Medscape is available in 5 Language Editions – Choose your Edition here.


Familial Glucocorticoid Deficiency

  • Author: Andrea Haqq, MD; Chief Editor: Stephen Kemp, MD, PhD  more...
Updated: Sep 25, 2013


In 1959, Familial glucocorticoid deficiency (FGD) was first described by Shepard, Landing, and Mason.[1] They reported 2 sisters with a gradual onset of skin pigmentation, marked muscular weakness, and convulsions in the second year of life. The first sister died at age 30 months; although detailed clinical studies were not conducted postmortem, examination revealed marked adrenocortical atrophy. The second sister had low levels of plasma 11-hydroxycorticosterone that did not respond to adrenocorticotropic hormone (ACTH). Aldosterone secretion was determined to be normal on the basis of reference range serum electrolytes and blood pressure on a salt-restricted diet.

In 1968, Migeon et al described 6 patients with a syndrome of adrenal unresponsiveness to ACTH characterized by hypoglycemia, hyperpigmentation, feeding problems in infancy, low urinary 17-hydroxycorticosteroids, an ability to conserve sodium and increase aldosterone secretion in response to salt deprivation, and a lack of elevation of 17-hydroxycorticosteroid secretion or plasma cortisol concentration with ACTH administration.[2] Two of these patients were brothers. Migeon postulated that the syndrome may be due to an inherited defect within the adrenal gland, causing primary unresponsiveness to ACTH.

In 1972, Kelch et al reported 3 patients with severe isolated glucocorticoid deficiency who did not respond to ACTH stimulation.[3] Analysis of the 3 families supported an autosomal recessive inheritance pattern because both females and males were affected. Researchers described variability in adrenal pathology among these 3 families, suggesting heterogeneity in the condition.

In 1973, Moshang et al studied 5 affected siblings, each of whom demonstrated primary glucocorticoid deficiency and normal mineralocorticoid function.[4] A progressive deterioration of glucocorticoid function was observed in these patients, which suggested an inherited degenerative process involving the adrenal zona fasciculata and reticularis rather than a primary unresponsiveness to ACTH, as initially proposed. The syndrome was beginning to be viewed as a heterogeneous group of disorders.

In 1975, Thistlethwaite et al reported 2 brothers with recurrent hypoglycemia precipitated by an infectious illness at age 21 months and age 19 months.[5] Both brothers were tall and hyperpigmented. Their electrolyte balances were within the reference range even on a sodium-restricted diet, which supported normal aldosterone function. The serum levels of ACTH and deoxycorticosterone in the brothers' blood were markedly elevated; all other plasma corticosteroid levels were within the reference range. Adrenocortical unresponsiveness to ACTH was found to be progressive in the elder brother.

In 1977, Spark and Etzkorn proposed an etiology involving a defect at the ACTH receptor or a postreceptor site.[6]



FGD is a rare autosomal recessive condition.[7, 8] Pathologic evaluation of children affected with this disorder reveals that the zona glomerulosa of the adrenal glands is well preserved. The zona fasciculata and zona reticularis are markedly atrophic. These changes are accompanied by low plasma cortisol concentrations because the zona fasciculata is primarily responsible for glucocorticoid production. Low circulating serum cortisol results in a lack of feedback inhibition to the hypothalamus; markedly increased ACTH levels are often observed. Because the zona glomerulosa is generally well preserved, mineralocorticoid production is usually unaffected. Plasma renin and aldosterone concentrations are usually within the reference range in the baseline state and demonstrate normal variability on salt restriction.

Molecular defects of the ACTH receptor gene, consisting of point mutations, are described in approximately 25-40% of patients with FGD. Mutations in the MC2 receptor accessory protein (MRAP) are responsible for another estimated 15-20% of cases of FGD.[9, 10] The remainder (approximately 50-60%) of patients with FGD have unknown mutations; these mutations may affect ACTH signal transduction, expression of the ACTH receptor, or differentiation of the adrenal cortex. The pathogenesis of Allgrove syndrome (AS), another distinct clinical entity, is due to a defect in a WD-repeat regulatory protein named for alacrima-achalasia-adrenal insufficiency neurologic (ALADIN) disorder.




