What is Adrenal Hypoplasia?

Adrenal hypoplasia is a condition where the outer layer of the adrenal glands, called the adrenal cortex, doesn’t properly develop. The reasons for this underdevelopment can vary. The condition can be split into two types: primary adrenal hypoplasia and secondary adrenal hypoplasia.

Primary adrenal hypoplasia is usually caused by a condition called adrenal hypoplasia congenita (AHC), or due to issues during the development of the adrenal glands. Adrenal hypoplasia congenita results in adrenal glands that don’t function properly and are enlarged. This happens due to problems during the development of adrenal glands in the fetus. There are different forms of this condition.

On the other hand, secondary adrenal hypoplasia occurs because of problems with the pituitary gland or hypothalamus. Both of these are parts of the brain responsible for producing and releasing hormones. When there’s dysfunction in these areas, it results in less production and release of a hormone called adrenocorticotropic hormone (ACTH). ACTH is key for the proper development and functioning of adrenal glands. So, reduced levels of this hormone can lead to insufficient development and dysfunction of the adrenal glands.

What Causes Adrenal Hypoplasia?

Adrenal hypoplasia means that the adrenal glands have not formed properly, and this condition can sometimes be inherited, known as adrenal hypoplasia congenita (AHC). There are four types of AHC that are often diagnosed in infancy or childhood, when the adrenal glands can’t produce enough of certain hormones.

One type is linked to the X-chromosome and comes from a mutation or deletion in the DAX-1 gene, which plays a crucial role in the normal function and development of the hypothalamic-pituitary-adrenal (HPA) axis in the body. Sometimes, this issue with the X-chromosome is part of a larger deletion, and patients may also show symptoms of Duchenne muscular dystrophy and glycerol kinase deficiency.

Another form of AHC is an autosomal recessive mutation in the steroidogenic factor 1 (SF-1) gene. This type can also be linked to an odd development pattern of the ends of the bones, slow growth before birth, and abnormalities in the genital area. There are several other rare syndromes and mutations that can also result in adrenal hypoplasia. Syndromes like triple-A syndrome and familial glucocorticoid deficiency, for example, involve the body’s resistance to the hormone ACTH.

Secondary adrenal hypoplasia can occur due to problems in the pituitary gland or the hypothalamus part of the brain. Some causes include defects in the pituitary gland development, tumors in the pituitary gland, a defect in the POMC gene, and a defect in the convertase 1 (PCSK1) enzyme. Other causes include ACTH hormone deficiency, diseases affecting the development of the pituitary gland, and developmental abnormalities of the central nervous system. Sometimes, long-term use of medications containing glucocorticoid can also lead to adrenal hypoplasia as the adrenal glands can become underactive.

Risk Factors and Frequency for Adrenal Hypoplasia

Congenital adrenal hypoplasia, also known as AHC, is a rare condition. It’s even less common than congenital adrenal hyperplasia, which affects 1 in 10,000 to 15,000 newborns worldwide. AHC is more often found in males as it can be linked to the X chromosome. In general, AHC occurs to around 1 in every 12,500 live births.

A specific type of AHC known as Triple-A syndrome or Allgrove syndrome is even rarer, with a prevalence of 1 in every 1,000,000 individuals. This condition only makes up about 1% of all AHC cases. It tends to be more common in the Middle East, Puerto Rico, and southern Europe.

Signs and Symptoms of Adrenal Hypoplasia

Adrenal hypoplasia is a condition that affects how the adrenal glands function, often leading to a decrease in their ability to work properly. This is also known as adrenal insufficiency. People with this condition generally start experiencing symptoms as babies or children, though there have been instances where symptoms first show up during adulthood. Typical symptoms include a general feeling of unwellness, nausea and vomiting, fatigue, loss of appetite, difficulty feeding, poor weight gain, and abdominal pain. If the adrenal insufficiency isn’t properly managed or diagnosed, it can lead to an adrenal crisis, which causes severe symptoms like fever, convulsions, and changes in consciousness. Other common symptoms include low blood sugar levels, high potassium levels, low sodium levels, and metabolic acidosis.

In addition to adrenal insufficiency, men with adrenal hypoplasia can also experience a lack of male sex hormones leading to underdeveloped reproductive tissues, infertility, and central precocious puberty. Other rarer symptoms may include:

Short height due to growth hormone deficiency
Respiratory symptoms like chronic respiratory distress
Triple-A syndrome which results in difficulty swallowing (esophageal achalasia), absence of tears (alacrima), and various neurological defects
Unusual skin pigmentation, hearing loss, and other anomalies

There are also rare forms of adrenal hypoplasia that can cause heart defects, brain and spinal cord abnormalities, and other anomalous physical features.

Testing for Adrenal Hypoplasia

In cases of X-linked AHC, a type of adrenal insufficiency, lab tests are used to look for imbalances in electrolytes. These can include low sodium levels, high potassium levels, low blood sugar, and a type of imbalance in bodily fluids known as metabolic acidosis. Tests can also indicate abnormal adrenal gland functioning, revealed by high levels of ACTH hormone and low levels of cortisol, the hormone our bodies use to respond to stress.

