Clinical characteristics: Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of CNC and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and can manifest as intracardiac obstruction of blood flow, embolic phenomenon, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in CNC, occurring in approximately 25% of affected individuals. Large cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in most adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. The median age of diagnosis is 20 years.
Diagnosis/testing: The clinical diagnosis of CNC is established in a proband with two or more major diagnostic criteria. The molecular diagnosis can be established in a proband with suggestive findings and a heterozygous germline pathogenic variant in PRKAR1A identified by molecular genetic testing.
Management: Treatment of manifestations: Surgical excision via open heart surgery for cardiac myxomas; surgical excision of cutaneous and mammary myxomas; bilateral adrenalectomy for Cushing syndrome; transsphenoidal surgery for pituitary adenoma; surgery for cancerous thyroid adenomas; orchiectomy for boys with aggressive LCCSCT and gynecomastia to avoid premature epiphyseal fusion and induction of central precocious puberty (mild gynecomastia may be treated medically); surgery to remove primary and/or metastatic PMS; standard treatment for pancreatic tumors.
Surveillance: Echocardiography annually beginning in childhood, biannually for those with a history of excised myxoma; clinical examination for cutaneous myxomas as needed; urinary free cortisol levels annually beginning in adolescence with diurnal cortisol levels, dexamethasome stimulation test, and adrenal CT as needed; annual serum IGF-1 beginning in adolescence, pituitary MRI, three-hour oral glucose tolerance test, and 90-minute thyrotropin-releasing hormone testing for those with gigantism/acromegaly; annual thyroid ultrasound beginning in adolescence; monitor growth rate and pubertal staging at each visit and testicular ultrasound annually in males beginning in childhood; transabdominal ultrasound of ovaries as needed in females; clinical assessment for PMS with MRI of the brain, spine, chest, abdomen, retroperitoneum, and pelvis as needed.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the PRKAR1A pathogenic variant in the family in order to identify as early as possible those who would benefit from initiation of surveillance and treatment. Surveillance is recommended for individuals at 50% risk when molecular genetic testing is not possible or is not informative.
Genetic counseling: CNC is inherited in an autosomal dominant manner. Approximately 70% of individuals diagnosed with CNC have an affected parent; approximately 30% have a de novo pathogenic variant. Each child of an individual with CNC has a 50% chance of inheriting the pathogenic variant. Once the PRKAR1A pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal and preimplantation genetic testing are possible.
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