Carney Complex

Carney complex is an autosomal dominant multiple neoplasia syndrome with spotty skin pigmentation, myxomas, endocrine overactivity and other tumours. It is caused by inactivating variants in PRKAR1A in about 70% of families.

It is rare, with a few hundred families described, and about 30% of cases are new variants. Presentation is usually in the second to third decades.

Major features include spotty skin pigmentation, cardiac and cutaneous myxoma, primary pigmented nodular adrenocortical disease, growth hormone excess, large cell calcifying Sertoli cell tumour, thyroid nodules or cancer, psammomatous melanotic schwannoma and breast myxomatosis.

Pathophysiology.

PRKAR1A encodes the regulatory subunit of protein kinase A. Loss of function increases cyclic AMP signalling, driving proliferation and hormone secretion in the adrenal cortex, pituitary somatotrophs and other tissues.

Cardiac myxoma can cause emboli, heart failure or sudden death, and is the leading cause of mortality.

• Lentigines of the face, lips, eyelids and genitalia, and blue naevi.
• Cardiac murmur, embolic stroke or heart failure (myxoma); cutaneous or breast myxomas.
• Cushing syndrome (primary pigmented nodular adrenocortical disease), acromegaly, testicular enlargement or precocious puberty (Sertoli cell tumours), thyroid nodules.

Red flags.

• Embolic event, new murmur or syncope.
• Rapid onset Cushing syndrome or visual loss.

• Clinical criteria: two major manifestations, or one major manifestation plus a PRKAR1A variant or an affected first degree relative.
• PRKAR1A sequencing and deletion analysis (about 70%). Family testing.
• Annual echocardiography from birth; IGF-1 and a growth hormone suppression test; late night salivary or urinary free cortisol and dexamethasone testing (paradoxical rise on the Liddle test); thyroid ultrasound; testicular ultrasound from childhood; pelvic ultrasound.
• MRI of the pituitary, adrenals and brain as indicated.

Differential diagnosis.

• Peutz-Jeghers syndrome, McCune-Albright syndrome, MEN1 and LEOPARD syndrome.
• Sporadic cardiac myxoma and sporadic Cushing syndrome.
• Other causes of lentigines.

• Cardiac myxoma: surgical excision at diagnosis, with repeat excision for recurrence.
• Primary pigmented nodular adrenocortical disease: bilateral adrenalectomy with lifelong hydrocortisone 15 to 25 mg daily in two or three divided doses (children 10 to 15 mg/m2 daily in three divided doses) and fludrocortisone 0.05 to 0.2 mg daily.
• Growth hormone excess: transsphenoidal surgery; octreotide long acting 20 mg every 4 weeks or lanreotide 90 to 120 mg every 4 weeks; pegvisomant 10 mg daily after a loading dose; cabergoline 0.5 to 3 mg weekly for mild excess.
• Thyroid cancer: thyroidectomy. Large cell calcifying Sertoli cell tumours: monitoring, and orchidectomy if growth or hormone effects. Schwannoma: surgical excision.
• Sick day rules for adrenal replacement: double the dose in illness and give 100 mg intramuscularly or intravenously for collapse.

Special groups. Children: surveillance starts early. Genetic counselling: 50% risk for each child.

Monitoring. Yearly echocardiography for life, yearly IGF-1 and cortisol tests, thyroid and testicular ultrasound at the intervals set by findings, and skin review.

Referral and escalation. Endocrinology with cardiology, cardiac surgery, endocrine surgery and clinical genetics.