The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty.

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.

Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

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.

Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in the MKRN3 Gene after Treatment with Gonadotropin-Releasing Hormone Analog.

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.

DLK1 Is a Novel Link Between Reproduction and Metabolism.

BACKGROUND: Delta-like homolog 1 (DLK1), also called preadipocyte factor 1, prevents adipocyte differentiation and has been considered a molecular gatekeeper of adipogenesis. A DLK1 complex genomic defect was identified in five women from a single family with central precocious puberty (CPP) and increased body fat percentage. METHODS: We studied 60 female patients with a diagnosis of CPP or history of precocious menarche. Thirty-one of them reported a family history of precocious puberty. DLK1 DNA sequencing was performed in all patients. Serum DLK1 concentrations were measured using an ELISA assay in selected cases. Metabolic and reproductive profiles of adult women with CPP caused by DLK1 defects were compared with those of 20 women with idiopathic CPP. RESULTS: We identified three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1. Serum DLK1 concentrations were undetectable in three affected women. Metabolic abnormalities, such as overweight/obesity, early-onset glucose intolerance/type 2 diabetes mellitus, and hyperlipidemia, were more prevalent in women with the DLK1 mutation than in the idiopathic CPP group. Notably, the human metabolic alterations were similar to the previously described dlk1-null mice phenotype. Two sisters who carried the p.Gly199Alafs*11 mutation also exhibited polycystic ovary syndrome and infertility. CONCLUSIONS: Loss-of-function mutations of DLK1 are a definitive cause of familial CPP. The high prevalence of metabolic alterations in adult women who experienced CPP due to DLK1 defects suggests that this antiadipogenic factor represents a link between reproduction and metabolism.

Long-Term Outcomes of Patients with Central Precocious Puberty due to Hypothalamic Hamartoma after GnRHa Treatment: Anthropometric, Metabolic, and Reproductive Aspects.

BACKGROUND: Hypothalamic hamartoma (HH) represents the commonest cause of organic central precocious puberty (CPP). Follow-up of these patients in adulthood is scarce. OBJECTIVE: To describe the anthropometric, metabolic, and reproductive parameters of patients with CPP due to HH before and after treatment with gonadotropin-releasing hormone analog (GnRHa). METHODS: We performed a retrospective and cross-sectional study in a single tertiary center including 14 patients (7 females) with CPP due to HH. RESULTS: The mean duration of GnRHa treatment was 7.7 ± 2.4 years in boys and 7.9 ± 2.1 years in girls. GnRHa treatment was interrupted at the mean chronological age (CA) of 12.1 ± 1.1 years in boys and 10.7 ± 0.5 years in girls. At the last visit, the mean CA of the male and female patients was 21.5 ± 3.2 and 24 ± 3.9 years, respectively. Eleven of the 14 patients reached normal final height (FH) (standard deviation score -0.6 ± 0.9 for males and -0.6 ± 0.5 for females), all of them within the target height (TH) range. The remaining 3 patients had predicted height within the TH range. The mean body mass index and the percentage of body fat mass was significantly higher in females, with a higher prevalence of metabolic disorders. All patients presented normal gonadal function in adulthood, and 3 males fathered a child. CONCLUSION: All patients with CPP due to HH reached normal FH or near-FH. A higher prevalence of overweight/obesity and hypercholesterolemia was observed in the female patients. Finally, no reproductive disorder was identified in both sexes, indicating that HH per se has no deleterious effect on the gonadotropic axis in adulthood.

Assessment of stress levels in girls with central precocious puberty before and during long-acting gonadotropin-releasing hormone agonist treatment: a pilot study.

