precoz central idiopática (PPCI), sin que contáramos con datos argentinos. Este aumento estaría vinculado con los cambios en el estilo de vida y los niveles de estrés resultantes del aislamiento que afectó particularmente a la población infantil. Objetivos. 1) Describir la evolución de la incidencia de PPCI con requerimiento de inhibición del eje hipotálamo-hipófiso-gonadal (EHHG) en niñas entre 2010 y 2021 en una cohorte del Área Metropolitana de Buenos Aires. 2) Comparar las características de las niñas, con dicho diagnóstico realizado durante la pandemia, con las de un grupo control. Métodos. Serie de tiempo interrumpida y estudio de casos y controles. Resultados. La incidencia anual fue estable entre 2010 y 2017. Desde 2017 hubo un ascenso anual que promedió el 59,9 % (IC95 % 18,6-115,5) y pareciera haberse acelerado durante la pandemia. Constatamos asociación entre haber desarrollado PPCI y haber requerido tratamiento inhibitorio entre el 01 de junio de 2020 y el 31 de mayo de 2021, y dos variables: edad de menarca materna (OR 0,46; IC95 % 0,28-0,77) y antecedente familiar de PPCI (OR 4,42; IC95 % 1,16-16,86). Conclusión. Evidenciamos desde 2017 un aumento significativo en la incidencia de PPCI con requerimiento de inhibición del EHHG. El incremento en la exposición a diversos desencadenantes ambientales durante la pandemia por COVID-19 podría haber ejercido mayor influencia en las niñas con alguna predisposición genética.

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The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.

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OBJECTIVE: The aim of this study is to determine the cutoff values of gonadotropin response to gonadotropin-releasing hormone analogs (GnRHas) corresponding to the activation of the hypothalamic-pituitary-gonadal axis that could differentiate central precocious puberty (CPP) from premature thelarche (PT) and using the electrochemiluminescence assay method. METHODS: A total of 49 girls underwent the stimulation test with an intramuscular injection of 3.75 mg leuprolide acetate. Based on the clinical and laboratory characteristics, they were divided into two groups: CPP (n = 22) and PT (n = 27). Baseline estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were collected before GnRHa administration and LH and FSH at 60 and 120 min, respectively, after GnRHa administration. RESULTS: The girls with CPP presented an increased height Z-score, advanced bone age, and higher baseline LH, FSH, estradiol, and LH/FSH ratio in relation to PT (p < 0.001). Stimulated LH differed significantly between the two groups, and the LH cutoff values were ≥4.29 IU/L (p < 0.001) and ≥3.95 IU/L at 60 and 120 min, respectively (p < 0.001). The LH peak was found at 60 min after stimulation. CONCLUSIONS: The GnRHa test is effective in distinguishing CPP from PT, and a single sampling, at 60 min, with LH concentrations above 4.29 may be the parameter of choice with the advantage of greater convenience and practicality.

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