United States

The exact incidence of FGD is unknown; it is a rare disease, and only isolated case reports are documented. From the original descriptions in 1959-1995, more than 50 such cases have been reported. The incidence of FGD may be underestimated because some patients may have episodes of recurring hypoglycemia or convulsions, but FGD may remain undiagnosed for many years.


The most frequent cause of FGD death is undiagnosed glucocorticoid insufficiency. Although this disease is easily treatable when recognized, if left untreated it may be fatal or lead to severe mental disability as a result of recurrent hypoglycemia secondary to glucocorticoid insufficiency. Out of more than 50 published cases, 18 patients died as a result of glucocorticoid insufficiency.

In early life, patients have feeding problems characterized by chronic spitting or vomiting and poor appetite. As a result, some patients may also experience poor weight gain. Hypoglycemic seizures secondary to glucocorticoid deficiency are a frequent complication of this disorder when inadequate treatment is provided. Finally, deep hyperpigmentation of the skin is the most common initial presenting sign and is almost always present at diagnosis. The hyperpigmentation is due to the action of ACTH on cutaneous melanocyte-stimulating hormone (MSH) receptors. This hyperpigmentation fades once proper treatment is initiated with glucocorticoids, which reduce ACTH concentrations.


Cases of the condition have been reported in white, black, East Indian, and Middle Eastern populations. FGD is a rare autosomal recessive condition with no racial predilection.


This disorder occurs with equal frequency in both males and females.


In many case reports in the literature, age of onset of symptoms ranges from birth to 9 years. Patients almost always present with symptoms by age 5 years. Patients usually present with onset of symptoms in the first year of life but may present in early childhood. In an analysis of the current medical literature, approximately 50% of cases occurred in the first year of life.

Contributor Information and Disclosures

Andrea Haqq, MD Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center

Andrea Haqq, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.


Bruce A Boston, MD Chief, Division of Pediatric Endocrinology, Director, Pediatric Endocrine Training Program, Associate Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health Sciences University and Doernbecher Children's Hospital

Bruce A Boston, MD is a member of the following medical societies: Alpha Omega Alpha, American Diabetes Association, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

  1. Shepard TH, Landing BH, Mason DG. Familial Addison's disease; case reports of two sisters with corticoid deficiency unassociated with hypoaldosteronism. AMA J Dis Child. 1959 Feb. 97(2):154-62. [Medline].

  2. Migeon CJ, Kenny EM, Kowarski A, et al. The syndrome of congenital adrenocortical unresponsiveness to ACTH. Report of six cases. Pediatr Res. 1968 Nov. 2(6):501-13. [Medline].

  3. Kelch RP, Kaplan SL, Biglieri EG, et al. Hereditary adrenocortical unresponsiveness to adrenocorticotropic hormone. The J of Pediatrics. 1972. 81:726-736. [Medline].

  4. Moshang T Jr, Rosenfield RL, Bongiovanni AM, Parks JS, Amrhein JA. Familial glucocorticoid insufficiency. J Pediatr. 1973 May. 82(5):821-6. [Medline].

  5. Thistlethwaite D, Darling JA, Fraser R, et al. Familial glucocorticoid deficiency. Studies of diagnosis and pathogenesis. Arch Dis Child. 1975 Apr. 50(4):291-7. [Medline].

  6. Spark RF, Etzkorn JR. Absent aldosterone response to ACTH in familial glucocorticoid deficiency. N Engl J Med. 1977 Oct 27. 297(17):917-20. [Medline].

  7. Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, et al. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012 May 27. 44(7):740-2. [Medline]. [Full Text].

  8. Meimaridou E, Hughes CR, Kowalczyk J, Guasti L, Chapple JP, King PJ, et al. Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013 May 22. 371(1-2):195-200. [Medline].

  9. Jain V, Metherell LA, David A, Sharma R, Sharma PK, Clark AJ, et al. Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein. Eur J Endocrinol. 2011 Dec. 165(6):987-91. [Medline]. [Full Text].

  10. Aza-Carmona M, Barreda-Bonis AC, Guerrero-Fernández J, González-Casado I, Gracia R, Heath KE. Familial glucocorticoid deficiency due to compound heterozygosity of two novel MC2R mutations. J Pediatr Endocrinol Metab. 2011. 24(5-6):395-7. [Medline].

