View source for Gigantism

{{Short description|Human growth disorder}}
{{Distinguish|Deep-sea gigantism|Island gigantism}}
{{Use dmy dates|date=July 2022}}
{{Infobox medical condition (new)
| name          = Gigantism
| synonyms      = Giantism
| image         = Robert_Wadlow_postcard.jpg
| caption       = [[Robert Wadlow]] stood {{height|ft=8|in=11}}
| pronounce     = 
| field         = [[Endocrinology]]
| symptoms      = Abnormal growth in height or size, weakness and [[insomnia]]
| complications = Excessive sweating, [[delayed puberty]], weakness and severe or recurrent headaches, strokes, vomiting or nausea, high fevers, daytime sleepiness or narcolepsy, dry mouth, frequent diarrheas, stomachaches, ear pains, memory loss, back pains, excessive muscle cramps, chest pains 
| onset         = 
| types         = 
| causes        = [[Hyperplasia]] in the [[pituitary gland]]
| risks         = 
| diagnosis     = 
| differential  = 
| prevention    = 
| treatment     = Surgically remove the enlarged [[pituitary gland]]
| medication    = [[Octreotide]], [[lanreotide]] or [[pegvisomant]]
| prognosis     = 
| frequency     = 
| deaths        = 
| image_size    = 220
}}
'''Gigantism''' ({{langx|el|γίγας}}, ''gígas'', "[[wiktionary:giant|giant]]", plural γίγαντες, ''gígantes''), also known as '''giantism''', is a condition characterized by excessive growth and height significantly above [[average height|average]]. In humans, this condition is caused by over-production of [[growth hormone]] in childhood.<ref>{{DorlandsDict|four/000044375|Gigantism}}</ref><ref>{{Cite web|url=http://pituitary.ucla.edu/resources|title=Gigantism {{!}} UCLA Pituitary Tumor Program|website=pituitary.ucla.edu|access-date=2017-04-27}}</ref><ref>{{Cite web|url=https://medlineplus.gov/ency/article/001174.htm|title=Gigantism: MedlinePlus Medical Encyclopedia|website=medlineplus.gov|language=en|access-date=2017-04-27}}</ref><ref>{{Cite web|date=2017-01-07|title=Gigantism and Acromegaly: Practice Essentials, Background, Pathophysiology and Etiology|url=http://emedicine.medscape.com/article/925446-overview}}</ref><ref>{{Cite news|url=https://www.msdmanuals.com/home/hormonal-and-metabolic-disorders/pituitary-gland-disorders/gigantism-and-acromegaly|title=Gigantism and Acromegaly – Hormonal and Metabolic Disorders – MSD Manual Consumer Version|work=MSD Manual Consumer Version|access-date=2017-04-27|language=en}}</ref>

It is a rare disorder resulting from increased levels of growth hormone before the fusion of the [[Epiphyseal plate|growth plate]] which usually occurs at some point soon after puberty. This increase is most often due to abnormal tumor growths on the [[pituitary gland]].<ref name=":0">{{Cite journal|last1=Rostomyan|first1=Liliya|last2=Daly|first2=Adrian F.|last3=Petrossians|first3=Patrick|last4=Nachev|first4=Emil|last5=Lila|first5=Anurag R.|last6=Lecoq|first6=Anne-Lise|last7=Lecumberri|first7=Beatriz|last8=Trivellin|first8=Giampaolo|last9=Salvatori|first9=Roberto|date=October 2015|title=Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients|journal=Endocrine-Related Cancer|volume=22|issue=5|pages=745–757|doi=10.1530/ERC-15-0320|issn=1479-6821|pmid=26187128|pmc=6533620}}</ref><ref name=":1">{{Cite journal|last1=Rostomyan|first1=Liliya|last2=Potorac|first2=Iulia|last3=Beckers|first3=Pablo|last4=Daly|first4=Adrian F.|last5=Beckers|first5=Albert|title=AIP mutations and gigantism|journal=Annales d'Endocrinologie|volume=78|issue=2|pages=123–130|doi=10.1016/j.ando.2017.04.012|pmid=28483363|year=2017}}</ref> Gigantism should not be confused with [[acromegaly]], the adult form of the disorder, characterized by [[Somatic (biology)|somatic]] enlargement specifically in the extremities and face.<ref>{{Cite journal|last1=Chanson|first1=Philippe|last2=Salenave|first2=Sylvie|date=2008-06-25|title=Acromegaly|journal=Orphanet Journal of Rare Diseases|volume=3|pages=17|doi=10.1186/1750-1172-3-17|pmid=18578866|pmc=2459162|issn=1750-1172 |doi-access=free }}</ref><ref>{{Cite journal|last1=Capatina|first1=Cristina|last2=Wass|first2=John A. H.|date=August 2015|title=60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly|journal=The Journal of Endocrinology|volume=226|issue=2|pages=T141–160|doi=10.1530/JOE-15-0109|issn=1479-6805|pmid=26136383|doi-access=free}}</ref>

