Endocrine Disorders: Hereditary


Many genes that comprise endocrine pathways have been discovered. A variety of endocrine disorders caused by variations in these genes are now well understood in terms of their molecular basis and mode of inheritance.

Keywords: endocrine disorders; genetics; endocrinopathies; dwarfism; pituitary; adrenal; diabetes insipidus; thyroid

Figure 1.

(GHN) pathway, showing the roles of interdependent genes required to produce transcription factors, ligands such as GHN, growth hormone receptors such as GHR, and other gene products needed for normal growth. Gene defects in the GHN pathway that cause disease include: (1) combined pituitary hormone deficiency (CPHD; HESX1); (2) CPHD (LHX3); (3) CPHD (PROP1); (4) CPHD (POU1F1); (5) isolated GHN deficiency (IGHD; GHRHR); (6) IGHD (GH1); (7) GHN resistance (GHR); and (8) GHN resistance (IGF1). SST; GHRH: GHN‐releasing hormone; IGF1R: insulin‐like growth factor 1 receptor; SST: soamatostatin; SSTR: SST receptor.

Figure 2.

A simplified G protein cycle coupled to adenylyl cyclase. Inappropriate activation of this pathway can result from mutations that cause: (1) hormone receptor activation in the absence of hormone, (2) guanosine diphosphate–guanosine triphosphate (GDP/GTP) exchange in the absence of activated receptor and (3) inhibition of (GTPase) activity. cAMP: cyclic adenosine monophosphate; Pi: inorganic phosphate.



Cogan JD and Phillips JA III (2001) Inherited defects in growth hormone synthesis and action. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds.) The Metabolic and Molecular Bases of Inherited Disease, 8th ed. pp. 4159–4180. New York: McGraw‐Hill

Collu R, Tang J, Castagne J, et al. (1997) A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin‐releasing hormone receptor gene. Journal of Clinical Endocrinology and Metabolism 82: 1361–1365.

Dattani MT, Martinez‐Barbera J‐P, Thomas PQ, et al. (1998) Mutations in the homeobox gene HESX1/Hesx1 associated with septo‐optic dysplasia in human and mouse. Nature Genetics 19: 125–133.

Duriez B, Duquesnoy P, Dastot F, et al. (1994) An exon‐skipping mutation in the BTK gene of a patient with X‐linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Letters 346: 165–170.

Hayashizaki Y, Hiraoka Y, Endo Y and Matsubara K (1989) Thyroid‐stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta‐subunit. EMBO Journal 8: 2291–2296.

Lagerstrom‐Fermer M, Sundvall M, Johnsen E, et al. (1997) X‐linked recessive panhypopituitarism associated with a regional duplication in Xq25–q26. American Journal of Human Genetics 60: 910–916.

Moseley CT, Phillips JA III and Rimoin DL (2002) Genetic disorders of the pituitary gland. In: Rimoin DL, Connor JM and Pyeritz RE (eds.) Principles and Practice of Medical Genetics, 4th ed. pp. 2135–2182. New York: Churchill Livingstone.

Netchine I, Sobrier M‐L, Krude H, et al. (2000) Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nature Genetics 25: 182–186.

Ross JL, Long LM, Loriaux DL and Cutler GB Jr (1985) Growth hormone secretory dynamics in Turner syndrome. Journal of Pediatrics 106: 202–206.

Salvatori R, Gondo RG, de Aguirar Oliveira MH, et al. (1999) Familial isolated growth hormone deficiency due to a novel mutation in the growth hormone‐releasing hormone receptor. Journal of Clinical Endocrinology and Metabolism 84: 917–923.

Shenker A (1996) Activating mutations in G protein‐coupled signaling pathways as a cause of endocrine disease. Growth, Genetics and Hormones 12: 33–38.

Takahashi Y, Kaji H, Okimura Y, et al. (1996) Brief report: short stature caused by a mutant growth hormone. New England Journal of Medicine 334: 432–436.

Trulzsch B, Nebel T and Paschke R (1999) The thyrotropin receptor mutation database. Thyroid 9: 521–522.

Woods KA, Camacho‐Hubner C, Savage MO and Clark AJL (1996a) Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin‐like growth factor 1 gene. New England Journal of Medicine 335: 1363–1367.

Woods KA, Fraser NC, Postel‐Vinay MC, Savage MO and Clar AJL (1996b) A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH‐binding protein. Journal of Clinical Endocrinology and Metabolism 81: 1686–1690.

Wu W, Cogan JD, Pfäffle RW, et al. (1998) Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nature Genetics 18: 147–149.

Further Reading

Baxter JD, Melmed S and New MI (eds.) (2002) Genetics in Endocrinology. Philadelphia, PA: Lippincott, Williams & Wilkins.

Web Links

Online Mendelian Inheritance in Man (OMIM). Source of information on genes, genetic disorders, DNA, genetic maps and mutations databases http://www.ncbi.nlm.nih.gov/omim

CYP21A2 (cytochrome P450, subfamily XXIA (steroid 21‐hydroxylase, congenital adrenal hyperplasia), polypeptide 2); LocusID: 1589. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1589

GNAS (GNAS complex locus); LocusID: 2778. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2778

IGF1 (insulin‐like growth factor 1 (somatomedin C)); LocusID: 3479. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3479

POU1F1 (POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1)); LocusID: 5449. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5449

TRHR (thyrotropin‐releasing hormone receptor); LocusID: 7201. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7201

CYP21A2 (cytochrome P450, subfamily XXIA (steroid 21‐hydroxylase, congenital adrenal hyperplasia), polypeptide 2); MIM number: 201910. OMIM: http://www3.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?201910

GNAS (GNAS complex locus); MIM number: 139320. OMIM: http://www3.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?139320

IGF1 (insulin‐like growth factor 1 (somatomedin C)); MIM number: 147440. OMIM: http://www3.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?147440

POU1F1 (POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1)); MIM number: 173110. OMIM: http://www3.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?173110

TRHR (thyrotropin‐releasing hormone receptor); MIM number: 188545. OMIM: http://www3.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?188545

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Phillips, John A(Jan 2006) Endocrine Disorders: Hereditary. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005522]