Triple-A syndrome or AAA syndrome is a rare

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

congenital disorder A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...

. In most cases, there is no family history of AAA syndrome. The syndrome was first identified by Jeremy Allgrove and colleagues in 1978, since then just over 100 cases have been reported. The syndrome, is called triple aaa due to the manifestation of the illness which include

achalasia Esophageal achalasia, often referred to simply as achalasia, is a failure of smooth muscle fibers to relax, which can cause the lower esophageal sphincter to remain closed. Without a modifier, "achalasia" usually refers to achalasia of the esoph ...

(a dysfunction of the esophagus), addisonianism ( adrenal insufficiency of primary type), and

alacrima Alacrima refers to an abnormality in tear production that could mean reduced tear production or absent tear production. Because a lack of tears presents in only in a few rare disorders, it aids in diagnosis of these disorders, including Triple-A ...

(insufficiency of

tears Tears are a clear liquid secreted by the lacrimal glands (tear gland) found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of ...

). Alacrima is usually the earliest manifestation. Neurodegeneration or atrophy of the nerve cells and autonomic dysfunction may be seen in the disorder, therefore some have suggested the disorder be called 4A syndrome. It is a progressive disorder that can take years to develop the full-blown clinical picture. The disorder also has variability and heterogeneity in presentation.

Presentation

Individuals affected by AAA have adrenal insufficiency/

Addison's disease Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adre ...

due to ACTH resistance, alacrima (absence of tear secretion), and

(a failure of a ring of muscle fibers in the lower part of the esophagus to relax) called the lower esophageal sphincter at the cardia (very upper portion of the stomach) The esophagus is the tube that carries food from the mouth to the stomach. Achalasia delays food going to the stomach and causes dilation of the thoracic esophagus. There may also be signs of autonomic dysfunction with AAA, such as pupillary abnormalities, an abnormal reaction to intradermal histamine, abnormal sweating, orthostatic hypotension (low blood pressure with standing), and disturbances of the heart rate. Unexplained

Hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

(low blood sugar) is often mentioned as an early sign. The disorder has also been associated with mild

mental retardation Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

. The syndrome is highly variable. However, one of the most common findings in all patients are the lack of tears. Lack of tears with crying is often mentioned in hindsight after the diagnosis has been made. AAA Syndrome may be diagnosed in early childhood or in adolescence. The disorder is typically managed by treating the symptoms with hormone replacement for adrenal insufficiency, lubricating drops for the eyes and managing low blood sugars.

Cause

Triple-A syndrome is associated with mutations in the ''AAAS'' gene which encodes a protein known as ALADIN (ALacrima Achalasia adrenal Insufficiency Neurologic disorder). In 2000, Huebner ''et al.'' mapped the syndrome to a 6 cM interval on human chromosome 12q13 near the type II keratin gene cluster. Since inheritance and gene for the association is known, early diagnosis can allow genetic counseling. Furthermore, genotypic heterogeneity has also been documented suggesting that there may be other genes involved in this genetic disorder as well as unknown environmental factors that result in the phenotypic expression of the disease. ALADIN protein is a component of the

nuclear pore complex A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are approximately 1,000 nuclear pore complexe ...

, situated toward its cytoplasmic side. Mutant ALADIN remains mis-localized in the cytoplasm and causes selective failure of nuclear protein import and hypersensitivity to

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

. Mutant ALADIN also causes decreased nuclear import of

aprataxin Aprataxin is a protein that in humans is encoded by the ''APTX'' gene. This gene encodes a member of the histidine triad (HIT) superfamily, some of which have nucleotide-binding and diadenosine polyphosphate hydrolase activities. The encoded pro ...

, a repair protein for DNA single-strand breaks, and DNA ligase I. These decreases in DNA repair proteins may allow accumulation of

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...

that trigger cell death.

Nucleoporin Nucleoporins are a family of proteins which are the constituent building blocks of the nuclear pore complex (NPC). The nuclear pore complex is a massive structure embedded in the nuclear envelope at sites where the inner and outer nuclear membra ...

ALADIN participates in spindle assembly. ALADIN is employed in specific meiotic stages, including spindle assembly, and spindle positioning. Female mice homozygously null for ALADIN are sterile.

Diagnosis

The diagnosis of this condition involves examination by a health provider. Clinical signs may lead to the diagnosis such as the lack of tears and digestive issues, such as acid reflux disease in infancy as well as symptoms of adrenal insufficiency such as frequent bouts of low blood sugars are highly suggestive of the disorder. Achalasia may be seen on plain X-rays and include an absence of fundal gas shadow, widened mediastinum and an air fluid level in mediastinum is also seen. The gold standard for confirming achalasia is a 24 hours manometry of oesophagus.This is a test that measures the pressure inside the esophagus. The test demonstrates non-relaxation of lower esophageal sphincter, increased tone of esophageal sphincter, atonic esophagus. Bird-beak sign and rat-tail sign can be appreciated on barium swallow. Lack of tears or alacrima is caused by the lack of production of lacrimal glands or ducts and defects in the nerves of the lacrimal gland caused by a dysfunction in the autonomic nervous system. The diagnosis is confirmed with genetic testing as well as clinical features.

Treatment

There is no definitive cure for this syndrome, because many of the mechanisms implicated have not yet been identified. The available treatments address only some of the symptoms. Lubricating drops and emulsions are used to remedy the absence of tear secretion. Achalasia can be treated with surgical intervention resulting in improved passage of food and drink into the stomach. Corticosteroids, such as hydrocortisone, are prescribed to solve the adrenal insufficiency. Early diagnosis may prevent morbidity and improve growth in children due to early treatment of adrenal insufficiency.

References

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