eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Allgrove (AAA) Syndrome

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
Daniel L Marks, MD, PhD, Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health Sciences University and Doerenbecher Children's Hospital; Jacalyn Bishop, MD, Pediatric Endocrinologist, Private Practice

Updated: Feb 20, 2009

Introduction

Background

In 1978, Allgrove and colleagues described 2 unrelated pairs of siblings with isolated glucocorticoid deficiency and achalasia of the esophagus cardia.¹ The latter condition involved delayed passage of food into the stomach and consequent dilation of the thoracic esophagus. Three of these individuals also had defective tear production, leading the authors to speculate that the combination of achalasia, adrenal deficiency, and alacrima represented an inherited familial disorder.² The authors also referred to the prior publications of Kelch et al and Counahan and West, who reported on patients with hereditary adrenal unresponsiveness to adrenocorticotropic hormone (ACTH).^3,4 Allgrove pointed out that these patients developed achalasia and suggested that all of the patients shared a common syndrome.

Similarly, patients originally reported as having isolated achalasia were subsequently given a diagnosis of adrenal insufficiency, highlighting the variable presentation of this syndrome. Indeed, the adrenal dysfunction in a subset of patients was not limited to glucocorticoid deficiency but was also shown to include mineralocorticoid deficiency.

In the years following, numerous authors published similar reports that have helped to define the primary and associated features of this syndrome. Several authors published descriptions of a more global autonomic disturbance associated with the original Allgrove triad, leading one author to suggest the name 4A syndrome (adrenal insufficiency, achalasia of the cardia, alacrima, autonomic abnormalities).⁵ Specific autonomic disturbances described in this syndrome include abnormal pupillary reflexes, poor heart rate variability, and orthostatic hypotension. Other phenotypic features occasionally associated with this syndrome are described below.

Several authors have investigated the genetic basis for Allgrove syndrome. Although many logical candidate genes have been investigated, including those coding for the ACTH receptor, vasoactive intestinal polypeptide (VIP), the vip-1 receptor, pituitary adenylate cyclase activating peptide, and neurotrophin-3, no mutant genes have been identified in patients with this syndrome. Linkage analysis in both European and Puerto Rican kindreds provides evidence for linkage to band 12q13 near the type II keratin gene cluster. The linkage to a region of the genome containing a keratin gene cluster is particularly intriguing because of the hyperkeratosis of the palms and soles that is observed in several patients.

Pathophysiology

No unifying pathologic features common to the 3 primary sites affected in this syndrome (esophagus, lacrimal glands, adrenal glands) are known. Linkage analysis provides evidence for an Allgrove syndrome locus on band 12q13 near the type II keratin gene cluster, but no specific gene mutation has been identified.

Globally, the pathology of this syndrome may be due to a progressive loss of cholinergic function throughout the body. Alternatively, this disorder may represent a dysfunction of melanocortin receptor signaling, as melanocortin receptors are known to regulate adrenal function and skin exocrine gland function.

A lacrimal gland biopsy from a child with Allgrove syndrome was examined with an electron microscope. Evidence of neuronal degeneration associated with depletion of secretory granules in the acinar cells was observed. The reduced or absent lacrimation that accompanies this change frequently leads to dehydration-induced keratopathy that can be observed with rose Bengal staining.

CT scanning reveals atrophic adrenal glands, but no reports of histologic analysis are available. As with all states of ACTH unresponsiveness, one may expect to see atrophy of the zona fasciculata; however, other changes more specific to this syndrome may have yet to be described.

Frequency

International

Incidence is unknown, and only scattered family and case reports are noted in the literature. Review of multiple kindreds and analysis of a large, highly inbred kindred provide evidence that this is a rare syndrome with an autosomal recessive inheritance. The probable recurrence risk for future pregnancies from parents with a child affected with Allgrove syndrome is 25%. The actual incidence is difficult to determine because of the variable presentation, including unexplained childhood death due to adrenal crisis and mild disease that is not apparent until adulthood.

