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Allgrove (AAA) Syndrome
INTRODUCTION

Background: In 1978, Allgrove and colleagues described 2 unrelated pairs of siblings with isolated glucocorticoid failure 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 patients with hereditary adrenal unresponsiveness to adrenocorticotropic hormone (ACTH). Allgrove pointed out that the patients from these prior reports had developed achalasia and suggested that all of these patients shared a common etiology.

Similarly, patients originally reported as having isolated achalasia were subsequently diagnosed with 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 shown to also 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 are identified in patients with this syndrome. Linkage analysis in both European and Puerto Rican kindreds provides evidence for linkage to chromosome 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 pathological 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 chromosome 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 and showed evidence of neuronal degeneration associated with depletion of secretory granules in the acinar cells. The reduced or absent lacrimation that accompanies this change frequently leads to dehydration-induced keratopathy that can be seen with rose Bengal staining.

Computed tomography demonstrates atrophic adrenal glands, but there are no published reports of histological analysis. As with all states of ACTH unresponsiveness, one might expect to see atrophy of the zona fasciculata; however, there may be other changes more specific to this syndrome that are not yet described.

Frequency:

  • Internationally: 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 an extremely rare syndrome with an autosomal recessive inheritance. The probable recurrence risk for future pregnancies from parents with a child affected by 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 neurological deterioration occurs in many patients. This most frequently includes mild mental retardation and autonomic neuropathy but may include ataxia and muscle weakness.
  • In the pediatric population, developmental delay is common, but 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 indicators that race affects the frequency exist.
  • 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 indicators that sex affects the frequency exist.

Age:

  • Age at onset of symptoms is variable. The glucocorticoid deficiency is not apparent at birth but develops over the first 2 decades of life.
  • Progression from normal adrenal function to adrenal insufficiency is documented in a number of individuals.

History:

  • Most 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 any early signs, especially for 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. Alacrima is defined as less than 2 mm of wetting.
  • Cardiac examination findings may be abnormal due to a number of autonomic nervous system defects that may accompany Allgrove syndrome. Diminished heart rate variations during deep breathing and Valsalva maneuver, and orthostatic hypotension 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 less frequent than in other forms of primary adrenal failure. Hyperkeratosis and fine fissuring of the palms of the hands may 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 neurological 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 may 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 chromosome 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.

Other Problems to be Considered:

Achalasia
Alacrima
Adrenal leukodystrophy
Autonomic neuropathy

WORKUP
 

Lab Studies:

  • Baseline ACTH and cortisol, ACTH stimulation testing are used to test for tear production.
  • Esophageal motility tests
    • Any patient who presents with the combination of achalasia and alacrima should have a complete evaluation of their pituitary-adrenal axis to rule out 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.
    • No such data exist for patients with isolated alacrima, so other clinical features must guide testing in this population.
    • In patients with symptoms of cortisol deficiency or combined alacrima and achalasia, baseline ACTH and cortisol values should be drawn and an ACTH stimulation test performed.
  • Serum sodium, serum potassium, aldosterone, renin: Although aldosterone dynamics usually are normal in 4A syndrome, several cases of mineralocorticoid deficiency have been reported.
  • Plasma antiadrenal antibodies
    • Normal plasma very long chain fatty acids (hexaeicosanoate) rule out adrenoleukodystrophy.

       

    • The presence of antiadrenal antibodies should direct the investigation to the possibility of Addison disease.
  • Other laboratory studies
    • If malnutrition is a major problem, a comprehensive metabolic panel and complete blood count are warranted.

       

    • Include testing of serum glucose, cerebrospinal fluid (CSF) glucose, protein, cell count, and a culture.

       

    • For patients presenting with seizure, a baseline serum glucose and lumbar puncture should be performed.
    • Although none of these tests is specific for Allgrove syndrome, they may provide further clues in making this diagnosis.

Imaging Studies:

  • Head MRI or CT scan if neurologic problems are observed
    • Patients frequently have atrophic lacrimal glands on CT scan.
    • If the patient presents with a seizure, imaging of the brain is useful to rule out other causes of new-onset seizures.
  • Abdominal CT scan may show the cortical atrophy of the adrenals similar to that seen with primary adrenal insufficiency but generally is not necessary to make the diagnosis.
  • Barium esophagram, esophageal manometry, and endoscopy
    • Various methods are used to demonstrate achalasia of the esophagus.
    • Perhaps the most readily available and commonly used test is the barium esophagram, although esophageal manometry and endoscopy also are used.
    • The barium esophagogram typically shows a dilated esophagus with minimal, if any, peristaltic movement. The meal will frequently pass slowly through a tight lower esophageal sphincter.

