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The Journal of Clinical Endocrinology... Jun 2023Central precocious puberty (CPP) can have a familial form in approximately one-quarter of the children. The recognition of this inherited condition increased after the...
CONTEXT
Central precocious puberty (CPP) can have a familial form in approximately one-quarter of the children. The recognition of this inherited condition increased after the identification of autosomal dominant CPP with paternal transmission caused by mutations in the MKRN3 and DLK1 genes.
OBJECTIVE
We aimed to characterize the inheritance and estimate the prevalence of familial CPP in a large multiethnic cohort; to compare clinical and hormonal features, as well as treatment response to GnRH analogs (GnRHa), in children with distinct modes of transmission; and to investigate the genetic basis of familial CPP.
METHODS
We retrospectively studied 586 children with a diagnosis of CPP. Patients with familial CPP (n = 276) were selected for clinical and genetic analysis. Data from previous studies were grouped, encompassing sequencing of MKRN3 and DLK1 genes in 204 patients. Large-scale parallel sequencing was performed in 48 individuals from 34 families.
RESULTS
The prevalence of familial CPP was estimated at 22%, with a similar frequency of maternal and paternal transmission. Pedigree analyses of families with maternal transmission suggested an autosomal dominant inheritance. Clinical and hormonal features, as well as treatment response to GnRHa, were similar among patients with different forms of transmission of familial CPP. MKRN3 loss-of-function mutations were the most prevalent cause of familial CPP, followed by DLK1 loss-of-function mutations, affecting, respectively, 22% and 4% of the studied families; both affected exclusively families with paternal transmission. Rare variants of uncertain significance were identified in CPP families with maternal transmission.
CONCLUSION
We demonstrated a similar prevalence of familial CPP with maternal and paternal transmission. MKRN3 and DLK1 loss-of-function mutations were the major causes of familial CPP with paternal transmission.
Topics: Male; Child; Humans; Puberty, Precocious; Retrospective Studies; Mutation; Fathers; Inheritance Patterns; Ubiquitin-Protein Ligases; Puberty
PubMed: 36611250
DOI: 10.1210/clinem/dgac763 -
Treatments in Endocrinology 2004Aromatase inhibitors have been used in the treatment of selective forms of precocious puberty since the mid-1980s. The primary aim of therapy is attenuation of the... (Review)
Review
Aromatase inhibitors have been used in the treatment of selective forms of precocious puberty since the mid-1980s. The primary aim of therapy is attenuation of the effects of estrogen on growth, skeletal maturation, and secondary sexual development. The first-generation agent, testolactone, has been demonstrated to be tolerable and effective in the treatment of familial male precocious puberty, while mixed results with testolactone have been achieved in girls with McCune-Albright syndrome. A favorable outcome with the use of testolactone in conjunction with conventional therapy in children with congenital adrenal hyperplasia has also been suggested. Although a few anecdotal reports of the use of newer generation aromatase inhibitors in precocious puberty exist, the extreme rarity of the relevant disorders remains a limiting factor in clinical investigation. In this review, the pathophysiology, presentation, and treatment of precocious puberty are described. Particular attention is devoted to the specific disorders in which aromatase inhibitors have been utilized, which are forms of peripheral (gonadotropin-independent) precocious puberty. The impact of untreated precocious puberty on growth and adult stature is discussed, and the actions of estrogen in the human skeleton are summarized. Finally, a detailed description of the existing literature pertaining to aromatase inhibitors in the pediatric population is provided. Emerging potential new indications are discussed. In conclusion, aromatase inhibitors, particularly testolactone, have a proven track record in the treatment of a few forms of precocious puberty. Continued exploration with new generation aromatase inhibitors in these disorders is ongoing. The wider application of aromatase inhibitors for the purposes of delaying skeletal maturation and increasing adult height in several conditions leading to short stature is currently a subject of intense investigation.
Topics: Aromatase Inhibitors; Bone Density; Bone Development; Estrogens; Humans; Puberty, Precocious
PubMed: 16026110
DOI: 10.2165/00024677-200403030-00002 -
Endocrinology and Metabolism Clinics of... Jun 2024Central precocious puberty (CPP) among males is less frequent than among females but more likely to have an underlying pathologic cause. Diagnosis of CPP is often... (Review)
Review
Central precocious puberty (CPP) among males is less frequent than among females but more likely to have an underlying pathologic cause. Diagnosis of CPP is often straightforward among males because increased testicular volume, the first sign of puberty, can be verified although careful central nervous system (CNS) assessment is generally necessary. Treatment with gonadotropin-releasing hormone agonist (GnRHa) is indicated, given in conjunction with any therapy needed for CNS lesions. Monitoring of treatment usually can consist of evaluating growth and physical puberty and with testosterone levels as the only lab data. Short-term and long-term outcome data indicate efficacy and safety, although data are limited. Such data need to be reported.
