Allgrove Syndrome  

Said Azzoug , Faiza Boutekdjiret , Farida Chentli
Endocrinological department Bab El Oued Hospital Algiers, Algeria
Author    Correspondence author
International Journal of Clinical Case Reports, 2015, Vol. 5, No. 16   doi: 10.5376/ijccr.2015.05.0016
Received: 15 Feb., 2015    Accepted: 27 Mar., 2015    Published: 17 Apr., 2015
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Azzoug et al., 2015, Allgrove Syndrome, International Journal of Clinical Case Reports, Vol.5, No.16 1-2 (doi: 10.5376/ijccr.2015.05.0016)

Abstract

Background Allgrove syndrome is a rare autosomal recessive disorder characterized by the association of the triad adrenal insufficiency, alacrima and achalasia.

Objective The aim of our study is to analyze the clinical characteristics of this rare syndrome.
Methods The medical records of eight patients (6M/2F) recorded over thirty three years period were reviewed.
Results In this report we demonstrate that the mean age at diagnosis is 10.75 years, in one patient the diagnosis was delayed at 27 years although the clinical symptoms began many years before. Alacrima was present in all patients, adrenal insufficiency was present in 75%, achalasia was present in 87.5% of cases, growth retardation and/or pubertal delay were reported in 75%, 62.5 % of patients have neurological dysfunction mainly pyramidal syndrome. Deficiency anemia was noted in 75%.

Conclusion: Allgrove syndrome is a rare hereditary disease which may have fatal consequences if undiagnosed, an earlier diagnosis and adequate treatment of the patient and genetic counseling for the family improve the prognosis of this disease.

Keywords
Allgrove syndrome; Adrenal insufficiency; Achalasia; Alacrima

Allgrove syndrome or triple A syndrome is a rare autosomal recessive disorder characterized by the association of Adrenal insufficiency, Alacrima and Achalasia. In addition, numerous neurological signs affecting the central or peripheral and autonomic nervous system may also be present.

In this work we aimed to describe clinical characteristics of patients with Allgrove syndrome encountered in our practice.
Observations
Eight patients (6M/2F) were recruited over a period of thirty three years. Mean age at diagnosis was of 10.75 ± 8.18 years. Diagnosis was made many years after the first symptom of the disease as shown in Table 1. Consanguinity was present in 87.5%.


Table 1 Age of first symptom and age at diagnosis


Presenting symptom was alacrima in four patients and signs of adrenal insufficiency in four patients among which two patients presented for cutaneous pigmentation. The whole clinical syndrome was present in 75%. Alacrima was present in all patients, whereas achalasia was present in 87.5% and adrenal insufficiency in 75%. Neurological signs were present in 62.5%, mental retardation was present in 25%. In addition, deficiency anemia was reported in 75% of cases may be as a consequence of achalasia and malabsorption syndrome. 75% of our patients present growth retardation or pubertal delay.
Discussion
Allgrove syndrome (AS) or triple A syndrome was first described in 1978 (Allgrove et al., 1978). It is characterized by the association of Alacrima, Achalasia and Adrenal insufficiency. Alacrima is the first sign of AS and appears during early years of life (Ornek et al., 2002) as was seen in our patients, but it is often overlooked. Adrenal insufficiency usually starts before puberty and is secondary to ACTH (Adrenocorticotropic hormone) insensitivity, mineralocorticoid function is often normal but deficiency has been reported (Lanes et al., 1980). Achalasia usually occurs at the same time or after the diagnosis of adrenal insufficiency, but it may occurs before, it is present in 75% as we observed. Association of alacrima and achalasia distinguished AS from familial glucocorticoid deficiency caused by mutations of ACTH receptor gene. Diagnosis of AS is often done during childhood, but sometimes it may be done in adulthood as was the case in one of our patients where it was made at 27 years and as was the case reported by Pedreira where diagnosis was made at 37 years (Pedreira et al., 2004). Neurological Abnormalities are so frequent as observed in our patients that the syndrome is often called the 4A syndrome (Gazarian et al., 1995). Mental retardation may also be present, seen in 25% of our patients, it may represents a primary feature of the syndrome or may be secondary to recurrent hypoglycemia of adrenal insufficiency in infancy. AS is secondary to a mutation of the AAAS gene located on chromosome 12q13.13 which encodes a protein known as Aladin or Adracalin with mainly nonsense mutations, resulting in expression of truncated protein (Orrell and Clark, 2002). It is inherited as an autosomal recessive trait, consanguinity is frequent, it was reported in 87.5% of our patients.
Involvement of both endocrine and nervous system is suggestive of a defect in autonomic nervous system as a causative effect, specifically degeneration of the parasympathic system resulting in a progressive loss of cholinergic function (Clark and Weber, 1998). Alternatively, defects in peroxisomal membranes proteins or mutations of transcription factors are also proposed.
References
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Lanes R., Plotnick L.P., Bynum T.E., et al, 1980, Glucocorticoid and partial mineralocorticoid deficiency associated with achalasia, J. Clin. Endocrinol. Metab., 50: 268-270
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Pedreira C.C., and Zacharin M.R., 2004, Allgrove syndrome: when a recognisable paediatric disorder occurs in adulthood, Med. J. Aust, 180: 74-75
Gazarian M., Cowell C.T., Bonney M., and Grigor W.G., 1995, The “4A” syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities, Eur. J. Paediatr., 154: 18-23
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Clark A.J., and Weber A., 1998, Adrenocorticotropin insensitivity syndromes, Endocrine Review, 19(6): 828-843
http://dx.doi.org/10.1210/edrv.19.6.0351

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