==Cause==
Gigantism is characterized by an excess of [[growth hormone]] (GH). The excess of growth hormone that brings about gigantism is virtually always caused by pituitary growths ([[adenoma]]s).<ref name=":1" /> These adenomas are on the [[Anterior pituitary|anterior pituitary gland]]. They can also cause overproduction of GH's hypothalamic precursor known as [[Growth hormone–releasing hormone|growth hormone releasing hormone]] (GHRH).<ref>{{Cite journal|last1=Zimmerman|first1=D|last2=Young|first2=W F|last3=Ebersold|first3=M J|last4=Scheithauer|first4=B W|last5=Kovacs|first5=K|last6=Horvath|first6=E|last7=Whitaker|first7=M D|last8=Eberhardt|first8=N L|last9=Downs|first9=T R|date=1993-01-01|title=Congenital gigantism due to growth hormone-releasing hormone excess and pituitary hyperplasia with adenomatous transformation.|journal=The Journal of Clinical Endocrinology & Metabolism|language=en|volume=76|issue=1|pages=216–222|doi=10.1210/jcem.76.1.8421089|pmid=8421089|issn=0021-972X}}</ref>

As a result of the excessive amounts of growth hormone, children achieve heights that are well above normal ranges.<ref>{{Cite journal|last1=Eugster|first1=Erica A.|last2=Pescovitz|first2=Ora H.|date=1999-12-01|title=Gigantism|journal=The Journal of Clinical Endocrinology & Metabolism|volume=84|issue=12|pages=4379–4384|doi=10.1210/jcem.84.12.6222|pmid=10599691|issn=0021-972X|doi-access=free}}</ref> The specific age of onset for gigantism varies between patients and gender, but the common age that excessive growth symptoms start to appear has been found to be around 13 years.<ref name=":0" /> Other health complications, such as [[hypertension]], may occur in [[Pediatrics|pediatric]] patients with [[Secretion|hyper-secretion]] of growth hormone. Characteristics more similar to those seen in [[acromegaly]] may occur in patients that are closer in age to [[adolescence]] since they are nearing growth plate fusion.<ref>{{Cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK278971/|title=Endotext|last1=Murray|first1=P. G.|last2=Clayton|first2=P. E.|date=2000|publisher=MDText.com, Inc.|editor-last=De Groot|editor-first=Leslie J.|location=South Dartmouth (MA)|pmid=25905205|editor-last2=Chrousos|editor-first2=George|editor-last3=Dungan|editor-first3=Kathleen|editor-last4=Feingold|editor-first4=Kenneth R.|editor-last5=Grossman|editor-first5=Ashley|editor-last6=Hershman|editor-first6=Jerome M.|editor-last7=Koch|editor-first7=Christian|editor-last8=Korbonits|editor-first8=Márta|editor-last9=McLachlan|editor-first9=Robert|chapter=Disorders of Growth Hormone in Childhood}}</ref>

===Hormonal cause===
[[Growth hormone]] (GH) and [[insulin-like growth factor 1|insulin-like growth factor-I]] (IGF-I) are two substances that have been identified as influencing growth plate formation and bone growth and, therefore, gigantism. Their specific mechanisms are still not well understood.<ref name=":0" /><ref>{{Cite journal|last=Shim|first=Kye Shik|date=March 2015|title=Pubertal growth and epiphyseal fusion|journal=Annals of Pediatric Endocrinology & Metabolism|volume=20|issue=1|pages=8–12|doi=10.6065/apem.2015.20.1.8|issn=2287-1012|pmc=4397276|pmid=25883921}}</ref>