Mortality/Morbidity

The primary cause of mortality is unrecognized adrenal crisis. The most frequent initial presentation is a hypoglycemic seizure secondary to glucocorticoid deficiency. Most patients have previously unrecognized alacrima at the time of presentation. This leads to severe keratopathy and corneal melting (dehydration-induced ulceration). Achalasia leading to frequent vomiting or regurgitation also commonly occurs and may lead to growth failure. Most children who are diagnosed with achalasia in the general population have isolated esophageal dysfunction and do not have any other features of Allgrove syndrome.

Although the 3 main features produce the primary morbidities associated with Allgrove syndrome, a slow neurologic deterioration occurs in many patients. This most frequently includes mild mental retardation and autonomic neuropathy but may include ataxia and muscle weakness as well.

In the pediatric population, developmental delay is common. Determining if this impairment is a primary feature of the syndrome or simply a reflection of the episodic hypoglycemia that occurs in association with glucocorticoid deficiency is difficult.

Race

Allgrove syndrome is considered an autosomal recessive disorder with variable presentation. No evidence suggests that race affects the frequency. Allgrove syndrome has been reported in male and female blacks, whites, Hispanics, Native Americans, Indians, and Arabs around the world.

Sex

Allgrove syndrome is considered an autosomal recessive disorder with a variable presentation. No evidence suggests that gender affects the frequency.

Age

Age at onset of symptoms varies. The glucocorticoid deficiency is not apparent at birth but develops during the first 2 decades of life. Progression from normal adrenal function to adrenal insufficiency is documented in numerous individuals. Biochemical analysis in siblings of index cases documented several cases in which normal adrenal function is followed years later by adrenal crisis or glucocorticoid deficiency in these same individuals. Alacrima is typically present from early infancy, whereas symptoms of achalasia may appear in individuals as young as 6 months or as late as early adulthood.

Clinical

History

• Many cases of Allgrove (AAA) syndrome present with classic symptoms of primary adrenal insufficiency, including hypoglycemic seizures and shock.
• Less frequently, a child may be evaluated initially for recurrent vomiting, dysphagia, and failure to thrive (achalasia) or for ocular symptoms associated with alacrima.
• At presentation, review of systems may be positive for crying without tears, hyperpigmentation, developmental delay, seizures, dysphagia, hypernasal speech, and symptoms related to orthostatic hypotension.
• A family history of early unexplained infant deaths and familial consanguinity provides important clues. Evaluate siblings for early signs, particularly alacrima because this defect is frequently present from birth.
• Although mental retardation and hyperpigmentation in the parents or grandparents of patients have been reported, these are not common or consistent findings and are not expected with autosomal recessive inheritance.

Physical

• A distinct facial appearance associated with Allgrove syndrome consists of a long thin face with a long philtrum, narrow upper lip, and a down-turned mouth. These features are not seen in unaffected siblings.
• Microcephaly is associated frequently with this disorder, but whether this is a primary manifestation or simply a reflection of recurrent hypoglycemia and/or malnutrition is unclear.
• Conjunctival injection and irritation may be the only obvious signs of alacrima. Slit lamp examination may reveal punctate keratopathy or corneal ulceration.
• Definitive diagnosis of alacrima can be made at bedside with the Schirmer test. This test evaluates the wetting of a special strip placed in the conjunctival sac for 5 minutes. Less than 10 mm of wetting is abnormal.
• Cardiac examination findings may be abnormal due to a number of autonomic nervous system defects that may accompany Allgrove syndrome. Orthostatic hypotension and diminished heart rate variations during deep breathing and Valsalva maneuver are well documented. Abnormal findings on respiratory examination may be secondary to recurrent aspiration accompanying achalasia.
• Skin examination of patients may reveal abnormal findings that assist in confirming diagnosis. Hyperpigmentation is common but may be observed less frequently than in other forms of primary adrenal failure. Hyperkeratosis and fine fissuring of the palms of the hands and soles of the feet represent a unique feature of this syndrome.
• Neurologic features are varied and have been the subject of several case reports and reviews. The most commonly described abnormal features of the neurologic examination are hyperreflexia, dysarthria, hypernasal speech with palatopharyngeal incompetence, and ataxia.
• Adults may exhibit progressive neural degeneration, develop parkinsonian features, and show mental deterioration.

