Allgrove (AAA) Syndrome

Updated: Mar 15, 2021
  • Author: Robert J Ferry, Jr, MD; Chief Editor: Robert P Hoffman, MD  more...
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Allgrove syndrome or Triple A (AAA) syndrome (online mendelian inheritance in man [OMIM] number 231550) is a rare autosomal recessive disease characterized by alacrima, achalasia of the esophageal cardia, and adrenal failure first described by Allgrove et al in 1978. [1] Over the following decade, 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). [2] Specific autonomic disturbances described in this syndrome include abnormal pupillary reflexes, poor heart rate variability, and orthostatic hypotension. Allgrove syndrome is increasingly considered a multisystem disease; the phenotype is complex and all the clinical features are progressive, suggesting a degenerative process. [3]

The protean presentation of this disorder is related to dysfunction of nuclear pore complexes (NPC), despite apparently normal structure of these large multiprotein assemblies. In more than 90% of cases, Allgrove syndrome arises from mutations of the ADRACALIN (or AAAS) gene encoding the ALADIN protein of the NPC. [4, 5] Linkage analyses in both European and Puerto Rican kindreds provide 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 intriguing because of hyperkeratosis of the palms and soles has been observed in several patients.



No unifying pathologic features common to the three 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. [6]

Oxidative stress may play a role in the pathogenesis of this disease. [3, 7] In patients with Allgrove syndrome, dermal fibroblasts have higher basal intracellular reactive oxygen species and are more sensitive to oxidative stress than wild-type fibroblasts. Additionally, failure of nuclear import of two DNA repair proteins has been described in the dermal fibroblast model. [7] Full-length human ferritin heavy chain protein (FTH1), which has a DNA-protective role in the nucleus, has been identified as an interacting protein partner for ALADIN in vitro. Unlike control cells, no nuclear FTH1 is apparent in the fibroblasts or lymphocytes of patients with Allgrove syndrome. implicating ALADIN in the nuclear localization of FTH1. Apoptosis of neuronal cells induced by hydrogen peroxide is significantly reduced by transfection of AAAS or FTH1 and maximally by both genes together. These findings suggest that oxidative stress is involved in disease progression. [3]

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. [8]

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.



Allgrove syndrome has 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. [9, 10] Studies implicate mutations in the AAAS gene, which codes for a WD-repeat protein termed ALADIN. [11, 12]

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 functional defect may reside in the ALADIN protein, which can be involved in either cytoplasmic trafficking or in normal peroxisomal function.




Allgrove syndrome, or AAA syndrome, is a rare autosomal recessive endocrine and neurologic disorder with an estimated prevalence of 1 per 1,000,000 individuals. [13] The probable recurrence risk for future pregnancies from parents with a child affected with Allgrove syndrome is 25%. [14] 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.

Race-, sex-, and age-related demographics

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.

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

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 has been 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. [15]



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. Whether these also occur in patients who received an early diagnosis and long-term effective medical and surgical management is unclear.

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 three main features produce the primary morbidities associated with Allgrove syndrome, a highly disabling neurodegenerative process ensues in approximately 60% of patients. Features include peripheral neuropathy, autonomic impairment, pyramidal and bulbar dysfunction, and cerebellar and neuroophthalmological signs. [3] 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.


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.


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.


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.


Patient Education

Glucocorticoid therapy

A medical alert bracelet or necklace that states "adrenal insufficiency" or similar language should be worn at all times.

Patients must be instructed on the appropriate management of stress dosing of glucocorticoids.

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. The injection should be given whenever the patient cannot tolerate enteral stress dosing (eg, vomiting, loss of consciousness, severe diarrhea), followed promptly by medical attention at the closest facility.

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.


Emphasize the importance of maintaining a regular schedule of topical ocular lubrication to prevent dehydration-induced keratopathy and opportunistic ocular infection.