More broadly, GH and IGF have both been identified to be involved in most stages of growth: embryonic, prenatal, and postnatal.<ref name=":3">{{Cite journal|last=Laron|first=Z|date=October 2001|title=Insulin-like growth factor 1 (IGF-1): a growth hormone|journal=Molecular Pathology|volume=54|issue=5|pages=311–316|issn=1366-8714|pmc=1187088|pmid=11577173|doi=10.1136/mp.54.5.311}}</ref><ref name=":4">{{Cite journal|last1=Lupu|first1=Floria|last2=Terwilliger|first2=Joseph D.|last3=Lee|first3=Kaechoong|last4=Segre|first4=Gino V.|last5=Efstratiadis|first5=Argiris|title=Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth|journal=Developmental Biology|volume=229|issue=1|pages=141–162|doi=10.1006/dbio.2000.9975|pmid=11133160|year=2001|doi-access=free}}</ref>  Moreover, the receptor gene for IGF has been shown to be particularly influential throughout various stages of development, especially prenatally. This is the same for GH receptor genes which have been known to drive overall growth throughout various pathways.<ref name=":3" /><ref name=":5">{{Cite journal|last1=Sanders|first1=Esmond J.|last2=Harvey|first2=Steve|title=Growth hormone as an early embryonic growth and differentiation factor|journal=Anatomy and Embryology|volume=209|issue=1|pages=1–9|doi=10.1007/s00429-004-0422-1|pmid=15480774|year=2004|s2cid=19528310}}</ref>

Growth hormone is a precursor ([[Upstream and downstream (DNA)|upstream]]) of IGF-I, but each has its independent role in hormonal pathways. Yet both seem to ultimately come together to have a joint effect on growth.<ref name=":4" />

===Diagnostic testing===
Evaluation of growth hormone hypersecretion cannot be excluded with a single normal GH level due to [[diurnal variation]]. However, a random blood sample showing markedly elevated GH is adequate for diagnosis of GH hyper-secretion. Additionally, a high-normal GH level that fails to suppress with administration of glucose is also sufficient for a diagnosis of GH hyper-secretion.<ref name=":6">De Mais, Daniel.  ASCP Quick Compendium of Clinical Pathology, 2nd Ed. ASCP Press, Chicago, 2009.</ref>

Insulin-like growth factor-1 (IGF-1) is an excellent test for evaluation of GH hyper-secretion. It does not undergo diurnal variation and will thus be consistently elevated in GH hyper-secretion and therefore patients with gigantism. A single normal IGF-1 value will reliably exclude GH hypersecretion.<ref name=":6" />

==Genetics==
[[File:Dwarfism and Gigantism.png|thumb|left|upright|Comparative illustration from Talbot's 1889 work ''[[Degeneration theory|Degeneracy]]: its causes, signs and results'']]
Finding a specific [[Genetics|genetic]] cause for gigantism has proven to be difficult. Gigantism is the primary example of growth hormone hyper-secretion disorders, a group of illnesses that are not yet deeply understood.<ref name=":0" />

Some common [[mutation]]s have been associated with gigantism. Pediatric gigantism patients have shown to have duplications of genes on a specific chromosome, Xq26. Typically, these patients also experienced an onset of typical gigantism symptoms before reaching the age of 5. This indicates a possible linkage between [[gene duplication]]s and the gigantism.<ref>{{Cite journal|last1=Trivellin|first1=Giampaolo|last2=Daly|first2=Adrian F.|last3=Faucz|first3=Fabio R.|last4=Yuan|first4=Bo|last5=Rostomyan|first5=Liliya|last6=Larco|first6=Darwin O.|last7=Schernthaner-Reiter|first7=Marie Helene|last8=Szarek|first8=Eva|last9=Leal|first9=Letícia F.|title=Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation|journal=New England Journal of Medicine|volume=371|issue=25|pages=2363–2374|doi=10.1056/nejmoa1408028|pmid=25470569|pmc=4291174|year=2014}}</ref>

Additionally, DNA mutations in the aryl hydrocarbon receptor interacting protein ([[AIP (gene)|AIP]]) gene are common in gigantism patients. They have been found to be present in about 29 percent of patients with gigantism.<ref name=":1" /> AIP is labeled as a [[tumor suppressor gene]] and a [[pituitary adenoma]] disposition gene.<ref name=":1" /><ref name=":7">{{Cite journal|last1=Beckers|first1=Albert|last2=Aaltonen|first2=Lauri A.|last3=Daly|first3=Adrian F.|last4=Karhu|first4=Auli|date=2013-04-01|title=Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene|journal=Endocrine Reviews|volume=34|issue=2|pages=239–277|doi=10.1210/er.2012-1013|pmid=23371967|issn=0163-769X|pmc=3610678}}</ref>

Mutations in AIP, found by [[DNA sequencing|sequencing]], can have deleterious effects by inducing the development of pituitary adenomas which in turn can cause gigantism.<ref name=":1" /><ref name=":7" />