Causes

• Allgrove syndrome appears to have an autosomal recessive pattern of inheritance.
• Parental consanguinity and previously affected siblings are the primary risk factors, although many patients have no such family history.
• Linkage analysis provides evidence for an Allgrove syndrome locus on band 12q13 near the type II keratin gene cluster. Recent studies implicate mutations in the AAAS gene, which codes for a WD-repeat protein termed ALADIN.
• Globally, the pathology of this syndrome may be due, in part, to a progressive loss of cholinergic function throughout the body.
• Patients with isolated familial glucocorticoid deficiency (type 1 FGD) have mutations in the melanocortin-2 (ACTH) receptors. Patients with Allgrove syndrome (type 2 FGD) have no mutations in the coding sequence or the promoter region of this receptor gene. In Allgrove syndrome, the defect appears to reside in the ALADIN protein, which may be involved in either cytoplasmic trafficking or in normal peroxisomal function.

Differential Diagnoses

Adrenal Hypoplasia
Adrenal Insufficiency
Familial Glucocorticoid Deficiency

Other Problems to Be Considered

Achalasia
Alacrima
Adrenal leukodystrophy
Autonomic neuropathy

Workup

Laboratory Studies

• Assess adrenal function in patients with Allgrove (AAA) syndrome.
  • Patients who present with the combination of achalasia and alacrima should undergo a complete evaluation of their pituitary-adrenal axis to exclude adrenal insufficiency.
  • Incidence of glucocorticoid deficiency in patients with isolated achalasia is low, and endocrine evaluation is not warranted unless symptoms consistent with glucocorticoid deficiency are present.
  • Because no such data are available for patients with isolated alacrima, other clinical features must guide testing in this population.
  • In patients with symptoms of cortisol deficiency or combined alacrima and achalasia, draw baseline adrenocorticotropic hormone (ACTH) and cortisol values and perform an ACTH stimulation test to assess adrenal function.
• Esophageal motility tests are pertinent in patients presenting with dysphagia, food regurgitation, or both.
• Determine serum sodium, potassium, aldosterone, and renin levels. Although aldosterone levels are usually normal in 4A syndrome, several cases of mineralocorticoid deficiency have been reported.
• The presence of plasma antiadrenal antibodies should direct the investigation to the possibility of Addison disease.
• Look for normal plasma very long chain fatty acids (hexa-eicosanoate) to exclude adrenoleukodystrophy.
• If malnutrition is present, a comprehensive metabolic panel and CBC count are warranted.
• For patients presenting with a seizure, obtain a baseline serum glucose concentration and perform a lumbar puncture.
• Although none of the above tests are specific for Allgrove syndrome, they may provide clues for making this diagnosis.

Imaging Studies

• MRI or CT scanning of the head (if neurologic problems are observed)
  • Patients frequently reveal atrophic lacrimal glands on CT scans.
  • If the patient presents with a seizure, imaging of the brain is useful to exclude other causes of new-onset seizures.
  • Abdominal CT scanning may reveal cortical atrophy of the adrenal glands similar to that observed with primary adrenal insufficiency; however, this is typically not necessary to make the diagnosis.
• Barium esophagography, esophageal manometry, and endoscopy
  • Various methods are used to demonstrate achalasia of the esophagus.
  • Perhaps the most readily available and commonly used test is barium esophagography, although esophageal manometry and endoscopy are also used.
  • Barium esophagography typically demonstrates a dilated esophagus with minimal, if any, peristaltic movement. The meal frequently passes slowly through a tight lower esophageal sphincter.

