Editing Precocious puberty (section)

== Causes ==
Early [[pubic hair]], [[breast]], or [[genital]] development may result from natural early maturation or from several other conditions.

=== Central ===
If the cause can be traced to the [[hypothalamus]] or [[pituitary]], the cause is considered central. Other names for this type are ''complete'' or ''true precocious'' puberty.<ref>David Gardner, Dolores Shoback. Basic And Clinical Endocrinology. McGraw-Hill Medical; 2011. 9th Edition. Pg. 550</ref>

Causes of central precocious puberty can include:
* [[Tuber cinereum hamartoma|hypothalamic hamartoma]] produces pulsatile [[gonadotropin-releasing hormone]] (GnRH)
* [[Langerhans cell histiocytosis]]
* [[McCune–Albright syndrome]]

Central precocious puberty can also be caused by [[brain tumor]]s, infection (most commonly [[tuberculous meningitis]], especially in developing countries), trauma, [[hydrocephalus]], and [[Angelman syndrome]].<ref>{{Cite journal | last1 = Dickerman | first1 = R. D. | last2 = Stevens | first2 = Q. E. | last3 = Steide | first3 = J. A. | last4 = Schneider | first4 = S. J. | title = Precocious puberty associated with a pineal cyst: is it disinhibition of the hypothalamic-pituitary axis? | journal = Neuro Endocrinology Letters | volume = 25 | issue = 3 | pages = 173–175 | year = 2004 | pmid = 15349080}}</ref> Precocious puberty is associated with advancement in bone age, which leads to early fusion of epiphyses, thus resulting in reduced final height and short stature.<ref>{{cite journal|last1=Kumar|first1=Manoj|last2=Mukhopadhyay|first2=Satinath|last3=Dutta|first3=Deep|title=Challenges and controversies in diagnosis and management of gonadotropin dependent precocious puberty: An Indian perspective|journal=Indian Journal of Endocrinology and Metabolism|date=2015-01-15|volume=19|issue=2|pages=228–235|doi=10.4103/2230-8210.149316|pmid=25729684|pmc=4319262 |doi-access=free }}</ref>

Adrenocortical oncocytomas are rare with mostly benign and nonfunctioning tumors. There have been only three cases of functioning adrenocortical oncocytoma that have been reported up until 2013. Children with adrenocortical oncocytomas will present with "premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone" which are some of the presentations associated with precocious puberty.<ref>{{Cite journal|last1=Subbiah|first1=Sridhar|last2=Nahar|first2=Uma|last3=Samujh|first3=Ram|last4=Bhansali|first4=Anil|date=May 2013|title=Heterosexual precocity: rare manifestation of virilizing adrenocortical oncocytoma|journal=Annals of Saudi Medicine|volume=33|issue=3|pages=294–297|doi=10.5144/0256-4947.2013.294|pmid=23793435|pmc=6078526|issn=0256-4947|quote = So far, in the pediatric age group, only three cases of functioning adrenocortical oncocytoma have been reported. We report a case of functioning adrenocortical oncocytoma in a 3 1/2-year-old female child who presented with premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone. She was managed successfully with right adrenalectomy, and the tumor histology was consistent with adrenal oncocytoma.}}</ref><ref>{{Cite journal|last1=Santos-Silva|first1=Rita|last2=Bonito-Vítor|first2=Artur|last3=Campos|first3=Miguel|last4=Fontoura|first4=Manuel|s2cid=9961260|date=2014|title=Gonadotropin-Dependent Precocious Puberty in an 8-Year-Old Boy with Leydig Cell Testicular Tumor|journal=Hormone Research in Paediatrics|volume=82|issue=2|pages=133–137|doi=10.1159/000358084|pmid=24862970|issn=1663-2818}}</ref>

Precocious puberty in girls begins before the age of 8. The youngest mother on record is [[Lina Medina]], who gave birth at the age of either 5 years, 7 months and 17 days<ref name="Telegraph">{{cite news|title=Six decades later, world's youngest mother awaits aid|url=http://www.telegraphindia.com/1020827/asp/foreign/story_1140311.asp|work=[[The Telegraph (Kolkata)|The Telegraph]]|date=August 27, 2002|access-date=April 13, 2016|archive-url=https://web.archive.org/web/20090722030008/http://www.telegraphindia.com/1020827/asp/foreign/story_1140311.asp|archive-date=July 22, 2009|url-status=dead}}</ref> or 6 years 5 months as mentioned in another report.<ref>{{cite magazine | url=http://www.time.com/time/magazine/article/0,9171,893791,00.html | magazine=[[Time (magazine)|Time]] | title=Little Mother | date=December 16, 1957 | access-date=January 9, 2008 | archive-url=https://web.archive.org/web/20090422210901/http://www.time.com/time/magazine/article/0,9171,893791,00.html | archive-date=April 22, 2009 | url-status=dead }}</ref>

