eMedicine Specialties > Pediatrics: General Medicine > Endocrinology
Allgrove (AAA) Syndrome: Treatment & Medication
Updated: Feb 20, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
- Glucocorticoid deficiency
- Careful replacement of glucocorticoids in patients with known adrenal insufficiency is critical to avoid an adrenal crisis and to allow for normal growth in children.
- Growth must be closely monitored because overtreatment with glucocorticoids impairs linear growth.
- Providing stress doses of hydrocortisone during illness or injury is also important.
- Every patient should always wear a medical alert bracelet or necklace and carry the emergency medical information card supplied with it.
- In adult patients, as well as those who have difficulty with compliance, replacing hydrocortisone with an equipotent dose of prednisone or dexamethasone is appropriate.
- Achalasia
- Achalasia is best managed with surgical correction.
- Monitoring patients for pulmonary complications (due to reflux and aspiration) and providing gastric acid reduction therapy in patients with symptomatic reflux after surgical intervention is important.
- Alacrima
- Alacrima is managed with regular application of topical lubricants and with punctal occlusion.
- Children may need to be frequently reminded to use artificial tears.
- Children must have an annual ophthalmologic evaluation.
Surgical Care
- The symptoms of alacrima improve with punctal occlusion. This procedure is only necessary when therapy with topical lubricants is unsuccessful because of poor compliance.
- The symptoms of lower esophageal sphincter spasm in patients with achalasia can be ameliorated partially with pneumatic dilatation. In patients who remain symptomatic after pneumatic dilatation, an anterior cardiomyotomy (modified Heller operation) may be performed. This surgical procedure involves directly cutting the muscles of the spastic sphincter. Both procedures have a risk of esophageal perforation and a high rate of postsurgical reflux.
- Patients with Allgrove syndrome who undergo surgery must be treated with stress doses of glucocorticoids in the perioperative period.
Consultations
- Ophthalmologist: A Schirmer test provides a semiquantitative measure of tearing. Other ophthalmologic testing, including slit lamp examination and fluorescein staining, is helpful in identifying patients with corneal pathology secondary to poor lacrimation.
- Neurologist: Neurologic tests highlight a myriad of neurologic and developmental issues. Palatopharyngeal incompetence, sensory impairment, ataxia, and muscle weakness are among the documented findings.
Diet
- Other than the diet changes mandated by the mechanical issues related to achalasia, no specific diet is indicated.
Activity
- In a subset of patients with autonomic disturbance, some activities may need to be limited because of problems with recurring orthostatic hypotension and diminished heart rate variability. Otherwise, no specific limitations on activity are necessary.
Medication
Corticosteroids
Careful replacement of glucocorticoids in patients with known adrenal insufficiency is critical to avoid adrenal crisis and to allow for normal growth in children. Growth must be monitored closely, as overtreatment with glucocorticoids impairs linear growth.
Providing stress doses of hydrocortisone during illness or injury is another important feature of medical management. Typically, a doubling or tripling of the oral dose is sufficient for routine illnesses. A larger increase in dose (provided IV if necessary) is required for severe illness and major trauma (see Adrenal Insufficiency).
Hydrocortisone (Hydrocortone, Cortef)
Has mineralocorticoid and glucocorticoid effects. Useful in management of inflammation caused by immune response.
Adult
10-15 mg PO on awakening and 5-10 mg PO in early afternoon; a third dose may be required in some patients, especially during stress
Pediatric
Maintenance: 10-15 mg/m2/d PO divided tid; morning dose may be increased relative to evening doses to more closely mimic the endogenous circadian rhythm of glucocorticoid secretion
Mild illness: Double PO maintenance dose for routine illness, triple the PO maintenance dose in high fever or more severe illness
Severe illness, surgery, or trauma: Up to 10-fold increase above PO dose, given IV, or approximately 100 mg/m2/d
Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia
Documented hypersensitivity; viral, fungal, or tubercular skin infections
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Avoid overtreatment, which leads to iatrogenic Cushing syndrome and poor linear growth; administer with meals to decrease GI upset; early-onset adverse effects include glucose intolerance, hypertension, agitation, and indigestion (less likely at physiologic doses); late-onset adverse effects include immune suppression and increased susceptibility to sepsis, adrenal suppression, hypertension, urinary calcium loss and osteopenia, gastric irritation, and bleeding (less likely at physiologic doses)
Prednisone (Deltasone)
Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
In patients who have difficulty complying, it is acceptable to replace hydrocortisone with an equipotent dose of prednisone (prednisone is 4-5 times as potent as hydrocortisone).