Other Tests

• Brainstem auditory evoked response
  • Numerous investigators have demonstrated hearing deficits associated with Allgrove syndrome.
  • Brainstem auditory evoked response (BAER) testing is useful in determining which patients have hearing deficits.
  • Both normal and abnormal responses compatible with bilateral sensorineural hearing loss are found.
• Autonomic testing
  • Investigation of the autonomic nervous system, including tilt-table and heart rate variability testing, is useful in demonstrating and following autonomic dysfunction.
  • Many patients have diminished heart rate variability and exaggerated orthostatic responses on tilt-table.
  • Formal pupillometry, when available, may demonstrate anisocoria and slowed constriction velocity.
• Ophthalmologic evaluation for lacrimal dysfunction
  • Ophthalmologic testing is warranted in children with Allgrove syndrome.
  • A Schirmer test provides a semiquantitative measure of tearing. It consists of placing a standardized test strip in the conjunctival sac and measuring the wetting of this strip over a 5-minute interval. Less than 10 mm of wetting during this time is defined as alacrima.
  • Other ophthalmologic testing, including slit lamp examination and fluorescein staining, is helpful to identify patients with corneal pathology secondary to poor lacrimation.
• Neurologic evaluation
  • A complete neurologic evaluation and developmental study may highlight the impaired neurologic and developmental function associated with this syndrome.
  • Palatopharyngeal incompetence, sensory impairment, ataxia, and muscle weakness are among the documented findings.

Histologic Findings

• A lacrimal gland biopsy from a child with Allgrove syndrome was examined with an electron microscope. Evidence of neuronal degeneration associated with depletion of secretory granules in the acinar cells was present. The reduced or absent lacrimation that accompanies this change frequently leads to the dehydration-induced keratopathy observed with rose Bengal staining.
• CT scanning reveals atrophic adrenal glands, but no published cases of histologic analysis have been reported. As with all states of ACTH unresponsiveness, one may expect to see atrophy of the zona fasciculata; however, other changes more specific to this syndrome may have yet to be described.

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.

Dosing

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

Interactions

Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

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.

Dosing

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

Interactions

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

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease

Precautions

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.

Dosing

Adult

0.05-0.2 mg/d PO

Pediatric

0.05-0.1 mg/d PO; higher doses may be necessary in adolescents

Interactions

Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects of fludrocortisone; decreases salicylate levels

Contraindications

Documented hypersensitivity; systemic fungal infections

Precautions

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.

Dosing

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

Interactions

Effects decrease with coadministration of barbiturates, phenytoin and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization

Contraindications

Documented hypersensitivity; active bacterial or fungal infection

Precautions

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

Follow-up

Further Inpatient Care

• Glucocorticoid replacement: Inpatient care of Allgrove (AAA) syndrome is primarily directed toward maintaining adequate glucocorticoid replacement.
• Reflux precautions
  • Patients with achalasia and patients who have undergone esophageal pneumatic dilatation or myotomy are at risk for reflux with recurrent aspiration.
  • Standard reflux precautions are warranted (eg, elevating head of bed, careful feeding of infants).
  • Acid reduction therapy is often warranted.
• Frequent application of topical eye lubrication is warranted, as patients with alacrima are at risk for developing severe keratopathy due to excessive ocular dehydration.

Complications

• Glucocorticoid therapy
  • Overtreatment with glucocorticoids leads to growth failure and features of Cushing syndrome.
  • Undertreatment, particularly during illness, can lead to adrenal crisis with hypotension, hypoglycemia, and possibly death.
• Achalasia
  • Recurrent aspiration, documented in many patients with achalasia, can lead to acute pneumonitis, choking, and death.
  • Achalasia is also associated with chronic lung disease, as indicated through radiographic studies and pulmonary function tests.
• Alacrima: Patients with reduced lacrimation are at high risk for developing keratoconjunctivitis sicca and other keratopathy associated with dehydration-induced ocular tissue damage.
• Autonomic neuropathy and other neurologic disturbance
  • Slow neurologic deterioration occurs in many patients. This most frequently includes mild mental retardation and autonomic neuropathy but may include ataxia and muscle weakness as well.
  • Pediatric patients commonly show developmental delay. Determining if this impairment is a primary feature of the syndrome or simply a reflection of the episodic hypoglycemia that occurs in association with glucocorticoid deficiency is difficult.