"Central precocious puberty (CPP) was reported in some patients with suprasellar [[arachnoid cysts]] (SAC), and SCFE ([[slipped capital femoral epiphysis]]) occurs in patients with CPP because of rapid growth and changes of growth hormone secretion."<ref>{{cite journal|last=Yamato|first=Fumiko|author2=Takaya, Junji |author3=Higashino, Hirohiko |author4=Yamanouchi, Yasuo |author5=Suehara, Hiroshi |author6= Kobayashi, Yohnosuke |s2cid=27162486|title=Slipped capital femoral epiphysis during the treatment of precocious puberty with a gonadotropin-releasing hormone-agonist: aetiological considerations|journal=European Journal of Pediatrics|date=March 2005|volume=164|issue=3|pages=173–174|doi=10.1007/s00431-004-1578-7|pmid=15592875}}</ref>

If no cause can be identified, it is considered [[idiopathic]] or constitutional.

=== Peripheral ===
Secondary sexual development induced by [[sex steroid]]s from other abnormal sources is referred to as ''peripheral precocious puberty'' or ''precocious pseudopuberty.'' It typically presents as a severe form of disease with children. Symptoms are usually as a sequelae from adrenal hyperplasia (because of [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase deficiency]] or [[Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency|11-beta hydroxylase deficiency]], the former being more common), which includes but is not limited to hypertension, hypotension, electrolyte abnormalities, ambiguous genitalia in females, signs of virilization in females. Blood tests will typically reveal high level of [[androgen]]s with low levels of cortisol.

Causes can include:
* Endogenous sources
** [[Gonad]]al tumors (such as [[arrhenoblastoma]])
** [[Adrenal]] tumors
** [[Germ cell tumor]]<ref>{{Cite journal | last1 = Masse | first1 = R. J. | last2 = Shaw | first2 = P. J. | last3 = Burgess | first3 = M. | doi = 10.1111/j.1440-1754.1993.tb03022.x | title = Intracranial choriocarcinoma causing precocious puberty and cured with combined modality therapy | journal = Journal of Paediatrics and Child Health | volume = 29 | issue = 6 | pages = 464–467 | year = 2008 | pmid =  8286166| s2cid = 21886832 }}</ref><ref>{{Cite journal | doi = 10.2165/00148581-200406040-00002 | last1 = Antoniazzi | first1 = F. | last2 = Zamboni | first2 = G. | s2cid = 21330464 | title = Central precocious puberty: current treatment options | journal = Paediatric Drugs | volume = 6 | issue = 4 | pages = 211–231 | year = 2004 | pmid = 15339200}}</ref>
** [[Congenital adrenal hyperplasia]]
** [[McCune–Albright syndrome]]
** [[Silver–Russell syndrome]]
** [[Familial male-limited precocious puberty]] (testotoxicosis)
* Exogenous hormones
** [[Environmental exogenous hormones]]
** As treatment for another condition

=== Isosexual and heterosexual ===
Generally, patients with precocious puberty develop [[phenotype|phenotypically]] appropriate [[secondary sexual characteristic]]s. This is called ''[[isosexual]]'' precocity.<ref name=":0">{{cite journal|last1=Jarzabek-Bielecka|first1=G|last2=Warchoł-Biedermann|first2=K|last3=Sowińska|first3=E|last4=Wachowiak-Ochmańska|first4=K|title=[Precocious puberty].|journal=Ginekologia Polska|date=April 2011|volume=82|issue=4|pages=281–6|pmid=21735696}}</ref>