Two specific mutations in the AIP gene have been identified as possible causes of pituitary adenomas. These mutations also have the ability to cause adenoma growth to occur early in life.<ref>{{Cite journal|last1=Vierimaa|first1=Outi|last2=Georgitsi|first2=Marianthi|last3=Lehtonen|first3=Rainer|last4=Vahteristo|first4=Pia|last5=Kokko|first5=Antti|last6=Raitila|first6=Anniina|last7=Tuppurainen|first7=Karoliina|last8=Ebeling|first8=Tapani M. L.|last9=Salmela|first9=Pasi I.|date=2006-05-26|title=Pituitary Adenoma Predisposition Caused by Germline Mutations in the AIP Gene|journal=Science|language=en|volume=312|issue=5777|pages=1228–1230|doi=10.1126/science.1126100|issn=0036-8075|pmid=16728643|bibcode=2006Sci...312.1228V|s2cid=37013760}}</ref> This is typical in gigantism.

Additionally, a large variety of other known genetic disorders have been found to influence the development of gigantism such as [[Multiple endocrine neoplasia type 1|multiple endocrine neoplasia type 1 and 4]], [[McCune–Albright syndrome]], [[Carney complex]], familial isolated pituitary adenoma, X-linked acrogigantism (X-LAG).<ref name=":1" /><ref>{{Cite journal|last1=Rostomyan|first1=Liliya|last2=Daly|first2=Adrian F.|last3=Beckers|first3=Albert|title=Pituitary gigantism: Causes and clinical characteristics|journal=Annales d'Endocrinologie|volume=76|issue=6|pages=643–649|doi=10.1016/j.ando.2015.10.002|pmid=26585365|year=2015}}</ref>

Although various gene mutations have been associated with gigantism, over 50 percent of cases cannot be linked to genetic causes, showing the complex nature of the disorder.<ref name=":0" />

==Treatment==
Many treatments for gigantism receive criticism and are not accepted as ideal. Various treatments involving surgery and drugs have been used to treat gigantism.<ref name=":2">{{Cite journal|last1=Goldenberg|first1=Naila|last2=Racine|first2=Michael S.|last3=Thomas|first3=Pamela|last4=Degnan|first4=Bernard|last5=Chandler|first5=William|last6=Barkan|first6=Ariel|date=2008-08-01|title=Treatment of Pituitary Gigantism with the Growth Hormone Receptor Antagonist Pegvisomant|journal=The Journal of Clinical Endocrinology & Metabolism|volume=93|issue=8|pages=2953–2956|doi=10.1210/jc.2007-2283|pmid=18492755|issn=0021-972X|pmc=2515082}}</ref>

===Pharmaceuticals===
[[Pegvisomant]] is one [[pharmaceutical drug]] which has received attention for being a possible treatment route for gigantism. Reduction of the levels of [[Insulin-like growth factor 1|IGF-I]] as a result of pegvisomant administration can be incredibly beneficial for the pediatric gigantism patients.<ref name=":2"/>

After treatment with pegvisomant, high growth rates, a feature characteristic of gigantism, can be significantly decreased.<ref name=":2" /> Pegvisomant has been seen to be a powerful alternative to other treatments such as [[somatostatin]] analogues, a common treatment method for acromegaly, if drug treatment is paired with [[Radiation therapy|radiation]].<ref>{{Cite journal|last1=Rix|first1=M.|last2=Laurberg|first2=P.|last3=Hoejberg|first3=A. S.|last4=Brock-Jacobsen|first4=B.|date=2005-08-01|title=Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl|journal=European Journal of Endocrinology|language=en|volume=153|issue=2|pages=195–201|doi=10.1530/eje.1.01956|issn=0804-4643|pmid=16061823|doi-access=free}}</ref>

Finding the optimal level of pegvisomant is important so normal body growth is not negatively affected. In order to do this, [[titration]] of the medication can be used as a way to find the proper administration level.<ref name=":2"/>

See [[acromegaly]] for additional treatment possibilities.