Topics: Humans; Puberty, Precocious; Male; Gonadotropin-Releasing Hormone; Child; Treatment Outcome
PubMed: 38677867
DOI: 10.1016/j.ecl.2024.01.005 -
Pediatrician 1987Isosexual precocious puberty refers to the appearance of phenotypically appropriate secondary sexual characteristics before age 8 years in girls and before 9 years in... (Review)
Review
Isosexual precocious puberty refers to the appearance of phenotypically appropriate secondary sexual characteristics before age 8 years in girls and before 9 years in boys. Isosexual precocity may be categorized into several subgroups depending upon etiology and clinical course: true and complete isosexual precocity refers to early activation of the intact hypothalamic-pituitary-gonadal axis; pseudo-isosexual precocity is due to sex steroid production which is independent of hypothalamic-pituitary regulation; incomplete forms of isosexual precocity include premature thelarche and premature adrenarche. Etiologic, diagnostic and therapeutic considerations are discussed.
Topics: Age Factors; Androgens; Child; Female; Humans; Hypothalamo-Hypophyseal System; Male; Menarche; Pituitary Hormone-Releasing Hormones; Puberty, Precocious; Sex Characteristics; Sexual Maturation
PubMed: 3331207
DOI: No ID Found -
Best Practice & Research. Clinical... Mar 2002This chapter describes several aspects of the management of treatment in girls and boys with central precocious puberty. Although there is some controversy about the... (Review)
Review
This chapter describes several aspects of the management of treatment in girls and boys with central precocious puberty. Although there is some controversy about the indication for gonadotrophin releasing hormone (GnRH) agonist treatment in the literature, a list of clear indications is presented and monitoring requirements for treatment are discussed with reference to the pertinent literature. The development of clinical, psychological, hormonal, sonographical and auxological parameters that can be expected during GnRH agonist treatment is described in detail. In view of the scant evidence-based knowledge, we review the final outcome of patients treated with GnRH agonists with respect to reversibility of hormonal suppression, reproductive function, final height and side effects. The data published so far show that GnRH agonist treatment using the modern depot preparations is not only convenient but also safe, with relatively minor side effects. The outcome in terms of final height is favourable in the majority of patients.
Topics: Adolescent; Child; Female; Humans; Leuprolide; Male; Puberty, Precocious; Treatment Outcome; Triptorelin Pamoate
PubMed: 11987906
DOI: 10.1053/beem.2002.0188 -
Hormones (Athens, Greece) Sep 2020Aristotle was the first author who described the existence of abnormalities in the timing of human puberty. In the classic Greek-Roman period, Pliny the Elder and...
Aristotle was the first author who described the existence of abnormalities in the timing of human puberty. In the classic Greek-Roman period, Pliny the Elder and Phlegon of Tralles described the first individual cases of precocious puberty in children. During the Middle Ages, precocious puberty in the male (but not in the female) was ignored. We present what is, to our knowledge, the first full description in European literature of male precocious puberty and its consequences in an adult. This case is included in a book of the miscellaneous genre of Spanish Renaissance literature (Jardin de Flores Curiosas) written by Antonio de Torquemada in the sixteenth century.
Topics: History, 16th Century; Humans; Male; Medicine in Literature; Puberty, Precocious; Spain
PubMed: 32037485
DOI: 10.1007/s42000-020-00177-y -
Human Reproduction Update 2001Precocious puberty is generally defined as the appearance of secondary sex characteristics before age 8 years in girls (or menarche before age 9 years) and before 9... (Review)
Review
Precocious puberty is generally defined as the appearance of secondary sex characteristics before age 8 years in girls (or menarche before age 9 years) and before 9 years in boys. The overall incidence of sexual precocity is estimated to be 1:5,000 to 1:10,000 children. The female-to-male ratio is approximately 10:1. In addition to the psychosocial disturbances associated with precocious puberty, the premature pubertal growth spurt (with less time for prepubertal growth) and the accelerated bone maturation result in reduced adult height. Precocious puberty may be gonadotrophin-dependent [i.e. of central origin with premature activation of the gonadotrophin-releasing hormone (GnRH) pulse generator] or gonadotrophin-independent (i.e. peripheral where the GnRH pulse generator is suppressed). This can be determined by GnRH testing. The pathophysiology is the basis for different diagnostic and therapeutic strategies, i.e. in the first case a stimulated LH/FSH ratio >1 and suppressive treatment with GnRH agonists (e.g. in hypothalamic hamartoma), and in the second decreased gonadotrophins and removal or suppression of the endogenous or exogenous sex steroid source (e.g. congenital adrenal hyperplasia). While several cases of gonadotrophin-independent precocious puberty due to oestrogen exposure via the transdermal, oral, or inhalative route have been reported, no case is known with the development of subsequent secondary central precocious puberty. Food contamination with oestrogens is theoretically possible, but would most probably be sporadic and, thus, would not lead to precocious puberty. As steroid hormones in meat production are banned in the European Union, no data on the impact of environmental oestrogenic substances on human maturation are currently available. In conclusion, the risk for children to develop precocious puberty through exposure to oestrogens (or androgens) in the environment or in food is very low. Nevertheless, studies of the effects of defined environmental oestrogenic substances on the human reproductive system and on pubertal development are warranted.