  11. Shivaprasad KS, Dutta D, Jain R, Ghosh S, Mukhopadhyay S, Chowdhury S. Familial glucocorticoid deficiency presenting with generalized hyperpigmentation in adolescence. Report of three siblings. Indian J Endocrinol Metab. 2012 Dec. 16:S382-4. [Medline]. [Full Text].

  12. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992 Aug 28. 257(5074):1248-51. [Medline].

  13. Clark AJ, McLoughlin L, Grossman A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet. 1993 Feb 20. 341(8843):461-2. [Medline].

  14. Metherell LA, Chapple JP, Cooray S, et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005 Feb. 37(2):166-70. [Medline].

  15. Metherell LA, Cooray S, Huebner A, et al. Mutations in a novel gene, encoding a single transmembrane domain protein are associated with familial glucocorticoid deficiency type 2. Endocr Res. 2004 Nov. 30(4):889-90. [Medline].

  16. Allgrove J, Clayden GS, Grant DB, Macaulay JC. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. 1978 Jun 17. 1(8077):1284-6. [Medline].

  17. Nihoul-Fekete C, Bawab F, Lortat-Jacob S, Arhan P. Achalasia of the esophagus in childhood. Surgical treatment in 35 cases, with special reference to familial cases and glucocorticoid deficiency association. Hepatogastroenterology. 1991 Dec. 38(6):510-3. [Medline].

  18. Allolio B, Reincke M. Adrenocorticotropin receptor and adrenal disorders. Horm Res. 1997. 47(4-6):273-8. [Medline].

  19. Artigas RA, Gonzalez A, Riquelme E, et al. A novel adrenocorticotropin receptor mutation alters its structure and function, causing familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2008 Aug. 93(8):3097-105. [Medline].

  20. Chan LF, Clark AJ, Metherell LA. Familial glucocorticoid deficiency: advances in the molecular understanding of ACTH action. Horm Res. 2008. 69(2):75-82. [Medline].

  21. Clark AJ, Cammas FM, Watt A, Kapas S, Weber A. Familial glucocorticoid deficiency: one syndrome, but more than one gene. J Mol Med. 1997 Jun. 75(6):394-9. [Medline].

  22. Elias LL, Huebner A, Metherell LA, et al. Tall stature in familial glucocorticoid deficiency. Clin Endocrinol (Oxf). 2000 Oct. 53(4):423-30. [Medline].

  23. Elias LL, Huebner A, Pullinger GD, Mirtella A, Clark AJ. Functional characterization of naturally occurring mutations of the human adrenocorticotropin receptor: poor correlation of phenotype and genotype. J Clin Endocrinol Metab. 1999 Aug. 84(8):2766-70. [Medline].

  24. Grant DB, Dunger DB, Smith I, Hyland K. Familial glucocorticoid deficiency with achalasia of the cardia associated with mixed neuropathy, long-tract degeneration and mild dementia. Eur J Pediatr. 1992 Feb. 151(2):85-9. [Medline].

  25. Heinrichs C, Tsigos C, Deschepper J, et al. Familial adrenocorticotropin unresponsiveness associated with alacrima and achalasia: biochemical and molecular studies in two siblings with clinical heterogeneity. Eur J Pediatr. 1995 Mar. 154(3):191-6. [Medline].

  26. Houlden H, Smith S, De Carvalho M, et al. Clinical and genetic characterization of families with triple A (Allgrove) syndrome. Brain. 2002 Dec. 125:2681-90. [Medline]. [Full Text].

  27. Huebner A, Elias LL, Clark AJ. ACTH resistance syndromes. J Pediatr Endocrinol Metab. 1999 Apr. 12 Suppl 1:277-93. [Medline].

  28. Imamine H, Mizuno H, Sugiyama Y, et al. Possible relationship between elevated plasma ACTH and tall stature in familial glucocorticoid deficiency. Tohoku J Exp Med. 2005 Feb. 205(2):123-31. [Medline].

  29. Kershnar AK, Roe TF, Kogut MD. Adrenocorticotropic hormone unresponsiveness: report of a girl with excessive growth and review of 16 reported cases. J Pediatr. 1972 Apr. 80(4):610-9. [Medline].

