Dysphagia due to Triple A Syndrome: Successful Treatment of Achalasia by Balloon Dilatation

Abstract

Triple A syndrome is a rare autosomal recessive inherited disorder which is characterized by alacrima, adrenal insufficiency, and achalasia. We report on a 14-year old girl with dysphagia, regurgitation, and vomiting since 5 years. At the age of five years an Addison crisis was diagnosed and cortisone substitution was initiated. In addition, the patient had episodes of conjunctivitis. Severe esophagitis and candida infection were diagnosed by esophago-gastro-duodenoscopy and treated with omeprazole and fluconazole. The esophageal barium swallow was typical for achalasia. Medical treatment of achalasia with oral nifedipine resulted only in a partial and temporal improvement. But after seven balloon dilatations dysphagia and nocturnal coughing improved clearly and a remarkable gain of weight could be seen. Direct sequencing showed a homozygous nonsense mutation in exon 11 of the AAAS gene leading to truncation at position 342 of the 546 amino acid protein.

Conclusion: Triple A syndrome has to be considered in patients with dysphagia. In our patient, the absence of tears since birth followed by adrenal insufficiency were early signs of the triple A syndrome. Balloon dilatation of the esophago-gastric junction is an effective treatment, which can avoid surgical interventions.

Triple A syndrome - achalasia - dysphagia - alacrima - adrenal insufficiency - balloon dilatation

References

• 1 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
• 2 Berquist WE, Byrne WJ, Ament ME, Fonkalsrud EW, Euler AR. Achalasia: Diagnosis, management, and clinical course in 16 children.  Pediatrics. 1983;  71 798-805
• 3 Boyle JT, Cohen S, Watkins JB. Successful treatment of achalasia in childhood by pneumatic dilatation.  J Pediatr. 1981;  99 35-40
• 4 Cronshaw JM, Matunis MJ. The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome.  Proc Natl Acad Sci USA. 2003;  100 5823-5827
• 5 Dumic M, Radica A, Jucik A, Stefanovic N, Murko Z. Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy.  Eur J Pediatr. 1987;  146 592-594
• 6 Dumic M, Radica A, Sabol Z, Plavsic V, Brkljacic L, Sarnavka V. et al . Adrenocorticotropic hormone insensitivity associated with autonomic nervous system disorders.  Eur J Pediatr. 1991;  150 696-699
• 7 Fritzen R, Bornstein SR, Scherbaum WA. Megaoesophagus in a patient with autoimmune polyglandular syndrome type II.  Clin Endocrinol (Oxf). 1996;  45 493-498
• 9 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;  154 18-23
• 10 Gockel I, Junginger T, Eckardt VF. Effects of pneumatic dilation and myotomy on esophageal function and morphology in patients with achalasia.  Am Surg. 2005;  71 128-131
• 11 Grant DB, Barnes ND, Dumic M, Ginalska-Malinowska M, Milla PJ, Petrykowski W von. et al . Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome.  Arch Dis Child. 1993;  68 779-782
• 12 Hammond PD, Moore DJ, Davidson GP, Davies RP. Tandem balloon dilatation for childhood achalasia.  Pediatr Radiol. 1997;  27 609-613
• 13 Handschug K, Sperling S, Yoon SJK, Hennig S, Clark AJL, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene.  Hum Mol Genet. 2001;  10 283-290
• 14 Houlden H, Smith S, De Carvalho M, Blake J, Mathias C, Wood NW. et al . Clinical and genetic characterization of families with triple A (Allgrove) syndrome.  Brain. 2002;  125 2681-2690
• 15 Huebner A, Elias LLK, Clark AJL. ACTH resistance syndromes.  J Pediatr Endocrinol Metab. 1999;  12 277-293
• 16 Khelif K, De Laet MH, Chaouachi B, Segers V, Vanderwinden JM. Achalasia of the cardia in Allgrove's (triple A) syndrome: histopathologic study of 10 cases.  Am J Surg Pathol. 2003;  27 667-672
• 17 Lanes R, Plotnick LP, Bynum TE, Lee PA, Casella JF, Fox CE. et al . Glucocorticoid and partial mineralocorticoid deficiency associated with achalasia.  J Clin Endocrinol Metab. 1980;  50 268-270
• 18 Lee H, Choi E, Seomun Y, Montgomery K, Huebner A, Lee E. et al . High-resolution transcript map of the region spanning D12S1629 and D12S312 at chromosome 12q13: triple A syndrome-linked region.  Genome Res. 2000;  10 1561-1567
• 19 Maksimak M, Perlmutter DH, Winter HS. The use of nifedipine for the treatment of achalasia in children.  J Pediatr Gastroenterol Nutr. 1986;  5 883-886
• 20 Mayberry JF, Aktionson M. Variations in the prevalence of achalasia in Great Britain and Ireland. An epidemiological study based on hospital admission.  Q J Med. 1987;  62 67-74
• 21 Meyers NA, Jolley SG, Taylor R. Achalasia of the cardia in children: a worldwide survey.  J Ped Surg. 1994;  29 1375-1379
• 22 Pineiro-Carrero VM, Sullivan CA, Rogers PL. Etiology and treatment of achalasia in the pediatric age group.  Gastrointest Endosc Clin N Am. 2001;  387-408
• 23 Prpic I, Huebner A, Persic M, Handschug K, Pavletic M. Triple A syndrome: genotype-phenotype assessment.  Clin Genet. 2003;  63 415-417
• 24 Rosemurgy A, Villadolid D, Thometz D, Kalipersad C, Rakita S, Albrink M, Johnson M, Boyce W. Laparoscopic Heller myotomy provides durable relief from achalasia and salvages failures after botox or dilation.  Ann Surg. 2005;  241 725-733
• 25 Smith CD, Stival A, Howell DL, Swafford V. Endoscopic therapy for achalasia before Heller myotomy results in worse outcomes than heller myotomy alone.  Ann Surg. 2006;  243 579-584
• 26 Spechler SJ. AGA technical review on treatment of patients with dysphagia caused by benign disorders of the distal esophagus.  Gastroenterology. 1999;  117 233-254
• 27 Spechler SJ, Castell DO. Classification of esophageal motility abnormalities.  Gut. 2001;  49 145-151
• 28 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;  109 478-482
• 30 Tullio-Pelet A, Salomon R, Hadj-Rabia S, Mugnier C, Laet MH de, Chaouachi B. et al . Mutant WD-repeat protein in triple-A syndrome.  Nat Genet. 2000;  26 332-335
• 31 Vaezi MF, Baker ME, Achkar E, Richter JE. The timed barium oesophagram: better predictor of long term success after pneumatic dilation in achalasia than symptom assessment.  Gut. 2002;  50 765-770
• 32 Weber A, Wienker TF, Jung M, Easton D, Dean HJ, Heinrichs C. 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 2061-2066

1 AH is supported by the Deutsche Forschungsgemeinschaft (Hu 395/3-3).

ast Both authors contributed equally to this work

Correspondence