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1.
Eur J Endocrinol ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38857188

RESUMO

OBJECTIVES: The etiology of central precocious puberty (CPP) has expanded with identification of new genetic causes, including the monogenic deficiency of MKRN3. We aimed to assess the prevalence of CPP causes and the predictors of genetic involvement in this phenotype. DESIGN: A retrospective cohort study for an etiological survey of patients with CPP from a single academic center. METHODS: All patients with CPP had detailed medical history, phenotyping, and brain MRI; those with negative brain MRI (apparently idiopathic) were submitted to genetic studies, mainly DNA sequencing studies, genomic microarray, and methylation analysis. RESULTS: We assessed 270 patients with CPP; 50 (18.5%) had CPP-related brain lesions [34 (68%) congenital lesions]; whereas 220 had negative brain MRI. Of the latter, 174 (165 girls) were included for genetic studies. Genetic etiologies were identified in 22 patients (20 girls), indicating an overall frequency of genetic CPP of 12.6% (22.2% in boys and 12.1% in girls). The most common genetic defects were MKRN3, DLK1, and MECP2 loss-of-function mutations, followed by 14q32.2 defects (Temple syndrome). Univariate logistic regression identified family history (OR 3.3; 95%CI 1.3-8.3; p = 0.01) and neurodevelopmental disorders (OR 4.1; 95%CI 1.3-13.5; p = 0.02) as potential clinical predictors of genetic CPP. CONCLUSIONS: Distinct genetic causes were identified in 12.6% patients with apparently idiopathic CPP, revealing the genetic etiology as a relevant cause of CPP in both sexes. Family history and neurodevelopmental disorders were suggested as predictors of genetic CPP. We originally proposed an algorithm to investigate the etiology of CPP including genetic studies.

2.
Endocr Rev ; 44(2): 193-221, 2023 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35930274

RESUMO

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.


Assuntos
Doenças Hipotalâmicas , Puberdade Precoce , Humanos , Puberdade Precoce/diagnóstico , Puberdade Precoce/genética , Hormônio Liberador de Gonadotropina/metabolismo , Doenças Hipotalâmicas/complicações , Hipotálamo , Puberdade , Ubiquitina-Proteína Ligases/metabolismo
3.
J Pediatr Endocrinol Metab ; 34(11): 1371-1377, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34298591

RESUMO

OBJECTIVES: Longer-acting gonadotropin-releasing hormone analogs (GnRHa) have been widely used for central precocious puberty (CPP) treatment. However, the follow-up of patients after this treatment are still scarce. Our aim was to describe anthropometric, metabolic, and reproductive follow-up of CPP patients after treatment with leuprorelin acetate 3-month depot (11.25 mg). METHODS: Twenty-two female patients with idiopathic CPP were treated with leuprorelin acetate 3-month depot (11.25 mg). Their medical records were retrospectively evaluated regarding clinical, hormonal, and imaging aspects before, during, and after GnRHa treatment until adult height (AH). RESULTS: At the diagnosis of CPP, the mean chronological age (CA) was 8.2 ± 1.13 year, and mean bone age (BA) was 10.4 ± 1.4 year. Mean height SDS at the start and the end of GnRHa treatment was 1.6 ± 0.8 and 1.3 ± 0.9, respectively. The mean duration of GnRHa treatment was 2.8 ± 0.8 year. Mean predicted adult heights (PAH) at the start and the end of GnRH treatment was 153.2 ± 8.6 and 164.4 ± 7.3 cm, respectively (p<0.05). The mean AH was 163.2 ± 6.2 cm (mean SDS: 0.1 ± 1). All patients were within their target height (TH) range. There was a decrease in the percentage of overweight and obesity from the diagnosis until AH (39-19% p>0.05). At the AH, the insulin resistance and high LDL levels were identified in 3/17 patients (17.6%) and 2/21 patients (9.5%), respectively. The mean CA of menarche was 12.2 ± 0.5 years. At the AH, PCOS was diagnosed in one patient (4.8%). CONCLUSIONS: Long-term anthropometric, metabolic, and reproductive follow-up of patients with CPP treated with longer-acting GnRHa revealed effectivity, safety, and favorable outcomes.