  30. Matsuura H, Shiohara M, Yamano M, Kurata K, Arai F, Koike K. Novel compound heterozygous mutation of the MC2R gene in a patient with familial glucocorticoid deficiency. J Pediatr Endocrinol Metab. 2006 Sep. 19(9):1167-70. [Medline].

  31. Metherell LA, Chan LF, Clark AJ. The genetics of ACTH resistance syndromes. Best Pract Res Clin Endocrinol Metab. 2006 Dec. 20(4):547-60. [Medline].

  32. Modan-Moses D, Ben-Zeev B, Hoffmann C, et al. Unusual presentation of familial glucocorticoid deficiency with a novel MRAP mutation. J Clin Endocrinol Metab. 2006 Oct. 91(10):3713-7. [Medline].

  33. Moshang T Jr. Familial glucocorticoid deficiency. N Engl J Med. 1978 Feb 2. 298(5):282-3. [Medline].

  34. Naville D, Barjhoux L, Jaillard C, et al. Stable expression of normal and mutant human ACTH receptor: study of ACTH binding and coupling to adenylate cyclase. Mol Cell Endocrinol. 1997 Apr 25. 129(1):83-90. [Medline].

  35. Naville D, Weber A, Genin E, et al. Exclusion of the adrenocorticotropin (ACTH) receptor (MC2R) locus in some families with ACTH resistance but no mutations of the MC2R coding sequence (familial glucocorticoid deficiency type 2). J Clin Endocrinol Metab. 1998 Oct. 83(10):3592-6. [Medline]. [Full Text].

  36. New MI, Rapaport R, Sperling MA. Adrenal insufficiency. Pediatric Endocrinology. WB Saunders; 1996. 301-305.

  37. O'Riordan SM, Lynch SA, Hindmarsh PC, Chan LF, Clark AJ, Costigan C. A novel variant of familial glucocorticoid deficiency prevalent among the Irish Traveler population. J Clin Endocrinol Metab. 2008 Jul. 93(7):2896-9. [Medline].

  38. Ramachandran P, Penhoat A, Naville D, et al. Familial glucocorticoid deficiency type 2 in two neonates. J Perinatol. 2003 Jan. 23(1):62-6. [Medline].

  39. Selva KA, LaFranchi SH, Boston B. A novel presentation of Familial Glucocorticoid Deficiency (FGD) and current literature review. J Pediatr Endocrinol Metab. 2004. 17:85-92. [Medline].

  40. Shah BR, Fiordalisi I, Sheinbaum K, Finberg L. Familial glucocorticoid deficiency in a girl with familial hypophosphatemic rickets. Am J Dis Child. 1988 Aug. 142(8):900-3. [Medline].

  41. Slavotinek AM, Hurst JA, Dunger D, Wilkie AO. ACTH receptor mutation in a girl with familial glucocorticoid deficiency. Clin Genet. 1998 Jan. 53(1):57-62. [Medline].

  42. Stempfel RS, Engel FL. A congenital familial syndrome of adrenocortical insufficiency without hypoaldosteronism. J Pediatr. 1960. 57:443-451. [Full Text].

  43. Tanae A, Aoyama M, Egi S, Imai M, Yoshihara S. Familial Addison's disease. Clinical studies on three cases of the same family. Acta Paediatr Jpn. 1971 Dec. 13(2):1-12. [Medline].

  44. Tsigos C, Arai K, Hung W, Chrousos GP. Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene. J Clin Invest. 1993 Nov. 92(5):2458-61. [Medline]. [Full Text].

  45. Tullio-Pelet A, Salomon R, Hadj-Rabia S, et al. Mutant WD-repeat protein in triple-A syndrome. Nat Genet. 2000 Nov. 26(3):332-5. [Medline].

  46. Weber A, Clark AJ. Mutations of the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. Hum Mol Genet. 1994 Apr. 3(4):585-8. [Medline].

  47. Weber A, Kapas S, Hinson J, et al. Functional characterization of the cloned human ACTH receptor: impaired responsiveness of a mutant receptor in familial glucocorticoid deficiency. Biochem Biophys Res Commun. 1993 Nov 30. 197(1):172-8. [Medline].

  48. Weber A, Toppari J, Harvey RD, et al. Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four families. J Clin Endocrinol Metab. 1995 Jan. 80(1):65-71. [Medline].

All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.