AAA Syndrome: Causes, Symptoms and complications.

DiseasesDic A, Genetic Disorders 1 Comment

Introduction

AAA syndrome is a rare autosomal recessive disorder characterized by adrenocorticotropic hormone (ACTH)-resistant adrenal insufficiency, alacrima and achalasia. Primary adrenal insufficiency or also known as Addison disease, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin.

The major feature of AAA syndrome is a reduced or absent ability to secrete tears (alacrima). Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood sugar (hypoglycemia). In addition, a variety of neurological problems which affects the central, peripheral and autonomic nervous systems may be there.

Genetics of AAA syndrome

This disorder is the result of mistake in the long arm of chromosome 12. The chromosome responsible for this condition is number 12q13, which means that there is a mistake on chromosome 12, on part 13 of the long arm. This syndrome is also caused by gene AAAS.

Background

In 1978, Allgrove and colleagues described two unrelated pairs of siblings with isolated glucocorticoid deficiency and achalasia of the esophagus cardia. The latter condition involved delayed passage of food into the stomach and consequent dilation of the thoracic esophagus. Three of these individuals also had defective tear production, leading to combination of achalasia, adrenal deficiency, and alacrima represented an inherited familial disorder. Allgrove noted that these patients developed achalasia and suggested that all these patients shared a common syndrome.

Similarly, patients originally reported as having isolated achalasia were subsequently given a diagnosis of adrenal insufficiency, highlighting the variable presentation of this syndrome. Indeed, the adrenal dysfunction in a subset of patients was not limited to glucocorticoid deficiency but was also shown to include mineralocorticoid deficiency.

Epidemiology of AAA syndrome

Ultrasound screening studies show that among males aged between 65 and 80 years, the prevalence of abdominal aortic aneurysm (AAA) is 4 to 8 percent. AAA prevalence in 65- to 80-year-old women is four to six times lower compared with their male counterparts, at approximately 1.3 percent. However, AAAs found on screening are generally small; those measuring ≥5.5 cm or greater are found in only 0.4 to 0.6 percent of those screened. Because the incidence of AAA rises sharply in individuals over 60 years of age, the future prevalence of AAA could increase substantially in association with the aging population.

The annual incidence of new AAA diagnoses is approximately 0.4 to 0.67 percent in Western populations. This equates to 2.5 to 6.5 aneurysms per 1000 person-years. Age significantly impacts the incidence, however, with steep increases in the incidence to 55 per 100,000 person-years in the 65- to 74-year-old age group. The incidence increases further to 112 per 100,000 person-years for those aged 75 to 85 years. Those aged greater than 85 years have an incidence at 298 per 100,000 person-years

Causes of AAA syndrome

Allgrove syndrome appears to have an autosomal recessive pattern of inheritance.
Parental consanguinity and previously affected siblings are the primary risk factors.
Linkage analysis provides evidence for an Allgrove syndrome locus on band 12q13 near the type II keratin gene cluster. Studies implicate mutations in the AAAS gene, which codes for a WD-repeat protein termed ALADIN.
In Allgrove syndrome, the functional defect may reside in the ALADIN protein, which can be involved in either cytoplasmic trafficking or in normal peroxisomal function.
Patients with isolated familial glucocorticoid deficiency (type 1 FGD) have mutations in the melanocortin-2 (ACTH) receptors. Patients with Allgrove syndrome (type 2 FGD) have no mutations in the coding sequence or the promoter region of this receptor gene.
Globally, the pathology of this syndrome may be due, in part, to a progressive loss of cholinergic function throughout the body.

Manifestation of AAA syndrome

Adrenal insufficiency
Adrenocorticotropic hormone resistance
Absent tears
Autonomic dysfunction
Low blood sugar
Orthostatic hypotension
Heart rate changes
Short stature
Osteoporosis
Thickened skin on palms
Thickened skin on soles
Increased skin pigmentation
Dilated esophagus
Seizures
Impaired vision

Diagnosis and Test

Physical exam may show signs of anemia or malnutrition.

Tests include:

Manometry, a test to measure how well the esophagus is working.
EGD or upper endoscopy, a test to examine the lining of the stomach and esophagus. It uses a flexible tube and camera.
Upper GI x-ray.
AAA gene sequencing.

Treatment and medications

There is no cure for triple A syndrome at this time; treatment typically focuses on managing individual signs and symptoms of the condition.

Glucocorticoid deficiency in individuals with known adrenal insufficiency (present with Addison disease) is typically treated by replacement of glucocorticoids.
The symptoms in individuals with achalasia may be improved partially with pneumatic dilatation (also called balloon dilation).
Alacrima is typically managed by applying topical lubricants (such as artificial tears or ointments), and with punctal occlusion (a procedure used to close the tear ducts that drain tears from the eye). The symptoms of alacrima typically improve with punctal occlusion. However, this procedure is usually only done when therapy with topical lubricants is unsuccessful.