Growth hormone deficiency pathophysiology: Difference between revisions
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==Genetics== | ==Genetics== | ||
==== ''POU1F1'' gene mutations ==== | ==== ''[[POU1F1]]'' gene mutations ==== | ||
* It is the most common known genetic cause of combined pituitary hormone deficiency.<ref name="pmid26608600">{{cite journal| author=Ziemnicka K, Budny B, Drobnik K, Baszko-Błaszyk D, Stajgis M, Katulska K et al.| title=Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency. | journal=J Appl Genet | year= 2016 | volume= 57 | issue= 3 | pages= 373-81 | pmid=26608600 | doi=10.1007/s13353-015-0328-z | pmc=4963446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26608600 }}</ref> | * It is the most common known genetic cause of combined pituitary hormone deficiency.<ref name="pmid26608600">{{cite journal| author=Ziemnicka K, Budny B, Drobnik K, Baszko-Błaszyk D, Stajgis M, Katulska K et al.| title=Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency. | journal=J Appl Genet | year= 2016 | volume= 57 | issue= 3 | pages= 373-81 | pmid=26608600 | doi=10.1007/s13353-015-0328-z | pmc=4963446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26608600 }}</ref> | ||
* It is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone releasing hormone (GHRH) receptor.<ref name="pmid1977085">{{cite journal| author=Li S, Crenshaw EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG| title=Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. | journal=Nature | year= 1990 | volume= 347 | issue= 6293 | pages= 528-33 | pmid=1977085 | doi=10.1038/347528a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1977085 }}</ref> | * It is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone releasing hormone (GHRH) receptor.<ref name="pmid1977085">{{cite journal| author=Li S, Crenshaw EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG| title=Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. | journal=Nature | year= 1990 | volume= 347 | issue= 6293 | pages= 528-33 | pmid=1977085 | doi=10.1038/347528a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1977085 }}</ref> | ||
* ''PROP1'' mutations result in failure to activate ''POU1F1/Pit1'' gene expression and probably cause pituitary hypoplasia.<ref name="pmid9462743">{{cite journal| author=Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM et al.| title=Mutations in PROP1 cause familial combined pituitary hormone deficiency. | journal=Nat Genet | year= 1998 | volume= 18 | issue= 2 | pages= 147-9 | pmid=9462743 | doi=10.1038/ng0298-147 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9462743 }}</ref> | * ''PROP1'' mutations result in failure to activate ''POU1F1/Pit1'' gene expression and probably cause pituitary hypoplasia.<ref name="pmid9462743">{{cite journal| author=Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM et al.| title=Mutations in PROP1 cause familial combined pituitary hormone deficiency. | journal=Nat Genet | year= 1998 | volume= 18 | issue= 2 | pages= 147-9 | pmid=9462743 | doi=10.1038/ng0298-147 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9462743 }}</ref> | ||
==== GH1 gene mutations ==== | ==== [[GH1]] gene mutations ==== | ||
* It is ''GH1'' is the gene encoding GH, located on chromosome. | * It is ''GH1'' is the gene encoding GH, located on chromosome 17. | ||
* Gene deletions, frameshift mutations, and nonsense mutations of ''GH1'' have been described as causes of familial GHD. | * Gene deletions, frameshift mutations, and nonsense mutations of ''GH1'' have been described as causes of familial GHD. | ||
==== Syndrome of bioinactive GH ==== | ==== Syndrome of [[bioinactive GH]] ==== | ||
* Bioinactive GH has the main symptoms and signs of isolated GHD with normal basal GH levels and low insulin-like growth factor I concentrations.<ref name="pmid15713716">{{cite journal| author=Besson A, Salemi S, Deladoëy J, Vuissoz JM, Eblé A, Bidlingmaier M et al.| title=Short stature caused by a biologically inactive mutant growth hormone (GH-C53S). | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 5 | pages= 2493-9 | pmid=15713716 | doi=10.1210/jc.2004-1838 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15713716 }}</ref> | * Bioinactive GH has the main symptoms and signs of isolated GHD with normal basal GH levels and low insulin-like growth factor I concentrations.<ref name="pmid15713716">{{cite journal| author=Besson A, Salemi S, Deladoëy J, Vuissoz JM, Eblé A, Bidlingmaier M et al.| title=Short stature caused by a biologically inactive mutant growth hormone (GH-C53S). | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 5 | pages= 2493-9 | pmid=15713716 | doi=10.1210/jc.2004-1838 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15713716 }}</ref> | ||
==== '''GH receptor signal transduction''' ==== | ==== '''GH receptor signal [[transduction]]''' ==== | ||
