AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1978, Allgrove and colleagues described 2 unrelated pairs of siblings with isolated glucocorticoid deficiency and achalasia of the esophagus cardia. 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. The authors also referred to the prior publications of Kelch and Counahan, who reported on patients with hereditary adrenal unresponsiveness to adrenocorticotropic hormone (ACTH). 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, a number of 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). 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. While 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 demonstrates atrophic adrenal glands, but there are no published reports of histologic analysis. As with all states of ACTH unresponsiveness, one may expect to see atrophy of the zona fasciculata; however, there may be other changes more specific to this syndrome that have not yet been described.

Frequency

International

Incidence is unknown, and only scattered family and case reports exist 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.
• While the 3 main features produce the primary morbidities associated with Allgrove syndrome, it is apparent that 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. There is no evidence that race affects the frequency.
• Allgrove syndrome has been reported in male and female African Americans, Caucasians, Hispanics, Native Americans, Indians, and Arabs around the world.

Sex

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

Age

• Age at onset of symptoms is variable. 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 a number of 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, while symptoms of achalasia may appear in individuals as young as 6 months or as late as early adulthood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Many cases 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.
• While 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 it is unclear if this is a primary manifestation or simply a reflection of recurrent hypoglycemia and/or malnutrition.
• 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Achalasia
Alacrima
Adrenal leukodystrophy
Autonomic neuropathy

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Assess adrenal function.
• • 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.
  • As no such data exist 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 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 of the head (if neurologic problems are observed)
• • Patients frequently reveal atrophic lacrimal glands on CT.
  • If the patient presents with a seizure, imaging of the brain is useful to exclude other causes of new-onset seizures.
  • Abdominal CT may depict 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
• • A number of 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 demonstrates 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, there may be other changes more specific to this syndrome that have not yet been described.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 monitored closely, 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, it is appropriate to replace hydrocortisone with an equipotent dose of prednisone or dexamethasone.
• 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 reminded frequently 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

• Ophthalmology: 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.
• Neurology: 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: 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).

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Glucocorticoid replacement: Inpatient care is directed primarily 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 managed effectively, there is no reason that he or she cannot have a normal lifespan and bear children.
• Cases of parkinsonism, peripheral neuropathy, and seizures developing in patients have been reported, but it is unclear if this also occurs in patients who received an early diagnosis and long-term effective medical and surgical management.

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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Inadequate glucocorticoid monitoring and therapy
• • 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• 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].
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Article Last Updated: Oct 3, 2006