Primary pigmented nodular adrenocortical disease

Overview

Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare form of adrenal hyperplasia that causes autonomous and excessive production of cortisol, leading to Cushing's syndrome. Unlike other adrenal disorders, PPNAD is characterized by the presence of multiple small pigmented nodules in the adrenal cortex. These nodules secrete cortisol independently of the normal regulatory mechanisms. PPNAD often presents in childhood or early adulthood and may occur as an isolated condition or as part of a genetic disorder called Carney complex. The condition is more common in females and can lead to significant health problems if not properly managed.

Causes

PPNAD is primarily caused by genetic mutations, most notably in the PRKAR1A gene. This gene encodes the regulatory subunit type 1-alpha of protein kinase A (PKA), which plays a crucial role in cell signaling and endocrine function. Mutations in PRKAR1A lead to dysregulation of PKA activity, resulting in abnormal adrenal cortex cell proliferation and hormone overproduction. Key causes include:

• Carney complex: PPNAD is frequently associated with this autosomal dominant disorder characterized by multiple endocrine and non-endocrine tumors, lentigines (skin pigmentation), and cardiac myxomas.

• Sporadic mutations: In some cases, PPNAD can occur without a family history, due to new (de novo) mutations in PRKAR1A or related genes.

PPNAD is distinct from other causes of Cushing’s syndrome, as it typically involves both adrenal glands and is ACTH-independent (not driven by pituitary hormone stimulation).

Symptoms

Symptoms of PPNAD are primarily those associated with Cushing’s syndrome due to elevated cortisol levels. These symptoms may develop gradually and vary in severity. Common clinical features include:

• Weight gain, especially around the abdomen and face (moon face)

• Thin skin that bruises easily

• Purple stretch marks (striae), particularly on the abdomen and thighs

• Muscle weakness, especially in the upper arms and thighs

• Hypertension (high blood pressure)

• Glucose intolerance or type 2 diabetes

• Osteoporosis or increased risk of fractures

• Irregular or absent menstrual periods in females

• Acne and increased facial/body hair (hirsutism)

• Psychiatric symptoms such as mood swings, depression, or anxiety

• In children: growth retardation and early onset of puberty

Because the disease progresses slowly, the signs may be subtle and go unrecognized for years, especially in pediatric patients.

Diagnosis

Diagnosing PPNAD involves a combination of hormonal testing, imaging studies, and genetic analysis. The goal is to confirm hypercortisolism and identify the adrenal source of hormone production. Diagnostic steps include:

• 24-hour urinary free cortisol: Measures excessive cortisol excretion

• Low- and high-dose dexamethasone suppression tests: In PPNAD, cortisol levels typically fail to suppress, or paradoxically increase with high-dose dexamethasone

• ACTH levels: Typically low or undetectable, confirming ACTH-independent Cushing’s syndrome

• Adrenal imaging (CT or MRI): Often shows normal-sized glands or small, pigmented nodules; imaging may appear deceptively normal

• Inferior petrosal sinus sampling: May be used to rule out pituitary causes of Cushing’s

• Genetic testing: Confirms mutations in the PRKAR1A gene and supports diagnosis, especially in suspected Carney complex cases

Treatment

The primary treatment for PPNAD is surgical, as medical therapies are generally ineffective in controlling autonomous cortisol secretion. Treatment options include:

Bilateral Adrenalectomy

• Standard approach: Removal of both adrenal glands is the definitive treatment to eliminate cortisol overproduction

• Post-surgical hormone replacement: Patients require lifelong glucocorticoid and mineralocorticoid replacement therapy

Unilateral Adrenalectomy (Rarely)

• May be considered in select cases with asymmetrical disease, although it often leads to recurrence due to continued hormone production from the remaining gland

Medical Management

• Used in cases where surgery is not possible or as a temporary measure

• Drugs such as ketoconazole, metyrapone, or mitotane may reduce cortisol synthesis but are not curative

Monitoring and Supportive Care

• Blood pressure and glucose monitoring

• Bone density assessments and supplementation with calcium/vitamin D

• Psychological support for mood and cognitive issues

Prognosis

The prognosis for individuals with PPNAD is generally favorable if diagnosed early and treated appropriately. Surgical removal of the adrenal glands typically results in resolution of Cushing's symptoms and prevention of long-term complications such as cardiovascular disease and osteoporosis. However, lifelong hormone replacement therapy is required after bilateral adrenalectomy, and patients must be educated about adrenal insufficiency and the need for emergency corticosteroid administration during illness or stress.

In patients with Carney complex, ongoing surveillance for other tumors and endocrine abnormalities is essential. With careful management and regular follow-up, most individuals with PPNAD can lead a normal and healthy life.