Achalasia as part of the Allgrove syndrome
J. Pérez de la Serna, A. Ruiz de León,
C. Sevilla-Mantilla, M. Díaz-Rubio (Madrid)
Achalasia is a motor disorder of the esophagus characterized by esophageal aperistalsis and failure of the lower esophageal sphincter (LES) to relax normally with swallowing. It may be primary or secondary to another disorder. Referring to the latter, achalasia has been reported secondary to Chagas' disease, tumors remote from the LES or that locally involve it, infiltrative disorders like amylosis, or diabetes mellitus. It has also been described in association with other diseases, mainly central or peripheral nervous system diseases, cerebellar ataxia, mental retardation, optic atrophy, familial disautonomy of Riley-Day, idiopathic intestinal pseudo-obstruction, trisomy 21, ACTH insensitivity, or as part of syndromes like multiple endocrine neoplasia type 2b, sicca syndrome and Allgrove syndrome . Allgrove syndrome is characterized by the presence of achalasia, ACTH insensitivity and deficient tear production, also known as Triple A syndrome. The first description was made by Allgrove in 1978, reporting the cases of two pairs of siblings in separate families . Since then, subsequent reports have led to an expansion of the clinical manifestations of this syndrome [3-23] which are summarized in Table I.
|Table I. Literature review of the Allgrove syndrome (Triple A syndrome).|
|Allgrove||M||Glucocorticoid||No||Hyperkeratosis of the|
|(1978) ||palms and soles,|
|F||Glucocorticoid||No||Enlargement of the thymus|
|Lanes (1980) ||F||Both||No||No|
|Geffner (1983) ||M||Glucocorticoid||No||No|
|(1985) ||neurogenic atrophy|
|Pombo (1985) ||M||Glucocorticoid||No||No|
|Rouberge (1986) ||F||Glucocorticoid||No||No|
|Ambrosino (1986) ||M||Glucocorticoid||No||No|
|Kalifa (1986) ||Report of 5 cases in a radiological series without details|
|Ehrich (1987) ||M||Both||Pychomotor retardation,||No|
|hypotonia optic atrophy,|
|Dumic (1987) ||M||Glucocorticoid||Sensory||Hyperkeratosis of palms|
|polyneuropathy,||and soles, insufficient|
|Shah (1988) ||F||Glucocorticoid||No||Familial hypophospha-|
|Stuckey (1988) ||F||Glucocorticoid||Autonomic neuropathy||Symmetric distal|
|Zucchini (1988) ||M||Glucocorticoid||No||Muscular hypotrophy.|
|Fernbach (1989) ||F||Glucocorticoid||No||No|
|Hammami (1989) ||F||Both||Absence of||Consanguinity, loss of|
|pupillary reflex||tongue papillae|
|Varkonyi (1990) ||F||Glucocorticoid||No||Hyperlipoproteinemia|
|Boudon (1990) ||M||Glucocorticoid||Absence of thermal||No|
|and pain sensibility|
|Tuck (1991) ||M||Glucocorticoid||No||No|
|Moore (1991) ||M||Glucocorticoid||Mental retardation||Consanguinity, typical|
|facies, partial duplica-|
|tion of urinary|
|F||Glucocorticoid||Axonal neuropathy||Muscular atrophy of|
|Mental retardation||limbs, consanguinity,|
|M||Glucocorticoid||Axonal neuropathy||Muscular atrophy of|
|pupillary dysfunction||limbs, consanguinity,|
|Grant (1992) *||M||Glucocorticoid||Parkinson disease,||Muscle wasting of the|
|loss of vibration and|
|position sense, pyramidal|
|Pérez de la Serna||F||Both||No||Muscular atrophy in|
|(1993) ||hands, limbs and soles,|
|* These two patients were previously described by Allgrove . Both are referred to gluco- and mineralocorticoid deficiency.|
The etiology of the triple A syndrome remains unknown. It has been reported from different regions of the world with no ethnic predilection. Both sexes may be affected and it has never occurred in successive generations.
The clinical manifestations of triple A syndrome are heterogeneous, depending on the degree of involvement of the different diseases which are present. Symptoms usually begin early in childhood with convulsions secondary to recurrent hypoglycaemia, which often lead to irreversible neurologic deficits [2, 3, 7, 10, 17]. Dysphagia, vomiting or complications like aspirative pneumonia, secondary to achalasia, may also be the initial presentation. Achalasia may precede the cortisol deficiency by several years [11, 12 ,24, 25]. Frequently, absent tear production is present when the first symptoms appear. Most parents report that the affected patient had never cried tears. Keratitis punctata is often associated. It has also been reported dry mouth as a consequence of xerostomia which leads to carious teeth as it is described in Sjögren syndrome .
