A 2.5-year-old boy presented with progressive darkening of lips for the past four months, and absence of tears noticed since early infancy. There was no history of dysphagia or neurological problems. Born to non-consanguineous parents, his two elder sisters had died at age 5 and 6 years after similar manifestations. On examination, he was underweight (9.2 kg, –3.07SDS), stunted (82.4 cm, –2.68SDS) and had small head (45.5 cm, –2.42SDS). Oral mucosa was deeply pigmented. The systemic examination was unremarkable. Laboratory investigations showed normal serum sodium and potassium but low morning serum cortisol (89.2 nmol/L) and elevated adrenocorticotropin levels (1470 pg/mL). Reduced tear production was confirmed by Schirmer test. Barium swallow and endoscopic evaluation showed no achalasia. Clinical exome sequencing showed a previously undescribed homozygous frameshift deletion c.762delC (p.Ser255Valfs* 36) at Exon 8 of the AAAS gene, further confirmed by Sanger sequencing. The mutation is considered pathogenic by prediction tools such as SIFT, Mutation Taster and Phenolyzer. The child was initiated on lubricant eye drops and hydrocortisone and showed improved growth over one year (weight 10.8 kg, –2.12 SDS and height 89.4 cm, –2.54 SDS).

Allgrove syndrome (or Triple A syndrome) is an autosomal recessively inherited disorder caused by mutations in the AAAS gene that encodes for a protein ALADIN involved in the movement of molecules into and out of the nucleus, probably affecting DNA repair mechanisms leading to cell death [1]. The syndrome may present with any one of the four cardinal features that include achalasia, Addison disease, alacrima and progressive neurological dysfunction, and the symptoms may evolve over a period of time [1]. Alacrima is often the earliest and most consistent finding. Presence of one more symptom warrants molecular analysis of the AAAS gene [2]. Although a lower prevalence of neurological dysfunction has been noted in Indian patients, this feature is known to manifest later [1]. The poor head growth in our patient probably indicates the beginning of neurological dysfunction. These patients are also prone to dermatological abnormalities such as hyperkeratosis. The AAAS gene mutations are known to affect siblings and may explain sibling deaths with adrenal failure [1,3]. A high index of clinical suspicion is required due to the rarity and presentation as incomplete triad of symptoms [4,5]. Molecular analysis of the AAAS gene helps in confirming diagnosis and prognostication.

Contributors: SG: data collection and literature search; DD: drafting of manuscript. The final version of the manuscript was approved by all authors.

Funding: None; Competing interests: None stated.

2. Kurnaz E, Duminuco P, Aycan Z, Savaº-Erdeve S, Muratoolu Þahin N, Keskin M, et al. Clinical and genetic characterisation of a series of patients with triple A syndrome. Eur J Pediatr. 2018;177:363-9.

3. Bouliari A, Lu X, Persky RW, Stratakis CA. Triple A syndrome: Two siblings with a novel mutation in the AAAS gene. Hormones (Athens). 2019;18:109-12.

4. Shah SWH, Butt AK, Malik K, Alam A, Shahzad A, Khan AA. AAA syndrome: Case report of a rare disease. Pak J Med Sci. 2017;33:1512-6.

5. Reimann J, Kohlschmidt N, Tolksdorf K, Weis J, Kuchelmeister K, Roos A. Muscle pathology as a diagnostic clue to allgrove syndrome. J Neuropathol Exp Neurol. 2017;76:337-41.