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Year : 2022  |  Volume : 23  |  Issue : 1  |  Page : 77-79

Triple-A syndrome: A rare cause of addisonian pigmentation

1 Department of Pediatric Dermatology, Institute of Child Health, Kolkata, West Bengal, India
2 Department of Pediatrics, MGM Medical College, Kishangang, Bihar, India
3 Department of Pediatrics, Institute of Child Health, Kolkata, West Bengal, India

Date of Submission10-Sep-2021
Date of Acceptance10-Nov-2021
Date of Web Publication31-Dec-2021

Correspondence Address:
Abhijit Saha
20 Dutta Para Lane, Rahul Apartment, Flat No 201 and 202, Uttarpara, Hooghly – 712 232, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.ijpd_155_21

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Triple-A syndrome (Allgrove syndrome) is a rare, autosomal recessive disorder classically described with the triad of alacramia, achalasia, and ACTH-resistant adrenal insufficiency. Very few cases have been reported so far in the literature. Rarity leads to misdiagnosis. Phenotypic heterogeneity further adds to the confusion as classical triads are not constantly present in each and every case. The presence of additional autonomic disturbances in some cases brings about the proposal of the name 4A syndrome instead of 3A syndrome. Basic defect is mutation of achalasia, adrenocortical insufficiency, and alacramia syndrome gene. The entity needs multidisciplinary approach including endocrinologist, pediatrician, dermatologist, and ophthalmologist for best possible outcome. Although there is no definitive treatment, early diagnosis is extremely important to save life and prevent neurological sequel from adrenal crisis, to avoid unnecessary investigations and inappropriate treatment, and to improve quality of life. We report a 13-year-old boy with triple-A syndrome diagnosed clinically presented with repeated episodes of seizure, Addisonian pigmentation, the absence of tear, and difficulty of swallowing.

Keywords: Absence of tear, Addisonian pigmentation, achalasia cardia

How to cite this article:
Dhar S, Saha A, Roy SK, Ghosh A. Triple-A syndrome: A rare cause of addisonian pigmentation. Indian J Paediatr Dermatol 2022;23:77-9

How to cite this URL:
Dhar S, Saha A, Roy SK, Ghosh A. Triple-A syndrome: A rare cause of addisonian pigmentation. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 Jan 20];23:77-9. Available from: https://www.ijpd.in/text.asp?2022/23/1/77/334668

  Introduction Top

Triple-A (AAA) syndrome (Allgrove syndrome) is characterized by the triad of alacrimia, achalasia, and ACTH-resistant adrenal insufficiency. The absence or reduction of tear should alert the physician, and proper awareness about this rare entity is necessary to reach to the diagnosis at the earliest. Here, we report a 13-year-old boy with hyperpigmentation, lack of tear, and difficulty swelling. The diagnosis of triple-A syndrome was made clinically. His parents expressed their inability to bear the cost of genetic testing.

  Case Report Top

A 13-year-old boy was brought to the emergency department semiconscious with myoclonic jerks. History revealed he had experienced similar episodes during the last year and a half, which were milder and had responded to oral administration of glucose. Lately, the patient reported asthenia and gradual generalized darkening of his skin, including the knuckles and tongue [Figure 1]. For the last 6 months, he was having difficulty swallowing, repeated episodes of regurgitation and weight loss, and associated achalasia cardia revealed by barium swallow radiograph. X-ray revealed achalasia cardia for which a Heller's cardiomyotomy was planned [Figure 2]. Since birth, he had never produced tears when crying and had been using artificial tears for 10 years.
Figure 1: 13-year-old boy presented with generalized darkening of the skin including knuckle and tongue

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Figure 2: Barium swallow X-ray revealed achalasia cardia

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On examination, vital signs and blood pressure were normal. Neurological examination was normal. His fasting blood sugar was very low (50 mg/dl, normal: 90–150 mg/dl in the 13–19 years' age group). He regained consciousness and seizures stopped following intravenous infusion of glucose. Laboratory investigations including serum electrolyte, serum Vitamin B12, and folic acid were within normal limit. Serum baseline cortisol levels at 8 AM and 4 PM were low and did not improve following ACTH infusion. His baseline serum ACTH level was raised (739 pg/ml, normal: 11–82 pg/ml in 4–16 years age group). Schirmer's test revealed lack of tears. A contrast-enhanced computed tomography scan of the abdomen showed adrenal glands of slightly reduced size [Figure 3]. Our diagnosis was triple-A syndrome (Allgrove syndrome) based on clinical and laboratory findings. We could not perform genetic testing due to financial constrain.
Figure 3: A contrast-enhanced computed tomography scan of the abdomen showed adrenal glands of slightly reduced size