In some cases, a patient may develop characteristics of the opposite sex. For example, a male may [[gynecomastia|develop breasts]] and other feminine characteristics, while a female may develop a deepened voice and facial hair. This is called ''heterosexual'' or ''contrasexual'' precocity. It is very rare in comparison to isosexual precocity and is usually the result of unusual circumstances. As an example, children with a very rare genetic condition called [[aromatase excess syndrome]] – in which exceptionally high circulating levels of estrogen are present – usually develop precocious puberty. Males and females are hyper-feminized by the syndrome.<ref name=":0" /> The "opposite" case would be the hyper-masculinisation of both male and female patients with [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency|congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency]], in which there is an excess of androgens. Thus, in the aromatase excess syndrome the precocious puberty is isosexual in females and heterosexual in males, whilst in the CAH it is isosexual in males and heterosexual in females.{{citation needed|date=August 2020}}

=== Research ===
Although the causes of early puberty are still somewhat unclear, girls who have a high-fat diet and are not physically active or are [[Obesity|obese]] are more likely to physically mature earlier.<ref name="Tanner">(Tanner, 1990).</ref><ref name="ncbi">{{Cite journal | last1 = Kaplowitz | first1 = P. B. | last2 = Slora | first2 = E. J. | last3 = Wasserman | first3 = R. C. | last4 = Pedlow | first4 = S. E. | last5 = Herman-Giddens | first5 = M. E. | title = Earlier onset of puberty in girls: relation to increased body mass index and race | journal = Pediatrics | volume = 108 | issue = 2 | pages = 347–353 | year = 2001 | pmid = 11483799| doi=10.1542/peds.108.2.347}}</ref><ref name="newscientist.com">{{cite magazine|first=Phil|last=McKenna|title=Childhood obesity brings early puberty for girls|magazine=[[New Scientist]]|date=2007-03-05|access-date=2010-05-22|url=https://www.newscientist.com/article/dn11307-childhood-obesity-brings-early-puberty-for-girls.html |archive-url = https://web.archive.org/web/20080419072722/http://www.newscientist.com/article/dn11307-childhood-obesity-brings-early-puberty-for-girls.html |archive-date = 2008-04-19}}</ref> "Obese girls, defined as at least 10 kilograms (22 pounds) overweight, had an 80 percent chance of developing breasts before their ninth birthday and starting menstruation before age 12 – the western average for menstruation is about 12.7 years."<ref name=newscientist.com/> In addition to diet and exercise habits, exposure to chemicals that mimic [[estrogen]] (known as [[xenoestrogen]]s) is another possible cause of early puberty in girls. [[Bisphenol A]], a [[xenoestrogen]] found in hard [[plastic]]s, has been shown to affect sexual development.<ref>{{Cite journal | last1 = Libertun | first1 = C. | last2 = Lux-Lantos | first2 = V. | last3 = Bianchi | first3 = M. | last4 = Fernández | first4 = M. | title = Neonatal Exposure to Bisphenol a Alters Reproductive Parameters and Gonadotropin Releasing Hormone Signaling in Female Rats | doi = 10.1289/ehp.0800267 | journal = Environmental Health Perspectives | year = 2009 | pmid =  19479018| pmc = 2685838| volume=117 | issue = 5 | pages=757–762| bibcode = 2009EnvHP.117..757F }}</ref> "Factors other than obesity, however, perhaps genetic and/or environmental ones, are needed to explain the higher prevalence of early puberty in black versus white girls."<ref name=ncbi/> While more girls are increasingly entering puberty at younger ages, new research indicates that some boys are actually starting later ([[delayed puberty]]).<ref name="www.msnbc.msn.com">{{cite web |first=Elizabeth|last=Cooney|title=Puberty gap: Obesity splits boys, girls. Adolescent males at top of the BMI chart may be delayed|publisher=[[NBC News]]|date=2010-02-11|access-date=2010-05-22|url=http://www.nbcnews.com/id/35332881|archive-url=https://web.archive.org/web/20160111055843/http://www.nbcnews.com/id/35332881|url-status=dead|archive-date=January 11, 2016}}</ref><ref name="www.sciencedaily.com">{{cite web|title=Childhood Obesity May Contribute to Later Onset of Puberty for Boys|website=[[Science Daily]]|date=February 2010|access-date=2010-05-22|url=https://www.sciencedaily.com/releases/2010/02/100201171651.htm}}</ref> "Increasing rates of obese and overweight children in the United States may be contributing to a later onset of puberty in boys, say researchers at the University of Michigan Health System."<ref name=www.sciencedaily.com/>

