Triple A syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Triple A syndrome, also called Allgrove syndrome, is an inherited condition that gets its name from three specific features: achalasia, adrenal insufficiency, and alacrima. Most people with triple A syndrome have all three of these features, although some have only two.

Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that connects the throat to the stomach. Achalasia can lead to severe feeding difficulties, vomiting, and weight loss. Signs and symptoms of achalasia can appear at any time between the ages of 6 months and late adolescence.

Adrenal insufficiency occurs when the small hormone-producing glands on top of each kidney (adrenal glands) do not produce enough hormones. Features of adrenal insufficiency can include fatigue, loss of appetite, weight loss, low blood pressure, low blood glucose (hypoglycemia), and seizures.

The third major feature of triple A syndrome is alacrima. Tear secretion is reduced or completely absent in people with alacrima. This feature is often the first noticeable sign of triple A syndrome in affected infants.

Approximately one-third of all people with triple A syndrome also have dysfunction of the autonomic nervous system (dysautonomia). The autonomic nervous system regulates involuntary bodily processes, including digestion, blood pressure, and body temperature. People with triple A syndrome may experience abnormal sweating, changes in the production of saliva, difficulty regulating blood pressure and heart rate, unequal pupil size (anisocoria), and other problems.

Additional features of triple A syndrome can include cognitive abilities that decline over time. Affected individuals may also have muscle weakness, difficulty coordinating movements (ataxia), speech problems (dysarthria), short stature, and a small head size (microcephaly). Adults with triple A syndrome often have brittle bones that are prone to fracture (osteoporosis). Optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain, has also been found in affected individuals.

People with triple A syndrome may develop skin abnormalities, such as darkening of the skin and thickening of the outer layer of the skin (hyperkeratosis) on the palms of the hands and the soles of the feet.

The symptoms of triple A syndrome typically develop gradually over a period of several years and can vary widely, even among members of the same family.

ORPHANET DEFINITION Triple A syndrome is a very rare multisystem disease characterized by adrenal insufficiency with isolated glucocorticoid deficiency, achalasia, alacrima, autonomic dysfunction and neurodegeneration.

Inheritance

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive

Frequency in the source

From: MedlinePlus Genetics, National Library of Medicine

Reported case(s): 100.0; Worldwide. This is a published case count, not prevalence. Point prevalence: <1 / 1 000 000; Worldwide; Class only.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Achalasia · Very frequent (99-80%)

A disorder of esophageal motility characterized by the inability of the lower esophageal sphincter to relax during swallowing and by inadequate or lacking peristalsis in the lower half of the body of the esophagus.

Adrenal insufficiency · Very frequent (99-80%)

Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands.

Alacrima · Very frequent (99-80%)

The complete absence of aqueous tear production. Typically, this is clinically measured by a Schirmer I test result of 0 millimeters of wetting on the filter paper strip after 5 minutes.

Generalized hyperpigmentation · Very frequent (99-80%)

Cough · Frequent (79-30%)

A sudden, audible expulsion of air from the lungs through a partially closed glottis, preceded by inhalation.

Decreased circulating cortisol level · Frequent (79-30%)

Abnormally reduced concentration of cortisol in the blood.

Feeding difficulties in infancy · Frequent (79-30%)

Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.

Hypernasal speech · Frequent (79-30%)

A type of speech characterized by the presence of an abnormally increased nasal airflow during speech associated with structural abnormality of the nasal passages.

Hypoglycemia · Frequent (79-30%)

A decreased concentration of glucose in the blood.

Hypotension · Frequent (79-30%)

Low Blood Pressure, vascular hypotension.

Impaired cortisol response to corticotropin releasing hormone stimulation test · Frequent (79-30%)

Failure of cortisol levels to respond adequately (by increasing) to the corticotropin releasing hormone stimulation test.

Increased circulating ACTH level · Frequent (79-30%)

An abnormal increased in the concentration of corticotropin, also known as adrenocorticotropic hormone (ACTH), in the blood.

Palmoplantar keratoderma · Frequent (79-30%)

Abnormal thickening of the skin of the palms of the hands and the soles of the feet.

Short stature · Frequent (79-30%)

A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).

Other findings in the same source

From: Orphanet

Additional reported features include Vomiting (Frequent (79-30%)); Weight loss (Frequent (79-30%)); Failure to thrive in infancy (Frequent (79-30%)); Hypoglycemic seizures (Frequent (79-30%)); Abnormality of the hypothenar eminence (Occasional (29-5%)); Ataxia (Occasional (29-5%)); Corneal ulceration (Occasional (29-5%)); Developmental regression (Occasional (29-5%)); Hyperreflexia (Occasional (29-5%)); Hypotonia (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

When it may begin

From: MedlinePlus Genetics, National Library of Medicine

All ages

Inheritance in the source

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive

Frequency and the population described

From: MedlinePlus Genetics, National Library of Medicine

Reported case(s): 100.0; Worldwide. This is a published case count, not prevalence. Point prevalence: <1 / 1 000 000; Worldwide; Class only.

Understanding the inheritance label

From: MedlinePlus Genetics

An autosomal recessive pattern usually involves disease-causing changes in both copies of a gene. Parents may each carry one altered copy without having the condition themselves. A genetic counsellor can explain carrier testing and reproductive implications using the actual laboratory findings, rather than the condition name alone.

Which doctor should you see?

The suggested department for discussing Triple A syndrome is Endocrinology, with a endocrinologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which hormone or metabolic finding is important in this case?
• How should test timing and current medicines be taken into account?
• What follow-up would show whether the care plan is working?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Triple A syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.