Doses can be adjusted based on symptoms and monitoring linear growth and weight gain.
Adult
2.5-7.5 mg/d PO; titrate up or down depending on clinical response
Pediatric
4-5 mg/m2/d PO; titrate up or down depending on clinical response
Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin, may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Administer with meals to decrease GI upset
Early-onset adverse effects include glucose intolerance, hypertension, agitation, and indigestion (less likely at physiologic doses)
Late-onset adverse effects include immune suppression and increased susceptibility to sepsis, adrenal suppression, hypertension, urinary calcium loss and osteopenia, gastric irritation, and bleeding (less likely at physiologic doses)
Fludrocortisone (Florinef)
Provides physiologic replacement of mineralocorticoid deficiency.
Dose must be sufficient to lower plasma renin activity to normal without inducing hypertension.
Adult
0.05-0.2 mg/d PO
Pediatric
0.05-0.1 mg/d PO; higher doses may be necessary in adolescents
Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects of fludrocortisone; decreases salicylate levels
Documented hypersensitivity; systemic fungal infections
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Excessive dosing can lead to hypertension;
monitor for dizziness, severe or continuing headaches, swelling of feet or lower legs, or unusual weight gain; administer with food to minimize adverse GI effects
Dexamethasone (Decadron)
For various allergic and inflammatory diseases. Decreases inflammation by suppressing migration of PMN leukocytes and reducing capillary permeability.
Adult
0.5 mg/d PO; titrate up or down depending on clinical response
Pediatric
0.03-0.15 mg/kg/d PO/IV/IM; titrate up or down depending on clinical response
Effects decrease with coadministration of barbiturates, phenytoin and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization
Documented hypersensitivity; active bacterial or fungal infection
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use
More on Allgrove (AAA) Syndrome |
| Overview: Allgrove (AAA) Syndrome |
| Differential Diagnoses & Workup: Allgrove (AAA) Syndrome |
 Treatment & Medication: Allgrove (AAA) Syndrome |
| Follow-up: Allgrove (AAA) Syndrome |
| References |
| « Previous Page | Next Page » |
References
Allgrove J, Clayden GS, Grant DB. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. Jun 17 1978;1(8077):1284-6. [Medline].
Kasar PA, Khadilkar VV, Tibrewala VN. Allgrove syndrome. Indian J Pediatr. Oct 2007;74(10):959-61. [Medline].
Kelch RP, Kaplan SL, Biglieri EG. Hereditary adrenocortical unresponsiveness to adrenocorticotropic hormone. J Pediatr. Oct 1972;81(4):726-36. [Medline].
Counahan R, West R. Ocular and fingertip abnormalities in isolated glucocorticoid deficiency. J Pediatr. Oct 1974;85(4):580-1. [Medline].
Gazarian M, Cowell CT, Bonney M. The "4A" syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities. Eur J Pediatr. Jan 1995;154(1):18-23. [Medline].
Chen W, Kelly MA, Opitz-Araya X. Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell. Dec 12 1997;91(6):789-98. [Medline].
Chu ML, Berlin D, Axelrod FB. Allgrove syndrome: documenting cholinergic dysfunction by autonomic tests. J Pediatr. Jul 1996;129(1):156-9. [Medline].
Clark AJ, Weber A. Adrenocorticotropin insensitivity syndromes. Endocr Rev. Dec 1998;19(6):828-43. [Medline].
Dumic M, Radica A, Jusic A. Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy. Eur J Pediatr. Nov 1987;146(6):592-4. [Medline].
Ehrich E, Aranoff G, Johnson WG. Familial achalasia associated with adrenocortical insufficiency, alacrima, and neurological abnormalities. Am J Med Genet. Mar 1987;26(3):637-44. [Medline].
Fagan JE, McArthur RG, Machida H. Palatopharyngeal incompetence in association with esophageal dysmotility, acquired glucocorticoid deficiency, and deficient tear production. Clin Invest Med. Jul 1987;10(4):345-9. [Medline].
Grant DB, Barnes ND, Dumic M. Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child. Jun 1993;68(6):779-82. [Medline].
Grant DB, Dunger DB, Smith I. 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].
Handschug K, Sperling S, Kim Yoon S. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Human Molecular Genetics. 2001;10:283-290. [Medline]. [Full Text].