* It is essential for normal signaling of the GH receptor. Mutations in the gene encoding signal transducer decrease the response of receptors to GH.<ref name="pmid17389811">{{cite journal| author=Hwa V, Camacho-Hübner C, Little BM, David A, Metherell LA, El-Khatib N et al.| title=Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. | journal=Horm Res | year= 2007 | volume= 68 | issue= 5 | pages= 218-24 | pmid=17389811 | doi=10.1159/000101334 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17389811 }}</ref> | * It is essential for normal signaling of the GH receptor. Mutations in the gene encoding signal transducer decrease the response of receptors to GH.<ref name="pmid17389811">{{cite journal| author=Hwa V, Camacho-Hübner C, Little BM, David A, Metherell LA, El-Khatib N et al.| title=Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. | journal=Horm Res | year= 2007 | volume= 68 | issue= 5 | pages= 218-24 | pmid=17389811 | doi=10.1159/000101334 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17389811 }}</ref> | ||
==== '''IGF-I gene mutations''' ==== | ==== '''[[Insulin-like growth factor-I|IGF-I]] gene mutations''' ==== | ||
* Mutations in the gene encoding IGF-I cause a unique syndrome of GHD.<ref name="pmid24243634">{{cite journal| author=Batey L, Moon JE, Yu Y, Wu B, Hirschhorn JN, Shen Y et al.| title=A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 1 | pages= E153-9 | pmid=24243634 | doi=10.1210/jc.2013-3106 | pmc=3879666 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24243634 }}</ref> | * Mutations in the gene encoding IGF-I cause a unique syndrome of GHD.<ref name="pmid24243634">{{cite journal| author=Batey L, Moon JE, Yu Y, Wu B, Hirschhorn JN, Shen Y et al.| title=A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 1 | pages= E153-9 | pmid=24243634 | doi=10.1210/jc.2013-3106 | pmc=3879666 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24243634 }}</ref> | ||
* patients with IGF-I gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, and sensorineural hearing loss. | * patients with IGF-I gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, and sensorineural hearing loss. | ||
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* Mutations in the gene coding for it causes less stable and subsequently less effect.<ref name="pmid19729943">{{cite journal| author=Domené HM, Hwa V, Argente J, Wit JM, Wit JM, Camacho-Hübner C et al.| title=Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences. | journal=Horm Res | year= 2009 | volume= 72 | issue= 3 | pages= 129-41 | pmid=19729943 | doi=10.1159/000232486 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19729943 }}</ref> | * Mutations in the gene coding for it causes less stable and subsequently less effect.<ref name="pmid19729943">{{cite journal| author=Domené HM, Hwa V, Argente J, Wit JM, Wit JM, Camacho-Hübner C et al.| title=Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences. | journal=Horm Res | year= 2009 | volume= 72 | issue= 3 | pages= 129-41 | pmid=19729943 | doi=10.1159/000232486 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19729943 }}</ref> | ||
==== '''IGF-I receptor mutations''' ==== | ==== '''[[Insulin-like growth factor-I|IGF-I]] receptor mutations''' ==== | ||
* Mutations in the gene encoding the receptor for IGF-I result in partial loss of function of the IGF-I receptor.<ref name="pmid22309212">{{cite journal| author=Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi J, Hanaki K et al.| title=Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation. | journal=Clin Endocrinol (Oxf) | year= 2012 | volume= 77 | issue= 2 | pages= 246-54 | pmid=22309212 | doi=10.1111/j.1365-2265.2012.04357.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22309212 }}</ref> | * Mutations in the gene encoding the receptor for [[Insulin-like growth factor-I|IGF-I]] result in partial loss of function of the IGF-I receptor.<ref name="pmid22309212">{{cite journal| author=Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi J, Hanaki K et al.| title=Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation. | journal=Clin Endocrinol (Oxf) | year= 2012 | volume= 77 | issue= 2 | pages= 246-54 | pmid=22309212 | doi=10.1111/j.1365-2265.2012.04357.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22309212 }}</ref> | ||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
Revision as of 22:00, 14 August 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]
Overview
Pathophysiology
- The somatotroph cells of the anterior pituitary gland produce growth hormone.
- They are regulated by two hypothalamic hormones; GH-releasing hormone (GHRH) stimulates and somatostatin inhibits them.
- GH best-known effect is increasing body mass:
- GH increases total body protein content and is associated with an increase in amino acid incorporation into cartilage and bone.[1]
- GH stimulates lipolysis decreasing total body fat content.