Assuntos
Estatura/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Leuprolida/uso terapêutico , Menarca/efeitos dos fármacos , Puberdade Precoce/tratamento farmacológico , Reprodução/efeitos dos fármacos , Criança , Feminino , Humanos , Leuprolida/administração & dosagem , Puberdade Precoce/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
4.
J Clin Endocrinol Metab ; 106(4): 1041-1050, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33383582

RESUMO

CONTEXT: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). OBJECTIVE: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. METHODS: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. RESULTS: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ±â€…1.2 years in girls and 7.1 ±â€…1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ±â€…1.6 vs 1.6 ±â€…1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ±â€…1.8 vs 1.1 ±â€…1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. CONCLUSION: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.


Assuntos
Puberdade Precoce/genética , Ubiquitina-Proteína Ligases/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Família , Feminino , Estudos de Associação Genética , Humanos , Doenças Hipotalâmicas/epidemiologia , Doenças Hipotalâmicas/genética , Mutação com Perda de Função , Masculino , Mutação de Sentido Incorreto , Puberdade Precoce/epidemiologia
5.
Neuroendocrinology ; 110(7-8): 705-713, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31671431

RESUMO

INTRODUCTION: Loss-of-function mutation of MKRN3 represents the most frequent genetic cause of familial central precocious puberty (CPP). The outcomes of gonadotropin-releasing hormone analog (GnRHa) treatment in CPP patients with MKRN3 defects are unknown. OBJECTIVE: To describe the clinical and hormonal features of patients with CPP with or without MKRN3 mutations after GnRHa treatment. Anthropometric, metabolic and reproductive parameters were evaluated. PATIENTS AND METHODS: Twenty-nine female patients with CPP due to loss-of-function mutations in the MKRN3 and 43 female patients with idiopathic CPP were included. Their medical records were retrospectively evaluated for clinical, laboratory, and imaging study, before, during, and after GnRHa treatment. All patients with idiopathic CPP and 11 patients with CPP due to MKRN3 defects reached final height (FH). RESULTS: At the diagnosis, there were no significant differences between clinical and laboratory features of patients with CPP with or without MKRN3 mutations. A high prevalence of overweight and obesity was observed in patients with CPP with or without MKRN3 mutations (47.3 and 50%, respectively), followed by a significant reduction after GnRHa treatment. No significant differences in the values of mean FH and target height were found between the 2 CPP groups after GnRHa treatment. Menarche occurred at the expected age in patients with or without CPP due to MKRN3 mutations (11.5 ± 1.3 and 12 ± 0.6 years, respectively). The prevalence of polycystic ovarian syndrome was 9.1% in patients with CPP due to MKRN3 mutations and 5.9% in those with idiopathic CPP. CONCLUSION: Anthropometric, metabolic, and reproductive outcomes after GnRHa treatment were comparable in CPP patients, with or without MKRN3 mutations, suggesting the absence of deleterious effects of MKRN3 defects in young female adults' life.


Assuntos
Fármacos para a Fertilidade Feminina/uso terapêutico , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Estatura/efeitos dos fármacos , Estatura/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/uso terapêutico , Gônadas/efeitos dos fármacos , Gônadas/fisiologia , Humanos , Mutação com Perda de Função , Sobrepeso/diagnóstico , Sobrepeso/epidemiologia , Sobrepeso/genética , Obesidade Infantil/diagnóstico , Obesidade Infantil/epidemiologia , Obesidade Infantil/genética , Prevalência , Prognóstico , Puberdade Precoce/diagnóstico , Puberdade Precoce/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
6.
Arch Endocrinol Metab ; 63(4): 438-444, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31460623

RESUMO

Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44.


Assuntos
Puberdade Precoce/genética , Proteínas de Ligação ao Cálcio , Inativação Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Kisspeptinas/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Metilação , Mutação , Fenótipo , Puberdade Precoce/etiologia , Receptores de Kisspeptina-1/genética , Ribonucleoproteínas/genética , Ubiquitina-Proteína Ligases
7.
Arch. endocrinol. metab. (Online) ; 63(4): 438-444, July-Aug. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1019366

RESUMO

ABSTRACT Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44


Assuntos
Humanos , Puberdade Precoce/genética , Fenótipo , Puberdade Precoce/etiologia , Ribonucleoproteínas/genética , Proteínas de Ligação ao Cálcio , Inativação Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Kisspeptinas/genética , Receptores de Kisspeptina-1/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Metilação , Mutação
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