High levels of beta-hCG in serum and [[cerebrospinal fluid]] observed in a 9-year-old boy suggest a pineal gland tumor. The tumor is called a ''chorionic [[gonadotropin]] secreting [[pineal]] tumor''. Radiotherapy and chemotherapy reduced tumor and beta-hCG levels normalized.<ref>{{Cite journal | last1 = Kuo | first1 = H. C. | last2 = Sheen | first2 = J. M. | last3 = Wu | first3 = K. S. | last4 = Wei | first4 = H. H. | last5 = Hsiao | first5 = C. C. | title = Precocious puberty due to human chorionic gonadotropin-secreting pineal tumor | journal = Chang Gung Medical Journal | volume = 29 | issue = 2 | pages = 198–202 | year = 2006 | pmid = 16767969}}</ref>

In a study using neonatal melatonin on rats, results suggest that elevated melatonin could be responsible for some cases of early puberty.<ref>{{Cite journal | last1 = Esouifino | first1 = A. I. | last2 = Villanúa | first2 = M. A. | last3 = Agrasal | first3 = C. | doi = 10.1016/0022-4731(87)90194-4 | title = Effect of neonatal melatonin administration on sexual development in the rat | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 4–6 | pages = 1089–1093 | year = 1987 | pmid =  3121932}}</ref>

Familial cases of idiopathic central precocious puberty (ICPP) have been reported, leading researchers to believe there are specific genetic modulators of ICPP. Mutations in genes such as [[LIN28]],<ref name="pmid23133486">{{cite journal|last=Park|first=Sung Won |author2=Lee, Seung-Tae |author3=Sohn, Young Bae |author4=Cho, Sung Yoon |author5=Kim, Se-Hwa |author6=Kim, Su Jin |author7=Kim, Chi Hwa |author8=Ko, Ah-Ra |author9=Paik, Kyung-Hoon |author10=Kim, Jong-Won |author11=Jin, Dong-Kyu |title=polymorphisms are associated with central precocious puberty and early puberty in girls|journal=Korean Journal of Pediatrics|date=1 January 2012|volume=55|issue=10|pages=388–92|doi=10.3345/kjp.2012.55.10.388|pmid=23133486|pmc=3488615}}</ref><ref name="pmid19448623">{{cite journal|last=Ong|first=Ken K |author2=Elks, Cathy E |author3=Li, Shengxu |author4=Zhao, Jing Hua |author5=Luan, Jian'an |author6=Andersen, Lars B |author7=Bingham, Sheila A |author8=Brage, Soren |author9=Smith, George Davey |author10=Ekelund, Ulf |author11=Gillson, Christopher J |author12=Glaser, Beate |author13=Golding, Jean |author14=Hardy, Rebecca |author15=Khaw, Kay-Tee |author16=Kuh, Diana |author17=Luben, Robert |author18=Marcus, Michele |author19=McGeehin, Michael A |author20=Ness, Andrew R |author21=Northstone, Kate |author22=Ring, Susan M |author23=Rubin, Carol |author24=Sims, Matthew A |author25=Song, Kijoung |author26=Strachan, David P |author27=Vollenweider, Peter |author28=Waeber, Gerard |author29=Waterworth, Dawn M |author30=Wong, Andrew |author31=Deloukas, Panagiotis |author32=Barroso, Inês |author33=Mooser, Vincent |author34=Loos, Ruth J |author35=Wareham, Nicholas J |title=Genetic variation in LIN28B is associated with the timing of puberty|journal=Nature Genetics|date=16 May 2009|volume=41|issue=6|pages=729–733|doi=10.1038/ng.382|pmid=19448623|pmc=3000552}}</ref> and LEP and LEPR, which encode [[leptin]] and the leptin receptor,<ref name="pmid22391636">{{cite journal|last=Su|first=Pen-Hua|author2=Yang, Shun-Fa |author3=Yu, Ju-Shan |author4=Chen, Suh-Jen |author5= Chen, Jia-Yuh |title=Study of leptin levels and gene polymorphisms in patients with central precocious puberty|journal=Pediatric Research|date=15 February 2012|volume=71|issue=4–1|pages=361–367|doi=10.1038/pr.2011.69|pmid=22391636|doi-access=free}}</ref> have been associated with precocious puberty. The association between LIN28 and puberty timing was validated experimentally in vivo, when it was found that mice with ectopic over-expression of [[LIN28]] show an extended period of pre-pubertal growth and a significant delay in puberty onset.<ref name="pmid20512147">{{cite journal |vauthors=Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn WS, Viswanathan SR, Takeuchi A, Grasemann C, Rinn JL, Lopez MF, Hirschhorn JN, Palmert MR, Daley GQ | title = Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies | journal = Nat Genet | volume = 42 | issue = 7 | pages = 626–30 |date=July 2010 | pmid = 20512147 | doi = 10.1038/ng.593 | pmc = 3069638 }}</ref>