Further manifestations of the ACTH insensitivity like skin pigmentation, hypotension or dehydration may be present. Neurologic symptoms will depend on the degree to which the nervous system is involved. Different degrees of muscular atrophy may also be found at the time of diagnosis [2, 5, 23]. Other reported associations include: hypophosphatemic rickets , hyperlipoproteinemia , absence of tongue papillae and Willebrand disease , and velopharyngeal incompetence with distinctive facial appearance .
Although cortisol deficiency is the most common form of presentation it does not appear to be congenital, developing later with obvious adrenal insufficiency . Mineralo-corticoid activity is usually normal, but there are reported cases where it is reduced, as well as glucocorticoid activity is reduced [3, 9, 10, 17]. Adrenal insufficiency is characterized by markedly elevated ACTH plasma levels, low cortisol in plasma and urine, and absence of antiadrenal antibodies. Low plasma aldosterone levels will be found if mineralocorticoid activity is reduced. Post mortem studies have shown atrophy of the zona fasciculata and reticularis of the adrenal glands [2, 17]. Some degree of decreased adrenal androgen production may be found .
Esophageal manometry and esophagograms eventually disclose esophageal dysmotility in almost all patients, independently of the presence of clinical dysphagia . Histologic examination of esophageal smooth muscle shows abnormalities of ganglion cells and nerve fibers similar to those seen in achalasia . The reported management and outcome of achalasia do not differ from typical achalasia.
The presence of alacrima and achalasia could be caused by disordered autonomic (parasympathetic) innervation of the esophagus and lacrimal glands [1, 24, 26]. CT scans may show absent or decreased lacrimal gland tissue . Other autonomically innervated organs may be involved, and abnormal vagal-parasympathetic innervation of sinoatrial node , abnormal pupillary responses to light and accommodation and delayed gastric emptying  have been reported.
Although parental consanguinity is not frequent, such features, together with the equal sex distribution, suggest that the mode of inheritance is consistent with an autosomal recessive trait. The fact that achalasia has been described along with familial acquired adrenocortical insufficiency, microcephaly and mental retardation , ataxia, optic atrophy and mental retardation , Sjögren syndrome [25, 29], absent tear production [24, 26, 30], and absent tear production and neurological abnormalities , suggests the possibility that these associations could constitute variants of the same entity. Moreover, these above mentioned clinical manifestations have been reported in association with the whole triple A syndrome (see Table I).
The question of a congenital or acquired adrenal ACTH receptor defect in children with Allgrove syndrome remains unanswered . It is difficult to define a single genetic defect which could cause the triad of this syndrome. One possibility is that it results from a deletion involving two or more contiguous genes. Isolated glucocorticoid deficiency has been interpreted as a congenital receptor or post-receptor defect in ACTH responsiveness, with presumably a similar defect in receptors that mediate the effects of regulatory factors upon esophageal and lacrimal gland function . Alternatively, Allgrove syndrome may reflect a primary autonomic neuropathic process which causes alacrima and esophageal dysmotility, and also, in some way, leads to an acquired form of ACTH unresponsiveness. This hypothesis which could explain the clinical manifestations of this syndrome is based on a defect in local vasoactive intestinal peptide (VIP) release . VIP has been shown to stimulate adrenocortical steroidogenesis directly  and nerve fibers immunoreactive for VIP are found in the lacrimal glands  and esophagus, but are notably missing from the latter in patients with achalasia.
It is recommended that other possibilities be investigated when any of the above mentioned are identified, mainly in childhood, because they may be associated at the time of diagnosis or appear during the evolution .
3. Lanes R, Plotnick LP, Bynum TE, Lee PA, Casella JF, Fox CE, Kowarski AA, Migeon CJ. Glucocoticoid and partial mineralocorticoid deficiency associated with achalasia. J Clin Endocrinol Metab 1980;50:268-270.
4. Geffner ME, Lippe BM, Kaplan SA, Berquist WE, Bateman JB, Paterno VI, Seegan R. Selective ACTH insensivity, achalasia and alacrima: a multisystem disorder presenting in childhood. Pediatr Res 1983;17:532-536.
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22. 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;151:85-89.
23. Pérez de la Serna J, Ruiz de León A, Sevilla Mantilla C, Ciriza C, Díaz-Rubio M. Tryple A syndrome (Allgrove syndrome). Evolution before and after successful achalasia pneumatic dilation. OESO 1993:Abstract 177.
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