Topics: Estrogens; Food Contamination; Gonadotropins; Humans; Incidence; Puberty, Precocious
PubMed: 11392376
DOI: 10.1093/humupd/7.3.292 -
Endocrinology and Metabolism Clinics of... Dec 1999Central precocious puberty (CPP) is physiologically normal puberty beginning early. It is the consequence of early increased regulation of gonadotropin releasing hormone... (Review)
Review
Central precocious puberty (CPP) is physiologically normal puberty beginning early. It is the consequence of early increased regulation of gonadotropin releasing hormone (GnRH) stimulation of pituitary gonadotropin release causing pubertal changes and accelerated growth. GnRH stimulation testing is the definitive diagnostic test--pubertal gonadotropin responses being indicative of CPP. Among patients with progressive CPP, GnRH analogue therapy is effective by decreased regulation of gonadotropin secretion. Pubertal progression is stopped, and accelerated growth rate and compromised adult height are precluded or alleviated. Outcome data have not identified unusual sequelae.
Topics: Bone Development; Child; Female; Growth; Humans; Male; Puberty; Puberty, Precocious; Treatment Outcome
PubMed: 10609126
DOI: 10.1016/s0889-8529(05)70108-0 -
Neurosurgical Review Dec 2021The aim of this review was to determine the role of surgery in treating hypothalamic hamartoma (HH) causing isolated central precocious puberty (CPP). Literature review... (Review)
Review
The aim of this review was to determine the role of surgery in treating hypothalamic hamartoma (HH) causing isolated central precocious puberty (CPP). Literature review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Patients with isolated CPP due to HH, managed with surgical resection, were included. We found 33 studies, reporting 103 patients (76 pedunculated, 27 sessile). Patients were considered "cured" if the symptoms of PP had regressed and the hormone profile had normalized after surgery. Indications for surgery included hamartoma deemed surgically resectable (n-12), for the purpose of tissue diagnosis (n-3), partial response/failure of preoperative therapy (n-9), and unable to afford/to avoid long-term medical therapy (n-7). The extent of resection was total (TR) (n-39), near total/subtotal (NTR/STR) (n-20), partial (PR) (n-35), or unspecified (n-9). On follow-up (range: 3 months-16 years), 73.6% (56/76) of patients with pedunculated HH were cured, while 17.1% (13/76) had partial relief. Only 3/27 (11.1%) of patients with sessile HH were cured. All patients with a pedunculated hamartoma who underwent TR (n=36) improved, with 88.88% cured of the symptoms. Surgery had no effect in 17/23 (73.9%) patients with sessile HH who underwent PR. Psychological symptoms improved in 10/11 patients. There was no mortality. Permanent complications, in the form of 3rd nerve palsy, occurred in 3.7% (2/54) of the patients. To conclude, in the current era of availability of GnRH analogs, surgical resection in a subset of patients may be acceptable especially for small pedunculated hamartomas.
Topics: Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Puberty, Precocious
PubMed: 33641048
DOI: 10.1007/s10143-021-01512-6 -
Journal of Pediatric Endocrinology &... Jun 2023The COVID-19 pandemic had profound effect on physical and mental health. Stress was due physical inactivity, increased screen time, social isolation, fear of... (Review)
Review
OBJECTIVES
The COVID-19 pandemic had profound effect on physical and mental health. Stress was due physical inactivity, increased screen time, social isolation, fear of illness/death, as well as relative lack of resources including healthy food and finances. These stressors may be associated with an increase in idiopathic central precocious puberty (ICPP). The aim of the study was to assess the incidence of ICPP in females during the COVID-19 pandemic and compare biochemical and radiological parameters of females diagnosed in the previous two years, looking at associations among BMI, screen time, isolation, and stress in relation to the development of early puberty.
METHODS
A retrospective chart review was performed of females diagnosed with ICPP. We divided subjects into a pandemic group and pre-pandemic group based on time of diagnosis. We compared anthropometric, serologic and radiologic data between the two groups. To assess psychosocial stress, we reviewed a COVID-19 impact survey which was administered to families at our endocrine clinic.
RESULTS
There were a total of 56 subjects in the study; 23 subjects in the pre-pandemic group and 33 in the pandemic group. The pandemic cohort had significantly higher estradiol and LH levels and larger ovarian volumes. Survey results showed parental report of stress was moderate in 38 % of subjects and severe in 25 % of parents. In children, reported stress was moderate in 46 % of subjects.
CONCLUSIONS
As puberty is influenced by exogenous factors including weight gain and psychosocial stress, we suspect that the environmental stress surrounding the pandemic influenced the increase in ICPP.
Topics: Female; Humans; Child; Puberty, Precocious; COVID-19; Pandemics; Retrospective Studies; New York City; COVID-19 Testing
PubMed: 37114861
DOI: 10.1515/jpem-2022-0628