Mutations in the kisspeptin (KISS1) and its receptor, KISS1R (also known as GPR54), involved in GnRH secretion and puberty onset, are also thought to be the cause for ICPP<ref name="pmid21664234">{{cite journal|last=Teles|first=Milena Gurgel|author2=Silveira, Leticia Ferreira Gontijo |author3=Tusset, Cintia |author4= Latronico, Ana Claudia |s2cid=27207961|title=New genetic factors implicated in human GnRH-dependent precocious puberty: The role of kisspeptin system|journal=Molecular and Cellular Endocrinology|date=1 October 2011|volume=346|issue=1–2|pages=84–90|doi=10.1016/j.mce.2011.05.019|pmid=21664234}}</ref><ref name="pmid20237166">{{cite journal|last=Silveira|first=LG |author2=Noel, SD |author3=Silveira-Neto, AP |author4=Abreu, AP |author5=Brito, VN |author6=Santos, MG |author7=Bianco, SD |author8=Kuohung, W |author9=Xu, S |author10=Gryngarten, M |author11=Escobar, ME |author12=Arnhold, IJ |author13=Mendonca, BB |author14=Kaiser, UB |author15=Latronico, AC|title=Mutations of the KISS1 gene in disorders of puberty|journal=The Journal of Clinical Endocrinology and Metabolism|date=May 2010|volume=95|issue=5|pages=2276–80|doi=10.1210/jc.2009-2421|pmid=20237166|pmc=2869552}}</ref> However, this is still a controversial area of research, and some investigators found no association of mutations in the LIN28 and KISS1/KISS1R genes to be the common cause underlying ICPP.<ref name="pmid21939553">{{cite journal|last=Tommiska|first=Johanna|author2=Sørensen, Kaspar |author3=Aksglaede, Lise |author4=Koivu, Rosanna |author5=Puhakka, Lea |author6=Juul, Anders |author7= Raivio, Taneli |title=LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty|journal=BMC Research Notes|date=1 January 2011|volume=4|issue=1|pages=363|doi=10.1186/1756-0500-4-363|pmid=21939553|pmc=3184284 |doi-access=free }}</ref>

The gene MKRN3, which is a maternally imprinted gene, was first cloned by Jong et al. in 1999.  MKRN3 was originally named Zinc finger protein 127.  It is located on human chromosome 15 on the long arm in the [[Prader-Willi syndrome]] critical region2, and has since been identified as a cause of premature sexual development or CPP.<ref>{{cite journal |vauthors=Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, etal | year = 2013 | title = Central precocious puberty caused by mutations in the imprinted gene MKRN3 | doi = 10.1056/nejmoa1302160| pmid = 23738509 | journal = N Engl J Med | volume = 368 | issue = 26| pages = 2467–2475 | pmc = 3808195 }}</ref> The identification of mutations in MKRN3 leading to sporadic cases of CPP has been a significant contribution to better understanding the mechanism of puberty.<ref>{{cite journal |vauthors=Macedo DB, Abreu AP, Reis AC, Montenegro LR, Dauber A, Beneduzzi D, Cukier P, Silveira LF, Teles MG, Carroll RS, etal | year = 2014 | title = Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3 | journal = J Clin Endocrinol Metab | volume = 99 | issue = 6| pages = E1097–1103 | doi=10.1210/jc.2013-3126| pmid = 24628548 | pmc = 4037732}}</ref> MKRN3 appears to act as a "brake" on the central hypothalamic-pituitary access.  Thus, loss of function mutations of the protein allow early activation of the GnRH pathway and cause phenotypic CPP. Patients with a MKRN3 mutation all display the classic signs of CCP including early breast and testes development, increased bone aging and elevated hormone levels of GnRH and LH.<ref>{{cite journal |vauthors=Abreu AP, Macedo DB, Brito VN, etal | year = 2015 | title = A new pathway in the control of the initiation of puberty: the MKRN3 gene | journal = Journal of Molecular Endocrinology | volume = 54 | issue = 3| pages = R131–R139 | doi=10.1530/jme-14-0315| pmid = 25957321 | pmc = 4573396}}</ref>