Allgrove Syndrome (Triple A Syndrome)

Definition

Allgrove syndrome, also known as Triple A syndrome, is a rare autosomal recessive disorder.
Caused by mutations in the AAAS gene, which encodes the ALADIN protein involved in nuclear transport.
Classic triad:
- Alacrima: absent or reduced tear production
- Achalasia: failure of the lower esophageal sphincter to relax
- Adrenal insufficiency: typically due to ACTH resistance

Epidemiology

Extremely rare: estimated prevalence is 1 in 1 million
Usually presents in childhood or adolescence
Affects both sexes equally
May be underdiagnosed due to variable presentation

Clinical Manifestations

Alacrima: often the earliest sign, noted in infancy "crying with no tears"
Achalasia: feeding difficulties, vomiting, weight loss
Adrenal insufficiency: fatigue, hypotension, hypoglycemia, hyperpigmentation
Neurological symptoms (in ~⅔ of cases):
- Autonomic dysfunction: abnormal sweating, orthostatic hypotension, pupillary abnormalities
- Peripheral neuropathy, ataxia, dysarthria
- Cognitive decline, seizures
Other features:
- Short stature
- Microcephaly
- Osteoporosis
- Optic atrophy
- Skin changes

Diagnosis

Clinical triad: alacrima + achalasia + adrenal insufficiency
Schirmer test: confirms alacrima

The Schirmer test is a simple diagnostic procedure used to measure tear production and assess for dry eye conditions. It involves placing filter paper strips under the lower eyelid and measuring the amount of moisture absorbed over 5 minutes. It is especially useful in diagnosing conditions like Sjögren’s syndrome and Allgrove syndrome.

Schirmer Test Interpretation

Wetting Length (after 5 minutes)	Interpretation
≥ 10 mm	Normal tear production
5–10 mm	Borderline dry eye
≤ 5 mm	Suggestive of dry eye or alacrima

ACTH stimulation test: shows adrenal insufficiency
Esophageal manometry or barium swallow: confirms achalasia
Genetic testing: identifies AAAS mutations

Treatment

Adrenal insufficiency: lifelong glucocorticoid (± mineralocorticoid) replacement
Alacrima: artificial tears and eye lubricants
Achalasia: pneumatic dilation, Heller myotomy, or botulinum toxin
Neurological symptoms: supportive care, physical therapy
Monitoring: regular endocrine, GI, and neuro follow-up

Prognosis

Variable depending on severity and organ involvement
Early diagnosis and management can prevent adrenal crises and improve quality of life
Progressive neurological decline may occur in some cases