Achalasia as part of the Allgrove syndrome

Primary Motility Disorders of the Esophagus

The Esophageal
Mucosa

The
Esophagogastric Junction

Barrett's
Esophagus

Volume: The Esophagogastric Junction
Chapter: Achalasia

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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 [1]. 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 [2]. 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).
Author	Sex	Adrenal	Neurological	Associated
		deficiency	abnormalities	pathology
Allgrove	M	Glucocorticoid	No	Hyperkeratosis of the
(1978) [2]				palms and soles,
				palm creases
	M	Glucocorticoid	No	Episodic anisocoria,
				palm creases
	F	Glucocorticoid	No	Enlargement of the thymus
	M	Glucocorticoid	No	No
Lanes (1980) [3]	F	Both	No	No
Geffner (1983) [4]	M	Glucocorticoid	No	No
Degli Esposti	M	Glucocorticoid	Muscular	No
(1985) [5]			neurogenic atrophy
	M	Glucocorticoid	Same neuromiopathy	No
	M	Glucocorticoid	No	No
Pombo (1985) [6]	M	Glucocorticoid	No	No
Rouberge (1986) [7]	F	Glucocorticoid	No	No
Ambrosino (1986) [8]	M	Glucocorticoid	No	No
Kalifa (1986) [9]		Report of 5 cases in a radiological series without details
Ehrich (1987) [10]	M	Both	Pychomotor retardation,	No
			hypotonia optic atrophy,
			ataxia, microcephaly
	M	Both	Same	No
Dumic (1987) [11]	M	Glucocorticoid	Sensory	Hyperkeratosis of palms
			polyneuropathy,	and soles, insufficient
			anisocoria	androgen production,
				defective sweating,
				palmar creases
Chrzanowska	M	Glucocorticoid	No
(1987) [12]	F	Glucocorticoid	Anisocoria,	No
			EEG abnormalities
Shah (1988) [13]	F	Glucocorticoid	No	Familial hypophospha-
				temic rickets
Author	Sex	Adrenal	Neurological	Associated
		deficiency	abnormalities	pathology
Stuckey (1988) [14]	F	Glucocorticoid	Autonomic neuropathy	Symmetric distal
				muscle wasting
Zucchini (1988) [15]	M	Glucocorticoid	No	Muscular hypotrophy.
				Foot orthopedic
				abnormalities
	F	Glucocorticoid	No	No
Fernbach (1989) [16]	F	Glucocorticoid	No	No
Hammami (1989) [17]	F	Both	Absence of	Consanguinity, loss of
			pupillary reflex	tongue papillae
	F	Both	Same	Consanguinity,
				Willebrand disease
Varkonyi (1990) [18]	F	Glucocorticoid	No	Hyperlipoproteinemia
Boudon (1990) [19]	M	Glucocorticoid	Absence of thermal	No
			and pain sensibility
			Psycho-motor retardation
Tuck (1991) [20]	M	Glucocorticoid	No	No
	M	Glucocorticoid	No	No
Moore (1991) [21]	M	Glucocorticoid	Mental retardation	Consanguinity, typical
				facies, partial duplica-
				tion of urinary
				collecting systems
	F	Glucocorticoid	Axonal neuropathy	Muscular atrophy of
			Mental retardation	limbs, consanguinity,
				typical facies
	M	Glucocorticoid	Axonal neuropathy	Muscular atrophy of
			pupillary dysfunction	limbs, consanguinity,
				typical facies
	F	Glucocorticoid	No	Consanguinity
	F	Glucocorticoid	Mental retardation	Consanguinity
	F	Glucocorticoid	No	Consanguinity, typical
				facies
	M	Glucocorticoid	Mental retardation	Consanguinity,
				typical facies
	M	Glucocorticoid	Mental retardation	Consanguinity
Grant (1992) [22]*	M	Glucocorticoid	Parkinson disease,	Muscle wasting of the
			intellectual deterioration,	hands
			loss of vibration and
			position sense, pyramidal
			signs
	M	Glucocorticoid	Same	No
Pérez de la Serna	F	Both	No	Muscular atrophy in
(1993) [23]				hands, limbs and soles,
				xerostomia
* These two patients were previously described by Allgrove [2]. 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 [23].

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 [13], hyperlipoproteinemia [18], absence of tongue papillae and Willebrand disease [17], and velopharyngeal incompetence with distinctive facial appearance [21].

Although cortisol deficiency is the most common form of presentation it does not appear to be congenital, developing later with obvious adrenal insufficiency [21]. 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 [11].

Esophageal manometry and esophagograms eventually disclose esophageal dysmotility in almost all patients, independently of the presence of clinical dysphagia [21]. Histologic examination of esophageal smooth muscle shows abnormalities of ganglion cells and nerve fibers similar to those seen in achalasia [1]. 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 [21]. Other autonomically innervated organs may be involved, and abnormal vagal-parasympathetic innervation of sinoatrial node [6], abnormal pupillary responses to light and accommodation and delayed gastric emptying [14] 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 [27], ataxia, optic atrophy and mental retardation [28], Sjögren syndrome [25, 29], absent tear production [24, 26, 30], and absent tear production and neurological abnormalities [31], 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 [21]. 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 [21]. 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 [32]. VIP has been shown to stimulate adrenocortical steroidogenesis directly [32] and nerve fibers immunoreactive for VIP are found in the lacrimal glands [33] 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 [20].

References

1. Feldman M. Southwestern internal medicine conference: esophageal achalasia syndromes. Am J Med Sci 1988;295/1:60-81.

2. Allgrove J. Clayden GS, Grant DB, Macaulay JC. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1978;i:1284-1286.

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.

5. Degli Esposti A, Ambrosioni G, Giardina A, Giovannini G, Laghi MG, Molinari PP, Salvatori P, Zaniboni MG. Sindrome familiari di ipoglicocorticismo da insensibilita all' ACTH, acalasia, alacrima, con associata neuromipatia distale. Minerva Pediatr 1985;37:353-359.

6. Pombo M, Devesa J, Taborda A, Iglesias M, García-Moreno F, Gaudiero GJ, Martinón JM, Castro-Gaga M, Peña J. Glucocorticoid deficiency with achalasia of the cardia and lack of lacrimation. Clin Endocrinol 1985;23:237-243.

7. Rouberge A, Beauvais P, Gourmelen M, Richardet JM. Insuffisance isolée en glucocorticoides avec achalasie et alacrymie. Ann Pediatr 1986;33:321-324.

8. Ambrosino MM, Genieser NB, Bangaru BS, Sklar C, Becker MH. The syndrome of the achalasia of the esophagus, ACTH insensitivity and alacrima. Pediatr Radiol 1986;16:328-329.

9. Kalifa G, Silberman B, Chaussain JL, Diebler C, Bennet J. La maladie d'Addison chez l'enfant: anomalies associées. Ann Radiol 1985;29:327-332.

10. Ehrich E, Aranoff G, Johnson WG. Familial achalasia associated with adrenocortical insuficiency, alacrima and neurological abnormalties. Am J Med Genet 1987;26:637-644.

11. Dumic M, Radica A, Jusic A, Stefanovic N, Murko Z. Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy. Eur J Pediatr 1987;146:592-594.