Allgrove (AAA) Syndrome 

Updated: Mar 15, 2021
Author: Robert J Ferry, Jr, MD; Chief Editor: Robert P Hoffman, MD 

Overview

Background

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.

Pathophysiology

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.

Etiology

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.

Epidemiology

Frequency

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]

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. 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.

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.

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.

Alacrima

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

 

Presentation

History

At presentation, review of systems may be positive for alacrima, hyperpigmentation, developmental delay, seizures, dysphagia, hypernasal speech, and symptoms related to orthostatic hypotension.

Many cases of Allgrove (AAA) syndrome present with classic symptoms of primary adrenal insufficiency and alacrima,[16] including hypoglycemic seizures and shock. Esophageal achalasia in pediatrics is rare, with less than 5% of patients presenting under the age of 15 years.[13] Achalasia typically presents with vomiting (84.6%), dysphagia (69.2%), weight loss (46.0%), and chronic cough (46.1%).[17] Often misdiagnosed as gastroesophageal reflux, achalasia should be considered as a differential in GERD unresponsive to treatment.[13]

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 considered to be an early symptom of Allgrove syndrome, and may appear during early infancy.

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 Examination

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.[18]

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.[19]

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.

Adults may exhibit progressive neural degeneration, develop parkinsonian features, and show mental deterioration. Neurologic features are varied and have been the subject of several case reports and reviews.[20] 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.[21]

 

DDx

 

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. Consider the following:

  • 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, 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 computed tomography (CT) scanning of the orbits.

If the patient presents with a seizure, magnetic resonance imaging (MRI) 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; esophageal manometry and endoscopy are also used.[18, 22]

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.[23] 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.

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.[8]

Computed tomography (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 corticosteroids 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 cortisone with an equipotent dose of prednisone or dexamethasone is appropriate.

Prednisone and dexamethasone are less preferred for maintenance than hydrocortisone which has balanced 1:1 effects of mineralocorticoid vs. glucocorticoid. Also, these corticosteroids are not preferred in children due to potential for growth-suppressive effects with greater potency and longer duration of action compared to hydrocortisone.

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. Frequent application of topical eye lubrication is warranted, as patients with alacrima are at risk for developing severe keratopathy due to excessive ocular dehydration. Children may need to be frequently reminded to use artificial tears. Children must have an annual ophthalmologic evaluation.

Surgical Care

Patients with Allgrove syndrome who undergo surgery must be treated with stress doses of glucocorticoids in the perioperative period.

Achalasia

The symptoms of lower esophageal sphincter spasm in patients with achalasia can be ameliorated partially with pneumatic dilatation.[24] 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.

Patients with achalasia and patients who have undergone esophageal pneumatic dilatation or myotomy are at risk for postsurgical reflux with recurrent aspiration.[25] Standard reflux precautions (eg, elevating head of bed, careful feeding of infants) and acid reduction therapy is often warranted.

Peroral endoscopic myotomy (POEM) is an effective minimally invasive alternative to laparoscopic Heller myotomy.[22, 26, 27, 28] First introduced by Ortega in 1980, POEM is a procedure that combines the benefits of myotomy with those of an endoscopic application[29] ; the current technique was introduced in 2008.[30] A meta-analysis found that POEM efficacy for dysphagia may be similar to that of laparoscopic myotomy, but with the added benefit of a shorter hospital stay. The rates of short-term clinical success (at 1-year follow-up) have been high, from 82% to 100%. Although long-term outcomes have not been reported yet, the 2-mo, 2-year and 3-year success rates were 91.3%, 91.0% and 88.5%, respectively.[31]

Alacrima

The symptoms of alacrima improve with punctal occlusion. This procedure is only necessary when therapy with topical lubricants is unsuccessful because of poor compliance.

Consultations

Allgrove (AAA) syndrome is multisystem disease which requires a multidisciplinary team of specialists. Endocrinologists, gastroenterologists, ophthalmologists, neurologists, developmental specialists, dentists, geneticists, and surgeons all have a role in managing patients with Allgrove syndrome.

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.

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.

Prevention

There is a 25% recurrence risk of Allgrove syndrome in future pregnancies.[14] Identification of the mutation(s) allows for prenatal diagnosis by chorionic villus sampling or amniocentesis, as well as preimplantation diagnosis. DNA confirmation in the proband also allows for early identification of currently asymptomatic siblings at risk in order to provide appropriate monitoring and treatment.[13, 14]

 

Medication

Corticosteroids

Class Summary

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 corticosteroids 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)

Hydrocortisone is preferred owing to its balanced (1:1) mineralocorticoid and glucocorticoid effects. It is useful in the management of inflammation caused by an immune response. The patient may still require daily supplementation with fludrocortisone to provide adequate mineralocorticoid activity.

Prednisone (Deltasone)

Prednisone is not preferred in children because of its potential for growth-suppressive effects with greater potency and a longer duration of action compared with hydrocortisone. It is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Prednisone 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 the monitoring linear growth and weight gain.

Dexamethasone (Decadron)

Dexamethasone is not preferred in children because of its potential for growth-suppressive effects with greater potency and a longer duration of action compared with hydrocortisone. It decreases inflammation by suppressing the migration of PMN leukocytes and reducing capillary permeability. Dexamethasone is the least preferred for maintenance or stress dosing because of its lack of mineralocorticoid activity.

Fludrocortisone (Florinef)

Fludrocortisone provides physiologic replacement of mineralocorticoid deficiency. The dose must be sufficient to lower plasma renin activity to normal without inducing hypertension.