What is the best approach to manage a patient with Carney complex?

Management of Carney Complex

All patients with confirmed or suspected Carney complex require immediate echocardiographic surveillance every 6-12 months for cardiac myxomas (the leading cause of mortality), annual comprehensive endocrine screening for primary pigmented nodular adrenocortical disease (PPNAD) and growth hormone excess, and genetic testing for PRKAR1A mutations to confirm diagnosis and guide family screening. 1, 2

Diagnostic Confirmation

Establish the diagnosis systematically by identifying at least two major criteria or one major criterion plus a PRKAR1A mutation: 1, 3

• Spotty brown-to-black lentigines on lips, conjunctiva, inner/outer canthi, vaginal or penile mucosa (present in majority of cases—these characteristically involve mucosal surfaces, distinguishing them from common freckles) 1, 2, 4, 3
• Cardiac myxomas detected on echocardiography 1, 3
• Primary pigmented nodular adrenocortical disease (PPNAD) causing Cushing syndrome 1, 3
• Growth hormone-producing pituitary adenomas causing acromegaly 1, 3
• Large cell calcifying Sertoli cell tumors or characteristic testicular calcifications on ultrasound 1
• Cutaneous and mucosal myxomas 1, 3
• Multiple blue nevi (including epithelioid blue nevus subtype) 1, 3
• Breast myxomatosis on fat-suppressed MRI or multiple ductal adenomas 1, 4, 3
• Psammomatous melanotic schwannoma 1
• Osteochondromyxoma 1, 3
• Thyroid carcinoma (nonmedullary) or multiple hypoechoic thyroid nodules 1, 3

Genetic testing for PRKAR1A mutations is mandatory—71% of patients meeting at least two major criteria have identifiable mutations, and at least 50% of patients with isolated PPNAD harbor PRKAR1A mutations. 1, 2, 4, 5

Cardiac Surveillance Protocol

Perform echocardiography every 6-12 months indefinitely, as cardiac myxomas are the leading cause of mortality in Carney complex. 2, 4, 5, 6

• Cardiac myxomas occur in 60% of patients with growth hormone excess versus only 36% without GH excess (OR: 2.78, P=0.014), suggesting GH may promote myxoma formation 7
• Myxomas can occur in any cardiac chamber, including right ventricle (though less common), and frequently recur after resection 6, 8, 9
• Use multimodality imaging (transthoracic echocardiography, transesophageal echocardiography, cardiac MRI) for complete tumor characterization before planned resection 6

Endocrine Screening Algorithm

Perform annual comprehensive endocrine screening starting at diagnosis: 1, 2, 4

Growth Hormone Excess Screening

• Measure serum IGF-1 levels annually (age-adjusted, sex-adjusted, and Tanner stage-matched) and assess clinically for acromegalic features (coarsened facies, prognathism, acral enlargement, teeth separation) 1, 2, 4
• In children and young people with suspected GH excess, biochemical alterations of the GH axis can occur without overt clinical acromegaly 1
• Offer biochemical screening for pituitary hormone excess to all patients with Carney complex (strong recommendation, high-quality evidence) 1
• Perform dynamic pituitary assessment for possible hypofunction and hyperfunction of other anterior pituitary hormones, as 25-35% have hypopituitarism and 65% have hyperprolactinemia 1
• Monitor both GH and IGF-1 at baseline and during follow-up, as baseline GH levels predict surgical outcomes 1

PPNAD/Cushing Syndrome Screening

• Screen annually for PPNAD starting at diagnosis, as at least 50% of individuals with isolated PPNAD have PRKAR1A mutations and may develop other manifestations later 1, 2, 4
• Assess for cushingoid features: central obesity, moon facies, buffalo hump, purple striae, hypertension, glucose intolerance 4, 8
• PPNAD causes ACTH-independent Cushing syndrome with normal or low ACTH levels 8

Thyroid Surveillance

• Perform annual thyroid ultrasound and TSH screening given the association with thyroid tumors (including papillary carcinoma) in Carney complex 2, 4, 3, 8

