Continuing Education Activity

Allgrove syndrome (AS) or 3A syndrome (AAA) is characterized by a triad of adrenocorticotrophic hormone (ACTH) resistant adrenal insufficiency, alacrimia, and achalasia along with progressive neurological impairment with or without mild mental retardation. This activity outlines the evaluation and management of Allgrove syndrome and highlights the role of the healthcare team in improving care for patients with this condition.

Objectives:

• Identify the etiology of Allgrove syndrome.
• Review the process for the evaluation of Allgrove syndrome.
• Summarize the management options available for Allgrove syndrome
• Discuss interprofessional team strategies for improving care coordination and communication to advance Allgrove syndrome and improve outcomes.

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Introduction

The year 1978 saw the first reported case of Allgrove syndrome (AS) or 3A syndrome (AAA).[1] It is characterized by a triad of adrenocorticotrophic hormone (ACTH) resistant adrenal insufficiency, alacrimia, and achalasia along with progressive neurological impairment with or without mild mental retardation.[2][3][4] The molecular basis for Allgrove syndrome appears to be an autosomal recessive pattern of inheritance. Parental consanguinity and previously affected siblings are the important risk factors in family history. 

The clinical presentation of classical signs and symptoms of the syndrome is dependent on the age of the patient. Ophthalmological abnormalities are usually present at birth, whereas adrenal and gastrointestinal abnormalities are apparent after six months to the first decade of life. Neurological dysfunction from the involvement of central or autonomic nervous systems is also common with Allgrove syndrome observed during the adolescent period.

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.

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.

Deterrence and Patient Education

Adrenal insufficiency is the most common cause of debilitation and mortality in patients with Allgrove syndrome. Appropriate education and advice are necessary regarding effective dosing and compliance with glucocorticoids. Medical bracelets or necklaces stating "adrenal insufficiency" should be worn all the time. The clinical team should provide parental education about the injectable steroids in case of emergency or unavailability of medical personnel.

Counseling regarding compliance with topical ocular lubricants and consistent follow-up with ophthalmology should be stressed to avoid future opportunistic infections and dehydration-induced corneal ulcers. Patients and their families should also receive a brochure detailing risk factors of gastroesophageal reflux disease in case of isolated achalasia. In the case of recurrent vomiting, cough, eating difficulties, physician follow-up is recommended.

Pearls and Other Issues

An intact mineralocorticoid production with primary adrenal insufficiency is the unique feature of Allgrove syndrome, but 15% of cases reported impaired mineralocorticoid production.[12]

Allgrove syndrome is also known as 4A syndrome if there are neurological findings such as autonomic dysfunctions or mental retardation, in addition to achalasia, adrenal insufficiency, and alacrima.[15]

Enhancing Healthcare Team Outcomes

Allgrove syndrome is a rare and underdiagnosed condition. Prompt diagnosis and treatment should start promptly in cases of suspected disease. An interprofessional team approach will improve patient outcomes. The team should include a neurologist, an ophthalmologist, a pediatrician, a gastroenterologist, and an endocrinologist. Parental and patient education should take place at every visit detailing the disease course, risk factors, and treatment. Lacrimal gland biopsy may be an option for making a definitive diagnosis of dry eyes secondary to alacrima. Frequent weight, dosing of steroids, and linear growth monitoring are regularly necessary.

Review Questions

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References

1.

Allgrove J, Clayden GS, Grant DB, Macaulay JC. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. 1978 Jun 17;1(8077):1284-6. [PubMed: 78049]

2.

Grant DB, Dunger DB, Smith I, Hyland K. Familial glucocorticoid deficiency with achalasia of the cardia associated with mixed neuropathy, long-tract degeneration and mild dementia. Eur J Pediatr. 1992 Feb;151(2):85-9. [PubMed: 1537368]

3.

Goizet C, Catargi B, Tison F, Tullio-Pelet A, Hadj-Rabia S, Pujol F, Lagueny A, Lyonnet S, Lacombe D. Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation. Neurology. 2002 Mar 26;58(6):962-5. [PubMed: 11914417]

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Palka C, Giuliani R, Brancati F, Mohn A, Di Muzio A, Calabrese O, Huebner A, De Grandis D, Chiarelli F, Ferlini A, Stuppia L. Two Italian patients with novel AAAS gene mutation expand allelic and phenotypic spectrum of triple A (Allgrove) syndrome. Clin Genet. 2010 Mar;77(3):298-301. [PubMed: 20447142]

5.

Weber A, Wienker TF, Jung M, Easton D, Dean HJ, Heinrichs C, Reis A, Clark AJ. Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet. 1996 Dec;5(12):2061-6. [PubMed: 8968764]

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Tullio-Pelet A, Salomon R, Hadj-Rabia S, Mugnier C, de Laet MH, Chaouachi B, Bakiri F, Brottier P, Cattolico L, Penet C, Bégeot M, Naville D, Nicolino M, Chaussain JL, Weissenbach J, Munnich A, Lyonnet S. Mutant WD-repeat protein in triple-A syndrome. Nat Genet. 2000 Nov;26(3):332-5. [PubMed: 11062474]

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Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. 2001 Feb 01;10(3):283-90. [PubMed: 11159947]

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Neer EJ, Schmidt CJ, Nambudripad R, Smith TF. The ancient regulatory-protein family of WD-repeat proteins. Nature. 1994 Sep 22;371(6495):297-300. [PubMed: 8090199]

9.

Cronshaw JM, Matunis MJ. The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5823-7. [PMC free article: PMC156285] [PubMed: 12730363]

10.

Stratakis CA, Lin JP, Pras E, Rennert OM, Bourdony CJ, Chan WY. Segregation of Allgrove (triple-A) syndrome in Puerto Rican kindreds with chromosome 12 (12q13) polymorphic markers. Proc Assoc Am Physicians. 1997 Sep;109(5):478-82. [PubMed: 9285947]

11.

Milenkovic T, Zdravkovic D, Savic N, Todorovic S, Mitrovic K, Koehler K, Huebner A. Triple A syndrome: 32 years experience of a single centre (1977-2008). Eur J Pediatr. 2010 Nov;169(11):1323-8. [PubMed: 20499090]

12.

Grant DB, Barnes ND, Dumic M, Ginalska-Malinowska M, Milla PJ, von Petrykowski W, Rowlatt RJ, Steendijk R, Wales JH, Werder E. Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child. 1993 Jun;68(6):779-82. [PMC free article: PMC1029374] [PubMed: 8333772]

13.

Alhussaini B, Gottrand F, Goutet JM, Scaillon M, Michaud L, Spyckerelle C, Viola S, Lamblin MD. Clinical and manometric characteristics of Allgrove syndrome. J Pediatr Gastroenterol Nutr. 2011 Sep;53(3):271-4. [PubMed: 21865973]

14.

Alakeel A, Raynaud C, Rossi M, Reix P, Jullien D, Souillet AL. [Allgrove syndrome]. Ann Dermatol Venereol. 2015 Feb;142(2):121-4. [PubMed: 25554662]

15.

Gazarian M, Cowell CT, Bonney M, Grigor WG. The "4A" syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities. Eur J Pediatr. 1995 Jan;154(1):18-23. [PubMed: 7895750]

Disclosure: Muhammad Mubbashir Sheikh declares no relevant financial relationships with ineligible companies.

Disclosure: Khaled Bittar declares no relevant financial relationships with ineligible companies.