Heinrichs C, Tsigos C, Deschepper J. 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].
Kimber J, McLean BN, Hammans SR. Allgrove or 4 "A" syndrome: an autosomal recessive syndrome causing multisystem neurological disease. J Neurol Neurosurg Psychiatry. 2003;74:654-657. [Medline]. [Full Text].
Lanes R, Plotnick LP, Bynum TE. Glucocorticoid and partial mineralocorticoid deficiency associated with achalasia. J Clin Endocrinol Metab. Feb 1980;50(2):268-70. [Medline].
Makari G, Hoffman WH, Carroll JE. Autonomic dysfunction and adrenocortical unresponsiveness to ACTH. J Child Neurol. Jul 1988;3(3):174-6. [Medline].
Moore PS, Couch RM, Perry YS. Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima. Clin Endocrinol (Oxf). Feb 1991;34(2):107-14. [Medline].
Moser HW, Moser AB, Frayer KK. Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology. Oct 1981;31(10):1241-9. [Medline].
Mountjoy KG, Robbins LS, Mortrud MT. The cloning of a family of genes that encode the melanocortin receptors. Science. Aug 28 1992;257(5074):1248-51. [Medline].
Mullaney PB, Weatherhead R, Millar L. Keratoconjunctivitis sicca associated with achalasia of the cardia, adrenocortical insufficiency, and lacrimal gland degeneration: Keratoconjunctivitis sicca secondary to lacrimal gland degeneration may parallel degenerative changes in esophageal and. Ophthalmology. Apr 1998;105(4):643-50. [Medline].
Nihoul-Fekete C, Bawab F, Lortat-Jacob S. Achalasia of the esophagus in childhood: surgical treatment in 35 cases with special reference to familial cases and glucocorticoid deficiency association. J Pediatr Surg. Oct 1989;24(10):1060-3. [Medline].
Prpic I, Huebner A, Persic M, et al. Triple A syndrome: genotype-phenotype assessment. Clin Genet. May 2003;63(5):415-7. [Medline].
Stratakis CA, Lin JP, Pras E. Segregation of Allgrove (triple-A) syndrome in Puerto Rican kindreds with chromosome 12 (12q13) polymorphic markers. Proc Assoc Am Physicians. Sep 1997;109(5):478-82. [Medline].
Stuckey BG, Mastaglia FL, Reed WD. Glucocorticoid insufficiency, achalasia, alacrima with autonomic motor neuropathy. Ann Intern Med. Jan 1987;106(1):61-3. [Medline].
Thomas RJ, Sen S, Zachariah N. Achalasia cardia in infancy and childhood: an Indian experience. J R Coll Surg Edinb. Apr 1998;43(2):103-4. [Medline].
Tsao CY, Romshe CA, Lo WD. Familial adrenal insufficiency, achalasia, alacrima, peripheral neuropathy, microcephaly, normal plasma very long chain fatty acids, and normal muscle mitochondrial respiratory chain enzymes. J Child Neurol. Apr 1994;9(2):135-8. [Medline].
Tsigos C, Arai K, Latronico AC. A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome. J Clin Endocrinol Metab. Jul 1995;80(7):2186-9. [Medline].
Tuck JS, Bisset RA, Doig CM. Achalasia of the cardia in childhood and the syndrome of achalasia alacrima and ACTH insensitivity. Clin Radiol. Oct 1991;44(4):260-4. [Medline].
Vaughan WH, Williams JL. Familial achalasia with pulmonary complications in children. Radiology. May 1973;107(2):407-9. [Medline].
Verma S, Brown S, Dakkak M. Association of adult achalasia and alacrima. Dig Dis Sci. May 1999;44(5):876-8. [Medline].
Weber A, Wienker TF, Jung M. Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet. Dec 1996;5(12):2061-6. [Medline].
Further Reading
Keywords
Allgrove (AAA) syndrome, 4A syndrome, triple-A syndrome, achalasia-addisonianism-alacrima syndrome, achalasia-addisonianism-alacrima-autonomic neuropathy syndrome, addisonian-achalasia syndrome, alacrima-achalasia-addisonianism, glucocorticoid deficiency, achalasia, hypoadrenalism with achalasia, isolated glucocorticoid deficiency, adrenal insufficiency, growth failure, developmental delay, hypoglycemia, microcephaly, hypoglycemia, hyperpigmentation, hyperkeratosis