- GH also increases bone mass by stimulating skeletal insulin-like growth factor-I and causing hypertrophy of osteoblasts, bone remodeling, and net mineralization.[2]
- GH causes epiphyseal plate widening and cartilage growth.
- GH deficiency results in alterations in the physiology of different systems of the body, manifesting as altered lipid metabolism, increased subcutaneous visceral fat, decreased muscle mass, decreased bone density, low exercise performance, and reduced quality of life.
Genetics
POU1F1 gene mutations
- It is the most common known genetic cause of combined pituitary hormone deficiency.[3]
- It is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone releasing hormone (GHRH) receptor.[4]
- PROP1 mutations result in failure to activate POU1F1/Pit1 gene expression and probably cause pituitary hypoplasia.[5]
GH1 gene mutations
- It is GH1 is the gene encoding GH, located on chromosome 17.
- Gene deletions, frameshift mutations, and nonsense mutations of GH1 have been described as causes of familial GHD.
Syndrome of bioinactive GH
- Bioinactive GH has the main symptoms and signs of isolated GHD with normal basal GH levels and low insulin-like growth factor I concentrations.[6]
GH receptor signal transduction
- It is essential for normal signaling of the GH receptor. Mutations in the gene encoding signal transducer decrease the response of receptors to GH.[7]
IGF-I gene mutations
- Mutations in the gene encoding IGF-I cause a unique syndrome of GHD.[8]
- patients with IGF-I gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, and sensorineural hearing loss.
Defective stabilization of circulating IGF-I
- Acid-labile subunit is important for the stabilization of the IGF-I.
- Mutations in the gene coding for it causes less stable and subsequently less effect.[9]
IGF-I receptor mutations
- Mutations in the gene encoding the receptor for IGF-I result in partial loss of function of the IGF-I receptor.[10]
References
- ↑ MURPHY WR, DAUGHADAY WH, HARTNETT C (1956). "The effect of hypophysectomy and growth hormone on the incorporation of labeled sulfate into tibial epiphyseal and nasal cartilage of the rat". J Lab Clin Med. 47 (5): 715–22. PMID 13319878.
- ↑ Veldhuis JD, Roemmich JN, Richmond EJ, Rogol AD, Lovejoy JC, Sheffield-Moore M; et al. (2005). "Endocrine control of body composition in infancy, childhood, and puberty". Endocr Rev. 26 (1): 114–46. doi:10.1210/er.2003-0038. PMID 15689575.
- ↑ Ziemnicka K, Budny B, Drobnik K, Baszko-Błaszyk D, Stajgis M, Katulska K; et al. (2016). "Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency". J Appl Genet. 57 (3): 373–81. doi:10.1007/s13353-015-0328-z. PMC 4963446. PMID 26608600.
- ↑ Li S, Crenshaw EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG (1990). "Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1". Nature. 347 (6293): 528–33. doi:10.1038/347528a0. PMID 1977085.
- ↑ Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM; et al. (1998). "Mutations in PROP1 cause familial combined pituitary hormone deficiency". Nat Genet. 18 (2): 147–9. doi:10.1038/ng0298-147. PMID 9462743.
- ↑ Besson A, Salemi S, Deladoëy J, Vuissoz JM, Eblé A, Bidlingmaier M; et al. (2005). "Short stature caused by a biologically inactive mutant growth hormone (GH-C53S)". J Clin Endocrinol Metab. 90 (5): 2493–9. doi:10.1210/jc.2004-1838. PMID 15713716.
- ↑ Hwa V, Camacho-Hübner C, Little BM, David A, Metherell LA, El-Khatib N; et al. (2007). "Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene". Horm Res. 68 (5): 218–24. doi:10.1159/000101334. PMID 17389811.
- ↑ Batey L, Moon JE, Yu Y, Wu B, Hirschhorn JN, Shen Y; et al. (2014). "A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency". J Clin Endocrinol Metab. 99 (1): E153–9. doi:10.1210/jc.2013-3106. PMC 3879666. PMID 24243634.
- ↑ Domené HM, Hwa V, Argente J, Wit JM, Wit JM, Camacho-Hübner C; et al. (2009). "Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences". Horm Res. 72 (3): 129–41. doi:10.1159/000232486. PMID 19729943.
- ↑ Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi J, Hanaki K; et al. (2012). "Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation". Clin Endocrinol (Oxf). 77 (2): 246–54. doi:10.1111/j.1365-2265.2012.04357.x. PMID 22309212.