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Achalasia, Alacrima, Adrenal Insufficiency, and Autonomic Dysfunction: Double A, Triple A, or Quaternary A Syndrome?

Peršić, Mladen*; Prpić, Igor*; Huebner, Angela; Severinski, Srećko*

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Journal of Pediatric Gastroenterology and Nutrition: October 2001 - Volume 33 - Issue 4 - p 503-504
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In 1978, Allgrove et al. (1) described simultaneous occurrence of achalasia, adrenocortical insufficiency, and alacrima—a triple A syndrome. More recent reports emphasize neurologic abnormalities and autonomic dysfunction as distinct features that very often accompany the three main symptoms (2–4). It has therefore been suggested that this disease be named 4A syndrome(3). Recently, the gene for the triple A syndrome (AAAS) has been cloned and characterized, permitting the molecular confirmation of the diagnosis (5,6).


A 22-month-old girl had typical clinical and radiologic signs of achalasia. The treatment consisted of calcium blockers (nifedipine) and endoscopic (bougie) dilatation, but at the age of 3.5 years, she had to be treated surgically. Since birth, she had “cried without tears,” but she had not shown any signs of eye discomfort. The girl is the youngest of three children of a nonconsanguineous family. Her older brother and sister are healthy. At the age of 5 years, her plasma cortisol level was normal and no significant neurologic abnormalities were detected.

At the age of 10 years, the symptoms of achalasia recurred. At the same time, she started to report general weakness, chronic fatigue, and impaired attention and concentration. A decline in her school achievement was noted.

The girl was very tall, 169 cm (>95th percentile), for age and of asthenic body habitus. All her muscles were hypotrophic, her adipose tissue was deficient, and her skin was dry with hyperkeratosis of soles and “cutis anserina.” Her head was dolichocephalic, her face expressionless, and her palate high and narrow. The dorsum of her hands and feet were very long and slender, with fingers and toes of normal length. The lower limbs were in valgus position.

Routine blood examinations revealed normal values, including growth hormone, prolactin, insulin growth factor-1, renin, and aldosterone. Homocysteine, methionine, and cysteine in blood were within normal levels, as well as the homocysteine level in urine. A Schirmer test was suggestive for hypolacrimia. Plasma cortisol levels and an adrenocorticotropic hormone stimulation test were concordant to cortisol deficiency, that is, adrenal insufficiency.

Neurologic examination revealed nasal speech with dysarthria, spastic increase of muscles tone, symmetric hyperreflexia, and positive Babinski sign. Romberg test results were negative, and her gait was clumsy.

Clinical testing of autonomic function showed postural hypotension; there was a fall of blood pressure more than 30/15 mmHg during the change from recumbent to standing position. Abnormal Valsalva ratio and heart rate variation during deep breathing was detected. Pupillary reflexes to light were inappropriate. Pharmacologic testing of pupillary disturbance was not performed.

Additional testing showed that the girl had astigmatism with myopia. Visual evoked potentials were prolonged (right eye, 135.6 milliseconds; left eye, 117.6 milliseconds) with normal wave morphologic features, which suggested dysfunction of the optical pathway. Somatosensory evoked potentials of median and tibial nerves were normal, as were the results of nerve conduction studies of the lower extremities.

Psychological testing demonstrated mild mental retardation (IQ, 69), with immature visual-motor coordination and emotional disturbances. The Wechsler Intelligence Scale for Children revealed learning disabilities and perceptual motor difficulties.

Results of brain computerized tomography, electroencephalography, abdominal ultrasound, skeletal radiographs (vertebral and thoracic), and color Doppler echocardiography were normal.

During hospitalization, balloon dilatation of the lower esophageal sphincter was performed, and symptoms of achalasia declined. Corticosteroid replacement therapy was started, and on follow-up after 3 months, the girl subjectively felt better. Simultaneous occurrence of achalasia, alacrima, adrenal insufficiency, and autonomic and central nervous system dysfunction in our patient confirmed the diagnosis of triple A syndrome.

Molecular analysis

Mutation analysis revealed a compound heterozygous mutation in the AAAS gene. On one allele, a C→A transversion of nucleotide 125 in exon 1 was identified, resulting in a change from glutamine to lysine at amino acid position 15 of the encoded protein (Q15K). The second allele carried a T→C transition at nucleotide 869 in exon 8, which leads to a substitution of s at amino acid position 263 by proline (S263P).


Achalasia, absent or sparse tears, and adrenal insufficiency are the major features of triple A syndrome (1). Other clinical features include proportionate short stature, microcephaly, abnormalities of the cornea, hypoglycemia, enlarged liver, broad thumbs, muscle atrophy, and skin changes (7).

