eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Familial Glucocorticoid Deficiency: Differential Diagnoses & Workup

Author: Andrea Haqq, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center
Coauthor(s): Bruce A Boston, MD, Director, Pediatric Endocrine Training Program, Associate Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health Sciences University and Doernbecher Children's Hospital
Contributor Information and Disclosures

Updated: Oct 7, 2008

Differential Diagnoses

Adrenal Hypoplasia
Adrenal Insufficiency
Allgrove (AAA) Syndrome
Congenital Adrenal Hyperplasia
Hypopituitarism

Other Problems to Be Considered

Adrenoleukodystrophy
Autoimmune polyglandular syndrome type 1

Workup

Laboratory Studies

  • Baseline 9 am serum cortisol and adrenocorticotropic hormone (ACTH) stimulation test
    • Familial glucocorticoid deficiency (FGD) is characterized in laboratory testing by a low or low-normal first morning serum cortisol and markedly elevated ACTH levels in contrast to a normal renin-aldosterone axis. Cortisol levels are typically in the range of less than 10-75 ng/mL (reference range is 50-150 ng/mL), whereas ACTH values are typically in the range of greater than 300-7000 ng/L (reference range is 10-80 ng/L).
    • The cortisol levels are unresponsive to exogenous ACTH stimulation (Cortrosyn stimulation test).
  • Plasma tests: Plasma results reveal normal very long chain fatty acid (VLCFA) levels, thus ruling out adrenoleukodystrophy.
  • Serum tests
    • Test sodium, potassium, aldosterone, and renin levels.
    • Supine and standing renin and aldosterone concentrations are within the reference range in FGD, revealing normal variability in response to salt restriction. Note that although renin and aldosterone levels are typically normal in FGD, rare cases of minor impairment in the renin-aldosterone axis have been reported .
    • The electrolyte abnormalities, including hyponatremia and hyperkalemia, are not usually present. These abnormalities typically characterize other adrenal diseases.
    • FGD is often characterized by low levels of serum dihydroxyepiandrosterone sulphate (DHEAS).
    • Consider a diagnosis of congenital adrenal hyperplasia in any infant with signs of glucocorticoid deficiency. The most common form, 21-hydroxylase deficiency, can be ruled out by reference range 17-hydroxyprogesterone levels. Virilized genitalia may be present in some female infants with congenital adrenal hyperplasia, although this does not occur in FGD.
  • Steroid deficiencies
    • Patients with adrenoleukodystrophy also present with multiple adrenal hormone deficiencies.
    • VLCFA levels are elevated in adrenoleukodystrophy.
  • Antiadrenal antibodies: Antiadrenal antibodies can usually be detected in patients with Addison disease (AD), an autoimmune form of adrenal insufficiency, and may be useful in ruling out AD as a diagnostic possibility.
  • Ophthalmologic examination: Ophthalmologic examination is indicated when the diagnosis of Allgrove syndrome (AS) is under consideration. AS is characterized by glucocorticoid deficiency, alacrima (absence of tears), achalasia of the cardia, and a wide spectrum of neurologic abnormalities.
    • Alacrima is determined by a Schirmer test that provides a semiquantitative measure of tearing. In this test, a standardized test strip is placed in the conjunctival sac and wetting of the strip over a 5-minutes interval is determined. Alacrima is defined as less than 10 mm of wetting.
    • Slit lamp examination and fluorescein staining may be helpful in illustrating corneal pathology secondary to decreased tear production.
    • Should these tests indicate a diagnostic possibility of AS, other investigations are warranted and include barium esophagraphy, esophageal manometry, endoscopy, neurologic evaluation, brainstem auditory evoked response (BAER), and autonomic testing.
    • These tests are outlined in Allgrove (AAA) Syndrome.
  • Hypoglycemia tests
    • Obtain a CBC count, serum glucose level, and a comprehensive metabolic panel with and without cerebrospinal fluid (CSF) studies for protein, glucose, cell count, and culture.
    • In any patient presenting with seizures, ruling out hypoglycemia as the inciting cause is imperative. In some cases, a lumbar puncture may also be indicated. These investigations are not specific in making a diagnosis of FGD, but they can provide important clues to the etiology of the seizure.
  • Pituitary hormone evaluation: Hypopituitarism can also lead to adrenal insufficiency. If ACTH levels are low in the setting of adrenal insufficiency, clinically evaluate other pituitary hormones with specific laboratory testing.

Imaging Studies

  • Adrenal MRI or CT scans reveal small adrenal glands in FGD.

Histologic Findings

  • Histologic examinations of the adrenal glands of children with FGD have characteristically revealed a well-preserved zona glomerulosa but a markedly atrophic zona fasciculata and zona reticularis.

More on Familial Glucocorticoid Deficiency

Overview: Familial Glucocorticoid Deficiency
Differential Diagnoses & Workup: Familial Glucocorticoid Deficiency
Treatment & Medication: Familial Glucocorticoid Deficiency
Follow-up: Familial Glucocorticoid Deficiency
References
[ CLOSE WINDOW ]

References

  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. Feb 1959;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. Nov 1968;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. May 1973;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. Apr 1975;50(4):291-7. [Medline].

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

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

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

  9. 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. Feb 2005;37(2):166-70. [Medline].

  10. 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. Nov 2004;30(4):889-90. [Medline].

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

  12. 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. Dec 1991;38(6):510-3. [Medline].

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

  14. 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. Aug 2008;93(8):3097-105. [Medline].

  15. 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].

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

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

  18. 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. Aug 1999;84(8):2766-70. [Medline].

  19. 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. Feb 1992;151(2):85-9. [Medline].

  20. 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. Mar 1995;154(3):191-6. [Medline].

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

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

  23. 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. Feb 2005;205(2):123-31. [Medline].

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

  25. 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. Sep 2006;19(9):1167-70. [Medline].

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

  27. 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. Oct 2006;91(10):3713-7. [Medline].

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

  29. 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. Apr 25 1997;129(1):83-90. [Medline].

  30. 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. Oct 1998;83(10):3592-6. [Medline]. [Full Text].

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

  32. 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. Jul 2008;93(7):2896-9. [Medline].

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

  34. 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].

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

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

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

  38. 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. Dec 1971;13(2):1-12. [Medline].

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

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

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

  42. 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. Nov 30 1993;197(1):172-8. [Medline].

  43. 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. Jan 1995;80(1):65-71. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

familial glucocorticoid deficiency, FGD, adrenocorticotropic hormone, ACTH, unresponsiveness, Allgrove syndrome, AS, hypoglycemia, hyperpigmentation, pallor, sweating, palpitations, anxiety, shakiness, hunger, abdominal symptoms, vision changes, jitteriness, respiratory distress, cyanosis, apnea, hypotonia, seizures, ambiguous genitalia, congenital adrenal hyperplasia, cutaneous candidiasis, polyglandular autoimmune syndrome, adrenoleukodystrophy, Wolman disease, distal motor neuropathy, distal sensory neuropathy, dysarthria, ataxia, Parkinsonian disease features, mild dementia, developmental delay, optic atrophy

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

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.

Coauthor(s)

Bruce A Boston, MD, 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 Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School
George P Chrousos, MD, FAAP, MACP, MACE is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and 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, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfiser, Inc. Honoraria Consulting

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

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

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.