Familial Glucocorticoid Deficiency Treatment & Management
- Author: Andrea Haqq, MD; Chief Editor: Stephen Kemp, MD, PhD more...
Treatment of familial glucocorticoid deficiency (FGD) includes the following:
- Immediate diagnosis and treatment of hypoglycemia is essential. Children with seizures or prolonged recurrent episodes of hypoglycemia are more likely to experience brain damage.
- When the cause of hypoglycemia is unknown, start an intravenous line and collect 5-10 mL of blood in a heparinized tube.
- When hypoglycemia is suspected, start treatment without waiting for the results of the blood or plasma glucose tests.
- In neonates, administer intravenous (IV) 10% dextrose at 2.5 mL/kg as a rapid IV bolus followed by a continuous IV infusion of 3-5 mL/kg/h (5-8 mg glucose per kg/min).
- In children, administer 50% dextrose diluted to 25% in water at an initial dose of 1 mL/kg IV followed by an IV infusion of 10% dextrose at 2-3 mL/kg/h (3-5 mg glucose per kg/min).
- If any difficulty in establishing IV access occurs, intramuscularly administer glucagon at 0.03 mg/kg (not to exceed 1 mg). Glucagon therapy has a transient effect and must be followed by an intravenous dextrose infusion as above.
- Glucocorticoid deficiency
- Treatment for FGD includes the replacement of glucocorticoids in order to avoid not only adrenal crisis but to allow normal growth in these children. Glucocorticoid replacement is achieved with hydrocortisone (12-16 mg/m2/24h PO divided into 3 doses). An equivalent dose of prednisone or dexamethasone may be administered to adults and the occasional patient who has difficulty with compliance. However, the potential for growth suppression with either prednisone or dexamethasone is greater than hydrocortisone; and, therefore, these agents should be used with caution. Administer the lowest dosage necessary to prevent symptoms of adrenal failure in order to avoid suppression of growth.
- The adequacy of a treatment regimen may be clinically judged by noting decreased hyperpigmentation, absence of weakness, and normalization of blood sugar values. Adequate glucocorticoid replacement should not cause any adverse effects. Suppression of adrenocorticotropic hormone (ACTH) levels in FGD can be very difficult and, therefore, should not be used as a goal for therapy.
- Overtreatment may result in poor linear growth, hypertension, edema, euphoria, insomnia, headache, steroid-induced acne, hyperglycemia, Cushing syndrome, peptic ulcers, and cataract formation.
- Intercurrent illness or stress necessitates a readjustment of glucocorticoid dosage. For minor stress, such as a fever or upper respiratory tract infection, double or triple the glucocorticoid dosage until the illness has resolved. If the patient is ill with vomiting or diarrhea and cannot tolerate oral fluids and medication, hospitalization may be necessary. In individuals with severe stress, such as surgery or serious illness, the daily requirement for parenteral hydrocortisone is 40-100 mg/m2/24h (approximately 3-10 times the maintenance dose) in 3-4 divided doses.
- With a major decline in the clinical condition of the patient (eg, development of hypotension, fever, decreasing mental status, acute intercurrent illness), promptly initiate treatment for possible adrenal crisis even before the diagnosis is confirmed.
- The treatment of an adrenal crisis includes fluid, dextrose, and glucocorticoid replacement in order to restore fluid volume and prevent hypoglycemia and death. Adequately treat any precipitating event such as an infection.
- Fluids administered (eg, 0.9% NaCl with 5% dextrose) should be administered at 1.5-2 times the maintenance rate (2250-3000 mL/m2/d). If the patient presents in shock, administer 0.9% NaCl (10-20 mL/kg) during the first hour of treatment. In addition, cortisol as a soluble ester (21-hemisuccinate or 21-phosphate) must be administered as an immediate IV bolus and every 6 hours (25 mg for infants; 50 mg for small children; 100-150 mg for larger children or adolescents).
- Once the clinical condition improves, gradually taper down the steroid dosage by one third every day until the patient is back to maintenance dose.
- All patients with FGD on replacement glucocorticoid therapy must be instructed on appropriate sick day management to adjust steroid dosage and taught how to administer parenteral hydrocortisone at home in cases of severe stress or when oral intake is compromised, and they should be provided a 24-hour physician contact number in case of emergency.
- All patients with FGD should wear a MedicAlert bracelet outlining their condition and medical treatment. Because of the rarity of this condition, provide families with a physician letter outlining FGD and its potential complications and treatments to present to an emergency care facility if a visit to the emergency department becomes necessary.
- Achalasia and alacrima
- In those cases of FGD associated with achalasia and alacrima, these conditions should be carefully monitored and managed.
- See Allgrove (AAA) Syndrome for full details.
FGD associated with achalasia and Allgrove syndrome (AS) requires surgical intervention (see Allgrove (AAA) Syndrome).
See the list below:
- Counsel patients with FGD and their families regarding the inheritance pattern of FGD, which is autosomal recessive.
- Observe siblings and other close relatives for potential symptoms of FGD.
- Screen family members with a Cortrosyn stimulation test to exclude this condition, which is potentially fatal if unrecognized and untreated.
- Some cases of FGD have been associated with mutations in the MC2R gene. Confirming this diagnosis by DNA analysis may be possible in some cases.
- Other consultations: In individuals with FGD associated with alacrima, achalasia, or AS, other consultations are warranted, including an ophthalmologist to assess alacrima and a neurologist to assess development and to address the neurologic manifestations of AS (see Allgrove (AAA) Syndrome).
In individuals with FGD, the renin-aldosterone axis is normal and no dietary manipulation, such as salt replacement, is needed.
No restriction of physical activity is necessary in adequately treated cases of FGD. In a small subset of patients with AS and autonomic disturbance, some activities may need to be limited because of problems, including recurring postural hypotension and decreased heart rate variability.
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].
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].
Kelch RP, Kaplan SL, Biglieri EG, et al. Hereditary adrenocortical unresponsiveness to adrenocorticotropic hormone. The J of Pediatrics. 1972. 81:726-736. [Medline].
Moshang T Jr, Rosenfield RL, Bongiovanni AM, Parks JS, Amrhein JA. Familial glucocorticoid insufficiency. J Pediatr. 1973 May. 82(5):821-6. [Medline].
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].
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].
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].
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].
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].
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].
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].
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].
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].
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].
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].
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].
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].
Allolio B, Reincke M. Adrenocorticotropin receptor and adrenal disorders. Horm Res. 1997. 47(4-6):273-8. [Medline].
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].
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].
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].
Elias LL, Huebner A, Metherell LA, et al. Tall stature in familial glucocorticoid deficiency. Clin Endocrinol (Oxf). 2000 Oct. 53(4):423-30. [Medline].
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].
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].
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].
Huebner A, Elias LL, Clark AJ. ACTH resistance syndromes. J Pediatr Endocrinol Metab. 1999 Apr. 12 Suppl 1:277-93. [Medline].
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].
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].
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].
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].
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].
Moshang T Jr. Familial glucocorticoid deficiency. N Engl J Med. 1978 Feb 2. 298(5):282-3. [Medline].
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].
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].
New MI, Rapaport R, Sperling MA. Adrenal insufficiency. Pediatric Endocrinology. WB Saunders; 1996. 301-305.
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].
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].
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].
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].
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].
Stempfel RS, Engel FL. A congenital familial syndrome of adrenocortical insufficiency without hypoaldosteronism. J Pediatr. 1960. 57:443-451. [Full Text].
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].
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].
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].
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].
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].
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].