Testicular Surveillance (Males)

• Perform testicular ultrasound to screen for large cell calcifying Sertoli cell tumors 1, 6, 9

Breast Surveillance (Females)

• Perform breast imaging with fat-suppressed MRI to detect myxomatosis and multiple ductal adenomas—these require specialized surveillance distinct from standard breast cancer screening 4, 3

Treatment of Growth Hormone Excess

When GH-secreting adenomas are identified, offer surgery as first-line treatment to reduce GH burden, even where surgical cure is unlikely (strong recommendation, moderate-quality evidence): 1

• Surgery performed by experienced pituitary neurosurgeons achieves ~50% remission rates in children and young people 1
• In genetic causes like Carney complex where the whole gland may be affected, selective adenomectomy, radical surgery, or hypophysectomy have all been described 1
• Consider pre-operative medical therapy with somatostatin analogues and/or GH receptor antagonists to rapidly control symptoms and support perioperative airway management 1

For post-operative residual disease, offer monotherapy or combination medical therapy (strong recommendation, moderate-quality evidence): 1

• Somatostatin analogues as primary medical therapy 1
• Dopamine agonists (primarily cabergoline) for mild GH excess or as adjunct therapy 1
• Pegvisomant (GH receptor antagonist) starting at 10 mg daily, titrated until IGF-1 normalizes—this can suppress growth velocity and should be considered earlier in children with gigantism 1
• Assess efficacy by both auxological measurements (height velocity) and serum levels of GH and IGF-1 1

Consider pituitary radiotherapy for uncontrolled tumor growth with incomplete surgical and medical response, except in patients with skull base fibrous dysplasia (strong recommendation, low-quality evidence): 1

• After radiotherapy, offer intermittent dose reduction or withdrawal of medical therapy to assess radiation efficacy on GH hypersecretion 1
• Radiotherapy may take up to 10 years to fully suppress GH, requiring continued medical therapy during this period 1

Treating GH excess may reduce cardiac myxoma formation and recurrence, given the strong association between GH excess and myxoma development (OR: 2.78). 7

Treatment of PPNAD/Cushing Syndrome

Bilateral adrenalectomy is the definitive treatment for PPNAD causing Cushing syndrome. 9

• Pathologic examination may reveal focal unilateral PPNAD, unilateral nonpigmented adrenocortical nodules, or bilateral adrenal medullary hyperplasia 9

Additional Surveillance Requirements

• Assess for osteochondromyxomas clinically and with imaging if symptomatic 1, 3
• Screen for psammomatous melanotic schwannoma (rare nerve sheath tumor) 1
• Evaluate for superficial angiomyxomas 9

Critical Pitfalls to Avoid

Do not dismiss lentigines as benign freckles—Carney complex lentigines characteristically involve mucosal surfaces (lips, conjunctiva, canthi, genital mucosa), not just skin, distinguishing them from common freckles. 2, 4

Do not overlook isolated endocrine findings—at least 50% of patients presenting with only PPNAD have PRKAR1A mutations and may develop life-threatening cardiac myxomas later. 1, 2, 4

Do not use standard breast cancer risk models—the breast manifestations in Carney complex (myxomatosis, ductal adenomas) require specialized surveillance with fat-suppressed MRI, distinct from BRCA-related breast cancer screening. 4

Do not assume right-sided cardiac involvement is rare—while less common than left-sided myxomas, right ventricular and right atrial myxomas do occur and require the same vigilant surveillance. 6

Do not delay genetic counseling—PRKAR1A mutations have autosomal dominant inheritance with almost full penetrance, requiring family screening and counseling. 1, 5

Long-Term Management Structure

Every confirmed or suspected Carney complex patient requires management by a multidisciplinary team with long-term follow-up: 5

• Coordinate care between cardiology, endocrinology, genetics, dermatology, and surgical specialties 5
• Close interaction between pediatric and adult endocrine services is required for transition to adult care 1
• There is no medical-specific treatment for Carney complex itself—management is directed at each individual manifestation 5