Other findings can include an increase in plasma renin activity, decreased levels of a hormone called aldosterone, and a lack of response to a substance called Cosyntropin which is used in a test to evaluate adrenal gland function. Levels of a substance called 17-OH-progesterone can also be normal or low. Furthermore, the functioning of androgen hormones can be impaired, which can result in low levels of both androstenedione and testosterone. There might also be a deficiency in growth hormone. If a Gonadotropin-releasing hormone (GnRH) test is taken, it might indicate impaired secretion of some specific hormones.

Genetic screening is highly recommended if adrenal hypoplasia is suspected, especially to identify carrier status of females in the family.

Imaging studies are also crucial for proper diagnosis. These can include a CT scan or an MRI that might show the adrenal glands to be smaller than normal. An ultrasound scan can also demonstrate that the adrenal glands are small for the age of the patient.

Assessment of the stomach and intestines, along with neurological evaluations, is also important. If a child has respiratory symptoms along with electrolyte disturbances and low blood sugar, adrenal hypoplasia might be a factor to consider. Specifically, in AHC due to a mutation in the DAX1 gene, there may be elevated levels of a substance called 11-deoxycortisol if the levels are checked early in life.

In some cases, a procedure known as the Schirmer test is recommended, particularly in a syndrome called the Triple-A syndrome.

Treatment Options for Adrenal Hypoplasia

It’s critical to distinguish between primary and secondary adrenal hypoplasia, as this affects the type of treatment a patient needs. In primary adrenal hypoplasia, there is a deficiency of all hormones produced by the adrenal glands, including cortisol, aldosterone, and sex steroids. However, in secondary adrenal hypoplasia, aldosterone replacement is not required because it is regulated by a system named renin-angiotensin-aldosterone. In this case, only cortisol and sex steroids, which are controlled by a hormone called ACTH, are decreased.

The basics of treating an adrenal crisis, which is a severe, potentially life-threatening condition where the adrenal glands do not produce enough hormones, are alike for children and adults. Yet, children require closer monitoring. For a specific form of this disorder, named X-linked AHC, treatment involves taking glucocorticoids, mineralocorticoids, and salt from two weeks old. Symptoms generally improve by two months, and hormone and enzyme levels return to normal. However, patients must continue to take glucocorticoids for the rest of their lives. For those receiving treatment, it’s recommended that they carry steroid emergency cards. Hydrocortisone is the first choice of steroid because it also has mineralocorticoid activity. If checking for adrenal insufficiency with a test called a cosyntropin stimulation test, another steroid called dexamethasone can be given beforehand without affecting the results.

If there is a growth hormone deficiency, growth hormone therapy (using medications called GnRH analogs) should be initiated. During adolescence, testosterone replacement is required when puberty is delayed to ensure standard development of secondary sexual characteristics and bone strengthening.

Emergency treatment of an adrenal crisis in adrenal hypoplasia needs to correct metabolic and electrolyte disturbances, including low blood volume (hypovolaemia) and low blood sugar (hypoglycemia). If the patient has low blood pressure (hypotension), aggressive fluid replacement, and glucocorticoid treatment may be necessary.

Conditions such as blockages in the urinary tract, kidney infections, and diseases affecting the area around the kidney can sometimes appear similar to adrenal hypoplasia caused by the adrenal gland not responding properly. It’s crucial for medical professionals to consider these and perform the necessary examinations for an accurate diagnosis.

What to expect with Adrenal Hypoplasia

Adrenal insufficiency, a condition associated with adrenal hypoplasia, can be life-threatening. Even with the best possible care, it can result in a shortened lifespan and high rates of serious health complications. To effectively manage the condition, it is crucial to determine the cause of the adrenal hypoplasia as this can provide clues about inherited traits and potential related health issues. Statistics reveal that the primary cause of death for 35% of patients with adrenal insufficiency is cardiovascular disease, while 15% succumb to infections.

Possible Complications When Diagnosed with Adrenal Hypoplasia

Some severe health issues can arise, including:

Adrenal crisis, a potentially deadly condition
Puberty that’s delayed or doesn’t occur
Difficulty in having children, known as infertility
Hypoglycemia, or low blood sugar levels
Being shorter than average when fully grown
Myopathy, a muscle disease, related to both Duchenne muscular dystrophy and glycerol kinase deficiency

Preventing Adrenal Hypoplasia

People with adrenal hypoplasia should wear a bracelet or some other form of identification that signals their condition. Understanding and managing this disease is key to preventing serious complications like adrenal crises. Regular appointments with a hormone specialist (endocrinologist) are necessary following diagnosis and particularly after experiencing an adrenal crisis. The general recommendation is a check-up every 6 to 12 months.

As they grow older, it’s crucial for patients to become more self-reliant and able to adjust their medication dosages based on their body’s needs. During times of stress, whether emotional or from long-term physical activity, an extra dose of a hormone called hydrocortisone may be needed.