BACKGROUND: The objective of the study was to determine the stress levels of girls with central precocious puberty (CPP) before and during treatment with a long-acting gonadotropin-releasing hormone agonist (GnRHa). METHODS: The Child Stress Scale (CSS) was used for 10 unrelated girls with CPP before and after the first year of GnRHa treatment. The CSS is divided into four subscales (physical, psychological, psychological with depressive component and psychophysiological reactions). Through a quantitative analysis, it is possible to classify stress into four stages: alarm, resistance, near-exhaustion and exhaustion. RESULTS: At diagnosis, 90% of the girls showed stress levels scores at the alarm or resistance stage on at least one subscale, mostly in terms of physical and psychological reactions. The mean total stress score was significantly higher before when compared to after GnRHa treatment (43.4±15.6 vs. 28.9±9.7; p<0.05). The mean stress scores obtained in all subscales, except the one on psychophysiological reactions, were significantly higher before GnRHa treatment. CONCLUSIONS: Higher stress levels were a common finding in girls with CPP before treatment. The significant stress level reduction after pubertal suppression reinforces the idea that sexual precocity is a stressful condition in children. The CSS might be a useful tool for psychological assessment of patients with CPP.

Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty.

Context: Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3. Objective: To identify the genetic etiology of CPP in a large multigenerational family. Design: Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin-secreting neuronal cell lines in vitro. Setting: Endocrine clinic of an academic medical center. Patients: Patients with familial CPP were studied. Results: A complex defect of DLK1 (∼14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 5' untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron-derived cell lines. Conclusion: We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.

A boy with Prader-Willi syndrome: unmasking precocious puberty during growth hormone replacement therapy.

Prader-Willi syndrome (PWS) is a genetic disorder frequently characterized by obesity, growth hormone deficiency, genital abnormalities, and hypogonadotropic hypogonadism. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty (CPP) is very rare. This study aimed to report the clinical and biochemical follow-up of a PWS boy with CPP and to discuss the management of pubertal growth. By the age of 6, he had obesity, short stature, and many clinical criteria of PWS diagnosis, which was confirmed by DNA methylation test. Therapy with recombinant human growth hormone (rhGH) replacement (0.15 IU/kg/day) was started. Later, he presented psychomotor agitation, aggressive behavior, and increased testicular volume. Laboratory analyses were consistent with the diagnosis of CPP (gonadorelin-stimulated LH peak 15.8 IU/L, testosterone 54.7 ng/dL). The patient was then treated with gonadotropin-releasing hormone analog (GnRHa). Hypothalamic dysfunctions have been implicated in hormonal disturbances related to pubertal development, but no morphologic abnormalities were detected in the present case. Additional methylation analysis (MS-MLPA) of the chromosome 15q11 locus confirmed PWS diagnosis. We presented the fifth case of CPP in a genetically-confirmed PWS male. Combined therapy with GnRHa and rhGH may be beneficial in this rare condition of precocious pubertal development in PWS.

A boy with Prader-Willi syndrome: unmasking precocious puberty during growth hormone replacement therapy

SUMMARY Prader-Willi syndrome (PWS) is a genetic disorder frequently characterized by obesity, growth hormone deficiency, genital abnormalities, and hypogonadotropic hypogonadism. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty (CPP) is very rare. This study aimed to report the clinical and biochemical follow-up of a PWS boy with CPP and to discuss the management of pubertal growth. By the age of 6, he had obesity, short stature, and many clinical criteria of PWS diagnosis, which was confirmed by DNA methylation test. Therapy with recombinant human growth hormone (rhGH) replacement (0.15 IU/kg/day) was started. Later, he presented psychomotor agitation, aggressive behavior, and increased testicular volume. Laboratory analyses were consistent with the diagnosis of CPP (gonadorelin-stimulated LH peak 15.8 IU/L, testosterone 54.7 ng/dL). The patient was then treated with gonadotropin-releasing hormone analog (GnRHa). Hypothalamic dysfunctions have been implicated in hormonal disturbances related to pubertal development, but no morphologic abnormalities were detected in the present case. Additional methylation analysis (MS-MLPA) of the chromosome 15q11 locus confirmed PWS diagnosis. We presented the fifth case of CPP in a genetically-confirmed PWS male. Combined therapy with GnRHa and rhGH may be beneficial in this rare condition of precocious pubertal development in PWS.