==Terminology==
{{multiple image
 | align = right
 | total_width = 400

 | image1 = Seeman Cajanus.jpg
 | caption1 = [[Daniel Cajanus]] (1704–1749), a [[Finland|Finnish]] giant

 | image2 = André the Giant in the late '80s.jpg
 | caption2 = [[André the Giant]], a [[wrestler]] and actor in ''[[The Princess Bride (film)|The Princess Bride]]''

 | image3 = Anna Swan with her parents.jpg
 | caption3 = Giantess [[Anna Swan]] with her parents
}}
The term is typically applied to those whose height is not just in the upper 1% of the population but several [[standard deviation]]s above mean for persons of the same sex, age, and ethnic ancestry. The term is seldom applied to those who are simply "tall" or "above average" whose heights appear to be the result of normal [[genetics]] and nutrition. Gigantism is usually caused by a [[Pituitary adenoma|tumor on the pituitary gland]] of the brain. It causes growth of  the hands, face, and feet.<ref>{{cite web |url=http://www.question.com/link/gigantis.html |title=Gigantism |publisher=Question.com |access-date=2012-03-14 |archive-url=https://web.archive.org/web/20120313201250/http://www.question.com/link/gigantis.html |archive-date=2012-03-13 |url-status=dead }}</ref>{{better source needed|date=July 2015}} In some cases the condition can be passed on genetically through a mutated gene.<ref>[https://www.nytimes.com/2011/01/06/health/06giant.html In a Giant's Story, a New Chapter Writ by His DNA – By Gina Kolata. The New York Times, January 5, 2011]</ref>

Other names somewhat obsolete for this pathology are hypersoma (Greek: ''hyper'' over the normal level; ''soma'' body) and somatomegaly (Greek; ''soma'' body, [[Genitive case|genitive]] ''somatos''  of the body; ''megas'', gen. ''megalou'' great).  In the past, while many of them were social outcasts because of their height, some (usually unintentionally) found employment in [[Frederick William I of Prussia|Friedrich Wilhelm I]]'s famous [[Potsdam Giants]] regiment.

Many of those who have been identified with gigantism have had multiple health problems involving the [[circulatory system|circulatory]] or [[skeletal system]], as the strain of maintaining a large, heavy body places abnormal demands on both the [[bone]]s and the [[heart]].

==See also==
{{Columns-list|colwidth=30em|
*[[Acromegaly]]
*[[Deep-sea gigantism]]
*[[Dwarfism]]
*[[Giant of Castelnau]]
*[[Goliath]]
*[[Homo heidelbergensis]]
*[[Hypothalamic–pituitary–somatic axis]]
*[[Island gigantism]]
*[[List of tallest people]]
*[[Local gigantism]]
*[[Marfan syndrome]]
*[[Megafauna]]
*[[Nephilim]]
*[[Overgrowth syndrome]]
*[[Sotos syndrome]]
}}

==References==
{{Reflist}}

==Bibliography==
* {{cite book
|last       = Driesbach
|first      = Jason
|title      = 4QSamuela and the Text of Samuel
|url        = https://books.google.com/books?id=tIr2DQAAQBAJ&pg=PA73
|year       = 2016
|publisher  = BRILL
|isbn       = 978-90-04-32420-6 
}}

== External links ==
{{Medical resources
|  DiseasesDB     = 30730 
|  ICD10          = {{ICD10|E|22|0|e|20}}, {{ICD10|E|34|4|e|20}} 
|  ICD9           = {{ICD9|253.0}} 
|  ICDO           = 
|  OMIM           = 
|  MedlinePlus    = 001174 
|  eMedicineSubj  = 
|  eMedicineTopic = 
|  MeshID         = D005877
|ICD11={{ICD11|5A60.0}}, {{ICD11|5B12}}}}
{{Commons category}}
* {{cite web |url= http://www.gghjournal.com/pdf/volume_10/10-1/feature_1_10_1.pdf |title= Brief overview of overgrowth syndromes in childhood |access-date= 2004-08-30 |archive-date= 2004-05-22 |archive-url= https://web.archive.org/web/20040522113628/http://www.gghjournal.com/pdf/volume_10/10-1/feature_1_10_1.pdf |url-status= dead }}&nbsp;{{small|(2.95&nbsp;MB)}}
* [http://clinicaltrials.gov/show/NCT01673646 Gigantism Clinical Trials from U.S. National Institutes of Health]
* [https://www.nlm.nih.gov/medlineplus/ency/article/001174.htm Gigantism information from U.S. National Library of Medicine, U.S. Department of Health and Human Services & the National Institutes of Health ]
* [https://www.ncbi.nlm.nih.gov/pubmed/11081170 Epidemiology of acromegaly from Pubmed.gov US National Library of Medicine & National Institutes of Health]
{{Growth disorder}}
{{Authority control}}

[[Category:Growth disorders]]
[[Category:Human height]]
[[Category:Growth hormones]]
[[Category:Neuroendocrinology]]
[[Category:People with gigantism| ]]
[[Category:Rare diseases]]