Allgrove Syndrome

Etiology

Allgrove’s syndrome results from mutations of the AAAS gene located on chromosome 12q13 that encodes a nuclear envelope protein known as ALADIN (alacrimia-achalasia-adrenal insufficiency neurologic) and highly expresses in different human tissues.[5][6][7][8][9] 

Linkage analysis shows evidence for an Allgrove syndrome locus on band 12q13.[10] The progressive loss of cholinergic functions also carries implications as an important pathological factor for the development of Allgrove syndrome. Clinically affected patients having AAAS gene mutations often have functional impairment with little or absence of any structural abnormalities.[3][4]

Epidemiology

Allgrove syndrome is a syndrome of unknown incidence and variable presentation with an autosomal recessive inheritance pattern. The probable recurrence risk with Allgrove syndrome is 25%. However, the actual incidence is difficult to determine because of the variable presentation. Most of the reported cases appear in Black, Native Americans, Arabs, and Asian descent males and females. Specific symptoms such as adrenal insufficiency are not prominent until the first two decades of life, whereas, alacrima typically occurs in early infancy, and symptoms of achalasia can be present in 6 months of age or late adolescence.[11][12]

History and Physical

The classic history and reasons for consultation include frequent complaints of the absence of tears while crying/dry eyes at birth due to alacrima, feeding difficulties, repeated vomiting, weight loss due to underlying achalasia, or seizure secondary to hypoglycemia resulting from the adrenal crisis, and delayed growth/milestones.

Other clues in the history that can aid in early recognition include the history of familial consanguinity, symptoms of autonomic failure (orthostatic hypotension), developmental delays, intellectual disabilities, seizures, and the presence of similar clinical findings in the siblings. Distinct physical features include microcephaly, long-thin facies with prominent philtrum, orthostasis, hypernasal speech, ataxia, skin thickening with fissuring of palms, and soles.[13][14] A specific examination can reveal abnormal Schirmer's test and the presence of corneal ulceration on slit-lamp examination.

Evaluation

Laboratory Evaluation

All the laboratory values are non-specific and are only used to detect the underlying conditions. The preferred labs are listed as follows:

• Complete blood count (CBC) and comprehensive metabolic panel (CMP) to rule out protein-calorie malnutrition
• Assessment of ACTH, cortisol, ACTH stimulation test is of prime importance in patients with Allgrove syndrome to diagnose adrenal insufficiency.
• Aldosterone and renin levels can detect mineralocorticoid deficiency.
• Determination of anti-adrenal antibodies can help in identifying Addison disease. 
• Lumbar puncture and baseline blood glucose can clue towards the underlying cause for seizures.
• Esophageal motility tests are pertinent in patients presenting with signs and symptoms of achalasia.

Other Diagnostic Modalities

• Computed tomography (CT) or magnetic resonance imaging (MRI) of Brain is preferred in patients presenting with seizures or other neurological symptoms. 
• Barium esophagogram is a preferred modality in patients having achalasia. Other alternatives include esophageal manometry and endoscopy [13]
• Ophthalmological evaluation for alacrima includes a Schirmer test, slit-lamp examination, and fluorescein staining.
• Brainstem auditory evoked response (BAER) testing is helpful in patients having hearing deficits.

Treatment / Management

Medical Management

Glucocorticoids (hydrocortisone, prednisone, dexamethasone, and fludrocortisone)

Hydrocortisone is the preferred steroid of choice in children owing to its balanced mineralocorticoid and glucocorticoid effects. However, daily dosing with fludrocortisone might still be needed to provide mineralocorticoid activity. Prednisone and dexamethasone are alternative to hydrocortisone in non-compliant patients. Regular monitoring of linear growth and weight gain is mandatory in patients on prednisone and dexamethasone due to growth suppressing effects and longer duration of action.

In patients with isolated alacrima, regular application of topical ocular lubricants is warranted to avoid the risk of dehydration-induced keratopathy. 

Surgical Management

Perioperative treatment with stress doses of glucocorticoids is necessary for all patients with Allgrove syndrome undergoing surgery. Pneumatic dilatation is the preferred procedure to relieve the lower esophageal sphincter spasm in patients with isolated achalasia.[14] Modified heller operation (anterior cardiomyotomy) is the alternative in patients with unsuccessful pneumatic dilatation. Operative complications include esophageal perforation and increased risk of post-surgical risk. Punctal occlusion can improve the symptoms of alacrima in patients not responding to topical ocular lubricants.(B3)

Differential Diagnosis

• Adrenal hypoplasia
• Familial glucocorticoid deficiency
• Addison disease

Prognosis

Prognosis depends on early recognition and effective management of patients. The leading cause of mortality is an undiagnosed adrenal crisis presenting as hypoglycemic seizure early in the course of the disease. 

Complications

• Complications are mostly related to the underlying classic sign and symptoms of AAA syndrome or from medical treatment.
• The overuse of glucocorticoids can lead to growth failure and Cushing syndrome. Undertreatment with steroids can result in adrenal crisis (hypotension, hypoglycemia, and increased risk of mortality)
• Alacrima can result in keratoconjunctivitis sicca.
• Achalasia can predispose patients to recurrent aspiration, choking, pneumonitis.
• Other complications include autonomic neuropathy, ataxia, developmental delay, mental retardation.