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  Discussion Top

Triple-A (AAA) syndrome (Allgrove syndrome) is a rare, autosomal recessive disorder characterized by the triad of alacrimia, achalasia, and ACTH-resistant adrenal insufficiency. Only about 100 cases have been reported so far, but others may have gone unreported because of misdiagnosis.[1] Alacrimia, absent or reduced tears, is the earliest and most consistent feature. Some cases may have additional autonomic disturbances, and the name 4A syndrome has been proposed.[2] Other important features of the syndrome are neurological manifestations,[3] short stature, and dysmorphic facial features. The underlying genetic defect is a biallelic mutation in the achalasia adrenocortical insufficiency alacramia syndrome (AAAS) gene causing a truncated protein and functional impairment.[4] However, in some patients, AAAS gene mutations are not found.[5] AAAS is located on chromosome 12q13 and encodes a 546 amino acid containing Alacramia-Achalasia-adrenal insufficiency-Neurologic disorders (ALADIN) protein which is a member of the nuclear pore complex. The exact role of ALADIN protein in the nuclear pore is not known. Its probable functions are structural scaffolding, protein, and/or RNA trafficking between cytoplasm and nucleus, redox homeostasis, and steroidogenesis. Different AAAS mutations lead to nonfunctional ALADIN protein and its mislocalization in the cytoplasm, hence no longer available at the nuclear pore.[6] This protein is highly expressed in the brain, gastrointestinal tract, and adrenal cortex, the major sites of disease expression.[7]

Early diagnosis is important to prevent life life-threatening adrenal crises. Diagnosis may be delayed because the classical triad is present only in 70% patients[8] and the age of appearance of achalasia and adrenal insufficiency ranges from early childhood to adulthood. Adrenal insufficiency in 3A syndrome does not affect mineralocorticoid function in most cases, as is demonstrated by normal blood pressure and electrolyte levels consistent with our case. The morphology and distribution of hyperpigmentation described in our case is classical for Addison's disease. Here, hyperpigmentation is due to ACTH-stimulated melanogenesis. The fact is further supported by biochemical alterations, such as hypoglycemia, low cortisol, and elevated ACTH level. Although B12 deficiency can produce similarly distributed hyperpigmentation, the absence of other cutaneous signs of Vitamin B12 deficiency and a normal serum Vitamin B12 level excludes it. There is no history of chronic drug ingestion.

Treatment is directed at alleviating symptoms and signs. Long-term follow-up is desirable, since some manifestations and neurological involvement may appear at a late age.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Ashraf H, Varshney N, Juned MD, Siddiqui SS. Allgrove syndrome (Triple-A Syndrome): A case report from north India. J Diabetes Endocr Pract 2019;2:13-5.  Back to cited text no. 1
  [Full text]  
Persic M, Prpić I, Huebner A, Severinski S. Achalasia, alacrima, adrenal insufficiency, and autonomic dysfunction: double a, triple a, or quaternary a syndrome? J Pediatr Gastroenterol Nutr 2001;33:503-4.  Back to cited text no. 2
Grant DB, Barnes ND, Dumic M, Ginalska-Malinowska M, Milla PJ, von Petrykowski W, et al. Neurological and adrenal dysfunction in the adrenal insuffieciency, alacrimia, achalsia (3A) syndrome. Arch Dis Child 1993;68:779-82.  Back to cited text no. 3
Houlden H, Smith S, de Carvalho M, Blake J, Mathias C, Wood NW, et al. Clinical and genetic characterisation of families with triple a (Allgrove) syndrome. Brain 2002;125:2681-90.  Back to cited text no. 4
Brooks BP, Kleta R, Stuart C, Tuchman M, Jeong A, Stergiopoulos SG, et al. Genotypic heterogeneity and clinical phenotype in triple a syndrome: A review of the NIH experience 2000-2005. Clin Genet 2005;68:215-21.  Back to cited text no. 5
Krumbholz M, Koehler K, Huebner A. Cellular localization of 17 natural mutant variants of ALADIN protein in triple a syndrome – Shedding light on an unexpected splice mutation. Biochem Cell Biol 2006;84:243-9.  Back to cited text no. 6
Huebner A, Yoon SJ, Ozkinay F, Hilscher C, Lee H, Clark AJ, et al. Triple a syndrome – Clinical aspects and molecular genetics. Endocr Res 2000;26:751-9.  Back to cited text no. 7
Roucher-Boulez F, Brac de la Perriere A, Jacquez A, Chau D, Guignat L, Vial C, et al. Triple-a syndrome: A wide spectrum of adrenal dysfunction. Eur J Endocrinol 2018;178:199-207.  Back to cited text no. 8


  [Figure 1], [Figure 2], [Figure 3]


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