Prognosis

• Provided the patient is effectively managed, a normal lifespan and childbirth are possible.
• Cases of parkinsonism, peripheral neuropathy, and seizures developing in patients have been reported, but whether this also occurs in patients who received an early diagnosis and long-term effective medical and surgical management is unclear.

Patient Education

• Glucocorticoid therapy
  • Patients must be instructed on the appropriate management of stress dosing of glucocorticoids.
  • A medical alert bracelet or necklace should be worn at all times.
  • Because of the possibility of severe stress or trauma in a situation where medical assistance is not immediately available, the patient and his or her family members should be instructed to inject hydrocortisone or dexamethasone intramuscularly in a dose appropriate for the size of the patient, typically 100 mg hydrocortisone or 2 mg dexamethasone for adolescents and adults.
• Gastroesophageal reflux
  • Families with an affected infant should be provided with instructions for reflux precautions for eating and sleeping.
  • Recurrent vomiting and eating difficulties should be evaluated by a physician.
• Alacrima: The importance of maintaining a regular schedule of topical ocular lubrication to prevent dehydration-induced keratopathy and opportunistic ocular infection should be emphasized to patients and their families.

Miscellaneous

Medicolegal Pitfalls

• Careful replacement of glucocorticoids in patients with known adrenal insufficiency is critical to avoid an adrenal crisis and to allow for normal growth in these children.
• Careful documentation of stress dose education and frequent monitoring of growth are essential.

References

1. 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].

2. Kasar PA, Khadilkar VV, Tibrewala VN. Allgrove syndrome. Indian J Pediatr. Oct 2007;74(10):959-61. [Medline].

3. Kelch RP, Kaplan SL, Biglieri EG. Hereditary adrenocortical unresponsiveness to adrenocorticotropic hormone. J Pediatr. Oct 1972;81(4):726-36. [Medline].

4. Counahan R, West R. Ocular and fingertip abnormalities in isolated glucocorticoid deficiency. J Pediatr. Oct 1974;85(4):580-1. [Medline].

5. 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].

6. 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].

7. Chu ML, Berlin D, Axelrod FB. Allgrove syndrome: documenting cholinergic dysfunction by autonomic tests. J Pediatr. Jul 1996;129(1):156-9. [Medline].

8. Clark AJ, Weber A. Adrenocorticotropin insensitivity syndromes. Endocr Rev. Dec 1998;19(6):828-43. [Medline].

9. 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].

10. 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].

11. 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].

12. 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].

13. 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].

14. 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].

15. 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].

16. 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].

17. 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].

18. Makari G, Hoffman WH, Carroll JE. Autonomic dysfunction and adrenocortical unresponsiveness to ACTH. J Child Neurol. Jul 1988;3(3):174-6. [Medline].

19. 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].

20. 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].

21. 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].

22. 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].

23. 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].

24. Prpic I, Huebner A, Persic M, et al. Triple A syndrome: genotype-phenotype assessment. Clin Genet. May 2003;63(5):415-7. [Medline].

25. 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].

26. Stuckey BG, Mastaglia FL, Reed WD. Glucocorticoid insufficiency, achalasia, alacrima with autonomic motor neuropathy. Ann Intern Med. Jan 1987;106(1):61-3. [Medline].

27. 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].

28. 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].

29. 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].

30. 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].

31. Vaughan WH, Williams JL. Familial achalasia with pulmonary complications in children. Radiology. May 1973;107(2):407-9. [Medline].

32. Verma S, Brown S, Dakkak M. Association of adult achalasia and alacrima. Dig Dis Sci. May 1999;44(5):876-8. [Medline].

33. 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].

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

Contributor Information and Disclosures

Author

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 Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Daniel L Marks, MD, PhD, Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health Sciences University and Doerenbecher Children's Hospital
Daniel L Marks, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and Oregon Medical Association
Disclosure: Nothing to disclose.

Jacalyn Bishop, MD, Pediatric Endocrinologist, Private Practice
Disclosure: Nothing to disclose.

Medical Editor

Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
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 financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Barry B Bercu, MD, Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital
Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Lawson-Wilkins Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern 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; Pfizer, Inc. Honoraria Consulting

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)