Triple A syndrome: Non-sense c.884G>A mutation making sense through its clinical triad

INTRODUCTION

Triple A syndrome (Allgrove syndrome) is a rare autosomal recessive disorder first described by Allgrove et al., characterized by the triad of achalasia, alacrimia, and adrenocorticotrophic hormone (ACTH) resistant-adrenal insufficiency.^[1] Global prevalence is estimated at 10 in 100,000, though it is more common in regions with high rates of consanguinity.^[2] The condition results from point, frame-shift, or splice-site mutations in AAAS gene, located on chromosome 12q13, leading to functional cellular derangements.^[2,3] This gene, highly expressed in brain, adrenals, and gastrointestinal tract mucosa, encodes alacrimia-achalasia-adrenal insufficiency neurologic disorder (ALADIN) protein. ALADIN is a 546 amino acid nuclear pore complex protein belonging to the tryptophanaspartic acid (WD) repeat domain containing family of genes, essential for intracellular macromolecule transport.^[3] Genetic heterogeneity is not uncommon, as not all patients with this syndrome demonstrate mutations in AAAS gene.^[3] Typically, symptoms manifest during childhood, most consistently with alacrimia. Achalasia and adrenal insufficiency develop later in the disease course. Delayed presentation into adulthood is rare.^[4] Approximately 70% of patients exhibit the complete triad, while about a third also show autonomic dysfunction, leading some authors to refer it as 4A syndrome; achalasia, alacrimia, adrenal insufficiency, and autonomic abnormalities.^[5] Other symptoms reported include neurological and dermatological manifestations, short stature, microcephaly, osteoporosis, and dysmorphic features, highlighting the wide array of phenotypes and lack of a clear genotype-phenotype correlation. Genetic testing is crucial for diagnosis but does not predict the phenotype or prognosis. The presence of two of the three cardinal clinical entities strongly suggests triple A syndrome. However, diagnosis can be challenging at onset, when patient typically presents with only one symptom. Differential diagnoses include other causes of adrenal insufficiency, such as familial glucocorticoid deficiency and adrenoleukodystrophy. The syndrome can also be confused with Sjögren’s syndrome when alacrimia and xerostomia are presenting symptoms. Definitive treatment is lacking. Management focuses on addressing individual signs and symptoms. Early diagnosis is crucial to prevent life-threatening adrenal crises. This report highlights a case of non-sense mutation positive triple A syndrome with classical clinical triad at presentation, without additional abnormality.

CASE REPORT

Clinical examination

Weighing 35 kg with height of 165 cm, he looked cachectic. Built was average, generalized wasting was noted. He was afebrile to touch, blood pressure of 86/54 mmHg with no evidence of postural hypotension, pulse rate 74/min, respiratory rate 12/min, and room air SpO₂ 96%. General physical examination revealed mild pallor without pedal edema or raised jugular venous pressure. There was blackish pigmentation of lips, gums, buccal mucosa, and tongue, with diffuse darkening of skin color involving knuckles and palmar creases [Figure 1]. Systemic examination was within normal limits.

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Figure 1:

Skin color at (a) 7-years of age, compared to (b) 25-years of age at presentation, (c) diffuse blackish pigmentation of tongue, (d) skin over extensor surface of knees, (e) knuckles, bilateral (f) shin and (g) palms, all suggestive of addisonian pigmentation.

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Further evaluation

Primary adrenocortical insufficiency was thus suggestive. This was further corroborated with contrast-enhanced computed tomography of abdomen, which showed bilateral atrophic adrenal glands [Figure 2]. However, ileo-caecal area appeared normal with no evidence of abdominal tuberculosis. Mantoux test was negative. As part of dysphagia evaluation, the patient underwent barium swallow and upper gastrointestinal endoscopy (UGIE). The former showed characteristic “bird-beak” appearance [Figure 3]. UGIE revealed dilated esophagus with food particles, associated with uncoordinated non-propulsive contraction of proximal dilated segment. High-resolution esophageal manometry was suggestive of Chicago type II achalasia [Figure 4]. Ophthalmological examination was suggestive of severe dry eye disease. Schirmer’s test was positive; wetting at end of 5 min in both eyes was 2 mm (normal: 10–15 mm). Tear film break-up time bilaterally was 5 seconds (normal: >10 seconds).

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Figure 2:

Contrast-enhanced computed tomography of abdomen showing bilateral diffusely atrophic adrenal glands (red arrows) in (a) axial and (b) coronal sections. Maximum width of body, medial limb, lateral limb of right and left adrenal gland are 2.1 mm, 1.4 mm, 1.3 mm and 1.7 mm, 2.2 mm, 1.5 mm, respectively.

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Figure 3:

Barium swallow in (a) antero-posterior oblique and (b) postero-anterior views demonstrating smooth, short-segment tapering at the lower esophageal sphincter with narrowing at gastroesophageal junction, giving the “bird-beak” appearance of esophagus (black arrows); dilated proximal esophageal segment (red arrows).

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Figure 4:

High-resolution esophageal manometry showing 100% failed peristalsis with pan-esophageal pressurization in 60% swallows (10 × 5 mL water swallows), suggestive of Chicago type II achalasia cardia. Distal contractile integral of esophagus is 314 mmHg.s.cm; integrated relaxation pressure at 4 s in the lower esophageal sphincter is 19 mmHg.

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DISCUSSION

Triple A syndrome is a quite rare disorder. Only 100 cases have been reported worldwide till now; very few from India. Our case was notable for its delayed diagnosis into adulthood despite the presence of early symptoms. Delayed recognition underscores the variability in onset and progression of this disorder. However, our patient had the classical clinical triad of alacrimia, achalasia, and adrenal insufficiency at presentation unlike cases reported previously. Vallet et al. documented a 19-year-old patient with predominant achalasia and alacrimia but without adrenal insufficiency at the time of diagnosis.^[6] An Indian report mentioned 2.5-year-old patient of Allgrove syndrome with alacrimia and adrenal insufficiency but without achalasia. Diagnosis was confirmed by demonstrating homozygous frameshift deletion c.762delC (p.Ser225Valfs*36) at exon 8 of AAAS gene.^[7] Sultan et al. reported a 16-year-old boy who developed dysphagia since early infancy,^[8] unlike our case whose swallowing difficulty started at 8-years of age. This highlights the potential for partial or evolving phenotypes. Goizet et al. reported a family with this syndrome exhibiting significant neurological manifestations such as peripheral neuropathy and ataxia, overshadowing the triad.^[9] Milenkovic et al. described a 12-year-old with autonomic dysfunction, recurrent infections, and intellectual disability in addition to the triad, indicating the breadth of phenotypic spectrum.^[10] Our patient lacked such neurological and systemic involvement. A review by Handschug et al. emphasized the importance of genetic testing in diagnosing atypical presentations, particularly in older patients with incomplete or late-onset symptoms.^[2] In sync, we made the definitive diagnosis by whole exome sequencing, demonstrating homozygous non-sense mutation c.884G>A at exon 9 of AAAS gene.

CONCLUSION

Our case underscores the importance of recognizing cardinal features and phenotypic variability of triple A syndrome for timely diagnosis and management. The versatility in clinical presentation, as evidenced by this case and other reports, highlights the need for a high index of suspicion and role of genetic testing in confirming the diagnosis.