The most common neurologic features are spasticity, increased tendon reflexes, peripheral neuropathy, myopathy, mental retardation or developmental delay, optic atrophy, dysarthria, and ataxia (2,8–10).

In the present case, there were indications of minor developmental delay and school problems. We assumed that these were a result of the parents' hyperprotective behavior. At the age of 10 years, when cortisol deficiency was detected, the girl exhibited neurologic and autonomic dysfunction concordant with triple A syndrome.

Recent reports stress the autonomic and neurologic dysfunction as typical symptoms of triple A syndrome (2,4). It was suggested that it should be renamed the 4A syndrome(3), although even this term has not become established. It is possible that subtle neurologic features are not detected in early childhood or that they develop progressively.

Neurologic and autonomic dysfunction were clearly present in our patient. Moreover, our patient had phenotypic characteristics, which have not been previously described in triple A syndrome: she was very tall (>95th percentile), had asthenic build, a high arched palate, and a very long and slender dorsum of the hands and feet with finger and toes of normal length. Considering the parents' and siblings' heights (father's height, 186 cm; mother's height, 168 cm; older brother, 178 cm; and the oldest sister, 168.5 cm), her present and predicted adult height was far above that which would be expected.

Additional laboratory and neuroimmaging testing were performed, which excluded Marfan syndrome, homocystinuria, Soto gigantism, adrenoleukodystrophy, and adrenomyeloneuropathy.

We found that our patient had visual pathway abnormality—a sign of central nervous system impairment. Grant et al. (2) suggested that alacrima, autonomic dysfunction, and abnormalities of the central nervous system may have an origin in common with achalasia. Visual evoked potentials performed in patients with triple A syndrome may be a useful tool in establishing the neurologic abnormalities or disease dynamics.

It is generally accepted that the disease is transmitted by autosomal recessive inheritance (7). The siblings of our patient are healthy and do not have any features of the syndrome. Weber et al. (11) mapped the gene to 12q13 in eight families, and the gene was also found by Stratakis et al. (12).

With the identification of a compound heterozygous mutation in the AAAS gene, the clinical diagnosis of triple A syndrome was confirmed. Both mutations have been found in other families with triple A syndrome in either homozygous or compound heterozygous forms (6). How these missense mutations impair AAAS protein function must await forthcoming functional analyses.


1. Allgrove J, Clayden GS, Grant DB, et al. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1978; 1: 1284–6.
2. Grant DB, Barnes ND, Dumić M, et al. Neurological and adrenal dysfunction in the adrenal insufficiency, alacrimia, achalasia (3A) syndrome. Arch Dis Child 1993; 68: 779–82.
3. Gazarian M, Cowell CT, Bonney M, et al. The “4A” syndrome: Adrenocortical insufficiency associated with achalasia, alacrimia, autonomic and other neurological abnormalities. Eur J Pediatr 1992; 151: 85–9.
4. Chu ML, Berlin D, Axelrod FB. Allgrove sy: Documenting cholinergic dysfunction by autonomic tests. J Pediatr 1996; 129: 156–9.
5. Tullio-Pelet A, Salomon R, Hadj-Rabia S, et al. Mutant WD-repeat protein in triple A syndrome. Nat Genet 2000; 26: 332–5.
6. Handschug K, Sperling S, Yoon SK, et al. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet 2001; 10: 283–90.
7. Winter RM, Baraitser M, eds. London Dysmorphology Database and London Neurogenetics Database. Oxford Medical Database. Oxford: Oxford University Press, 1998.
8. Grant DB, Dunger DB, Smith I, et al. Familial glucocorticoid deficiency with achalasia of the cardia associated with mixed neuropathy, long-tract degeration and mild dementia. Eur J Pediatr 1992; 151: 85–9.
9. Kasa E, Ozkinay F, Tutuncuoglu S, et al. Four siblings with achalasia, alacrimia and neurological abnormalities in a consanguineous family. Clin Genet 1996; 49: 296–300.
10. Ehrich E, Aranoff G, Johnson WG. Familial achalasia associated with adrenocortical insufficiency, alacrima, and neurological abnormalities. Am J Med Genet 1987; 26: 637–44.
11. Weber A, Wienker TF, Jung M, et al. Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet 1996; 5: 2061–6.
12. Stratakis CA, Lin JP, Pras E, et al. Segregation of Allgrove syndrome in Puerto Rican kindreds with chromosome 12 (12q13) polymorphic markers. P Assoc Am Phys 1997; 109: 478–82.
© 2001 Lippincott Williams & Wilkins, Inc.