Triple A Syndrome (Allgrove, AAAS, AR) MCQ — NEET PG Practice Question | NEETPGAI
Triple A Syndrome (Allgrove, AAAS, AR)
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A 7-year-old boy of consanguineous parents presents with recurrent hypoglycemic seizures (glucose 38 mg/dL), marked hyperpigmentation of gums and palms, dry eyes requiring artificial tears since infancy, and progressive dysphagia with regurgitation. Investigations show undetectable cortisol with markedly elevated ACTH (>1000 pg/mL), preserved aldosterone levels, and esophageal manometry confirming achalasia. Genetic testing reveals a homozygous nonsense mutation in the AAAS gene on **chromosome 12q13**. Which of the following best explains the pathophysiology of this patient's adrenal insufficiency?
A. Loss-of-function mutation in ALADIN protein disrupts nuclear pore complex integrity, impairing nucleocytoplasmic transport of DNA repair proteins in adrenocortical cells
B. X-linked mutation in NR0B1 causing adrenal hypoplasia congenita with early mineralocorticoid deficiency and salt wasting
C. Autoimmune destruction of adrenal cortex mediated by anti-21-hydroxylase antibodies with concurrent autoimmune polyendocrinopathy
D. Deficiency of AIRE protein leading to loss of central immune tolerance and autoimmune adrenalitis with ACTH-resistant insufficiency
Explanation
Why option 1 is correct
The clinical presentation—alacrima, achalasia, ACTH-resistant adrenal insufficiency with preserved mineralocorticoid secretion, and neurologic features—is pathognomonic for Triple A (Allgrove) syndrome caused by homozygous loss-of-function mutations in AAAS on chromosome 12q13. ALADIN is a WD-repeat protein essential for nuclear pore complex (NPC) integrity and nucleocytoplasmic transport of selective cargoes including DNA repair proteins (aprataxin, ferritin heavy chain). Loss-of-function disrupts NPC function specifically in adrenocortical cells, lacrimal glands, esophageal myenteric neurons, and motor neurons, explaining the classic tetrad of achalasia, alacrima, adrenal insufficiency, and neurologic dysfunction. The preserved aldosterone and normal renin distinguish this from X-linked adrenal hypoplasia congenita (Sperling Pediatric Endocrinology 5e; Huebner GeneReviews Triple A 2023).
Why each distractor is wrong
Option 2: X-linked adrenal hypoplasia congenita (AHC) results from mutations in NR0B1 on chromosome Xp21 and presents with severe salt wasting due to mineralocorticoid deficiency—this patient has preserved aldosterone and normal renin, ruling out AHC. Additionally, the patient is male with a homozygous autosomal recessive mutation, not X-linked.
Option 3: Autoimmune Addison disease (APS-1) is associated with mutations in AIRE on chromosome 21 and presents with anti-21-hydroxylase antibodies and concurrent autoimmune polyendocrinopathy (thyroiditis, hypoparathyroidism, candidiasis). This patient has no serologic evidence of autoimmunity and lacks the typical APS-1 phenotype; the genetic mutation is in AAAS, not AIRE.
Option 4: While AIRE deficiency does cause ACTH-resistant adrenal insufficiency in APS-1, the mutation is on chromosome 21, not chromosome 12q13. Furthermore, APS-1 presents with autoimmune manifestations (candidiasis, hypoparathyroidism, vitiligo) and lacks the characteristic alacrima, achalasia, and neurologic features of Triple A syndrome.