Other Tests:

  • Brainstem auditory evoked response
    • A number of investigators have demonstrated hearing deficits associated with this 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 any child 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 highlights myriad neurologic and developmental issues identified 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 dehydration-induced keratopathy that is seen with rose Bengal staining.

CT scan demonstrates atrophic adrenal glands, but no published cases of histological analysis have been reported. As with all states of ACTH unresponsiveness, one might 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

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 also is 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 surgical 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 a 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: These tests highlight myriad neurologic and developmental issues. Palatopharyngeal incompetence, sensory impairment, ataxia, and muscle weakness are among the documented findings.

Diet: Other than 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

Drug Category: Corticosteroids -- Careful replacement of glucocorticoids in patients with known adrenal insufficiency is critical not only to avoid an adrenal crisis, but also 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. Generally speaking, a doubling or tripling of the oral dose is sufficient for routine illnesses. A larger increase in dose (provided intravenously if necessary) is appropriate for severe illness and major trauma (see Adrenal Insufficiency).

Drug Name
 		 Hydrocortisone (Hydrocortone, Cortef) -- Has mineralocorticoid and glucocorticoid effects. Useful in management of inflammation caused by immune response.
Adult Dose 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 Dose 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 with 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
Contraindications Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia
Pregnancy C - Safety for use during pregnancy has not been established.
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)
Drug Name
 		 Prednisone (Deltasone) -- Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.
In patients who have difficulty with compliance, it is acceptable to replace hydrocortisone with an equipotent dose of prednisone (prednisone is 4-5 times as potent as hydrocortisone).
Doses can be adjusted based on symptoms and monitoring linear growth and weight gain.
Adult Dose 2.5-7.5 mg/d PO; titrate up or down depending on clinical response
Pediatric Dose 4-5 mg/m2/d PO; titrate up or down depending on clinical response
Contraindications Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
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
Pregnancy B - Usually safe but benefits must outweigh the risks.
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)
Drug Name
 		 Fludrocortisone (Florinef) -- Provides physiologic replacement of mineralocorticoid deficiency.
Dose must be sufficient to lower plasma renin activity to normal without inducing hypertension.
Adult Dose 0.05-0.2 mg/d PO
Pediatric Dose 0.05-0.1 mg/d PO; higher doses may be necessary in adolescents
Contraindications Documented hypersensitivity; systemic fungal infections
Interactions Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects of fludrocortisone; decreases salicylate levels
Pregnancy C - Safety for use during pregnancy has not been established.
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
Drug Name
 		 Dexamethasone (Decadron) -- For various allergic and inflammatory diseases. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.
Adult Dose 0.5 mg/d PO; titrate up or down depending on clinical response
Pediatric Dose 0.03-0.15 mg/kg/d PO/IV/IM; titrate up or down depending on clinical response
Contraindications Documented hypersensitivity; active bacterial or fungal infection
Interactions Effects decrease with coadministration of barbiturates, phenytoin and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization
Pregnancy C - Safety for use during pregnancy has not been established.
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 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 often is warranted.
  • Frequent application of topical eye lubrication: Patients with alacrima are at risk for development of 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 is documented in many patients with achalasia, which can lead to acute pneumonitis, choking, and death.

       

    • Achalasia also is associated with chronic lung disease as indicated by both radiographic studies and pulmonary function tests.
  • Alacrima: Patients with reduced lacrimation are at high-risk for development of 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.
  • Developmental delay
    • 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 the patient 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 occurs in patients who had early diagnosis and long-term effective medical and surgical management.

Patient Education:

  • Glucocorticoid therapy
    • Patients must be instructed in 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 a severe stress or trauma in a situation where medical assistance is not immediately available, the patient and their 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 eating and sleeping with reflux precautions.
    • 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

Medical/Legal Pitfalls:
 

  • Inadequate glucocorticoid monitoring and therapy
    • Careful replacement of glucocorticoids in patients with known adrenal insufficiency is critical not only to avoid an adrenal crisis but also to allow for normal growth in children.
    • Careful documentation of stress dose education and frequent monitoring of growth are essential.
 

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