[Advances in the etiology, diagnosis and treatment of central precocious puberty]. / Avanços na etiologia, no diagnóstico e no tratamento da puberdade precoce central.

The onset of puberty is first detected as an increase in the amplitude and frequency of pulses of gonadotropin-releasing hormone (GnRH) after a quiescent period during childhood. The reemergence of pulsatile GnRH secretion leads to increases in the secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by the pituitary gland, and the consequent activation of gonadal function. Early activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty (CPP), which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. CPP is diagnosed on the basis of clinical signs of progressive pubertal development before the age of 8 years in girls and 9 years in boys, pubertal basal and/or GnRH-stimulated LH levels, and advanced bone age. Magnetic resonance imaging of the central nervous system is essential for establishing the CPP form as organic or idiopathic. Depot GnRH-analogues represent the first-line of therapy in CPP. Very recently, the genetic component of CPP was demonstrated by the evidence that the deficiency of the MKRN3 gene, located on long arm of chromosome 15, causes familial CPP in humans. In this current review, clinical and therapeutic aspects of the CPP will be discussed, contributing to adequate diagnosis and criterious approach of this relevant condition of pediatric endocrinology.

Avanços na etiologia, no diagnóstico e no tratamento da puberdade precoce central / Advances in the etiology, diagnosis and treatment of central precocious puberty

O início da puberdade caracteriza-se pelo aumento de amplitude e frequência dos pulsos do hormônio secretor de gonadotrofinas (GnRH) após um período de relativa supressão hormonal durante a infância. A reemergência da secreção pulsátil do GnRH resulta em aumento na secreção de gonadotrofinas, hormônio luteinizante (LH) e folículo estimulante (FSH), pela hipófise anterior e consequente ativação gonadal. A ativação prematura do eixo hipotálamo-hipófise-gonadal resulta em puberdade precoce dependente de gonadotrofinas, também conhecida como puberdade precoce central (PPC), e se caracteriza pelo desenvolvimento dos caracteres sexuais secundários antes dos 8 anos nas meninas e 9 anos nos meninos. O início do desenvolvimento puberal provém da interação complexa de fatores genéticos, nutricionais, ambientais e socioeconômicos. O diagnóstico clínico da PPC baseia-se em reconhecimento de desenvolvimento puberal progressivo, concentrações púberes de LH em condição basal e/ou após estímulo com GnRH e avanço de idade óssea. A ressonância magnética de encéfalo é útil no estabelecimento de diagnóstico diferencial entre as formas orgânica ou idiopática. Os análogos de GnRH de ação prolongada representam o tratamento de escolha da PPC. O componente genético da PPC foi recentemente fortalecido pela evidência de mutações no gene MKRN3, localizado no braço longo do cromossomo 15, em crianças com PPC familial. Nessa revisão, dados clínicos e terapêuticos da PPC serão amplamente discutidos, visando à atualização e à conduta criteriosa dessa condição clínica de grande relevância na endocrinologia pediátrica.

The onset of puberty is first detected as an increase in the amplitude and frequency of pulses of gonadotropin-releasing hormone (GnRH) after a quiescent period during childhood. The reemergence of pulsatile GnRH secretion leads to increases in the secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by the pituitary gland, and the consequent activation of gonadal function. Early activation of the hypothalamic–pituitary–gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty (CPP), which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. CPP is diagnosed on the basis of clinical signs of progressive pubertal development before the age of 8 years in girls and 9 years in boys, pubertal basal and/or GnRH-stimulated LH levels, and advanced bone age. Magnetic resonance imaging of the central nervous system is essential for establishing the CPP form as organic or idiopathic. Depot GnRH-analogues represent the first-line of therapy in CPP. Very recently, the genetic component of CPP was demonstrated by the evidence that the deficiency of the MKRN3 gene, located on long arm of chromosome 15, causes familial CPP in humans. In this current review, clinical and therapeutic aspects of the CPP will be discussed, contributing to adequate diagnosis and criterious approach of this relevant condition of pediatric endocrinology.