Carney complex

Carney complex is a multisystem condition caused by constitutional (germline) pathogenic variants in the PRKAR1A gene. Classically, it manifests as skin pigmentation, endocrine dysfunction and cardiac myxoma.

A diagnosis of Carney complex can be established in a patient with two or more major diagnostic criteria and/or by identification of a heterozygous constitutional (germline) pathogenic variant.

Endocrinological features, with the major diagnostic criteria marked in bold, include:

• acromegaly (somatotroph hyperplasia and/or adenoma):
  • tall stature (rare);
  • acral enlargement; and
• corticotrophinoma (very rare);
• primary pigmented adrenal hyperplasia:
  • Cushing syndrome;
• thyroid carcinoma or multiple hypoechoic nodules on thyroid ultrasound in a patient under 18 years of age;
• gonadal lesions:
  • large-cell calcifying sertoli cell tumour;
  • leydig cell tumour (rare):
    • premature or accelerated puberty in boys; and
  • ovarian cystadenoma.

Dermatological features, with the major diagnostic criteria marked in bold, include:

• spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa);
• lentigines;
• myxoma; and
• epithelioid-type blue naevus.

Cardiac features, with the major diagnostic criteria marked in bold, include:

• cardiac myxoma:
  • collapse;
  • congestive cardiac failure; and
  • embolic phenomena.

Breast features, with the major diagnostic criteria marked in bold, include:

• myxomatosis; and
• ductal adenoma.

Other major diagnostic criteria include:

• osteochondrotic myxoma; and
• melanotic schwannoma.

Clinical features possibly associated with Carney complex but not considered diagnostic include:

• intense freckling (without darkly pigmented spots or typical distribution);
• common-type blue naevus;
• café-au-lait macules or other birthmarks;
• elevated insulin-like growth factor 1 (IGF-1) levels and non-suppressed growth hormone levels on oral glucose tolerance test in the absence of overt clinical features of acromegaly;
• cardiomyopathy;
• pilonidal sinus;
• history of Cushing syndrome, acromegaly or sudden death in extended family;
• multiple skin tags or other skin lesions;
• lipomas;
• colonic polyps (usually in association with acromegaly);
• hyperprolactinaemia (usually mild and almost always combined with clinical or subclinical acromegaly);
• single, benign thyroid nodule in a child younger than 18 years of age;
• multiple thyroid nodules in an individual older than 18 years of age (detected on ultrasound examination); and
• family history of carcinoma, in particular of the thyroid, colon, pancreas and ovary, as well as other multiple benign or malignant tumours.

Carney complex is most commonly (70%–80% of cases) caused by constitutional (germline) pathogenic variants in the PRKAR1A gene.

Some cases show linkage to a region on chromosome 2p16, but the gene responsible in these cases is unknown. Single gene testing of PRKAR1A (code R156.1) is available. PRKAR1A is also included in R21, R104, R145, R160, R217, R236, R293, R359 and R412 panels. If test results are negative, discussion with a multidisciplinary team is recommended to consider somatic testing for mosaicism or further testing depending on clinical phenotype. Large deletions in PRKAR1A are associated with a more severe phenotype.

For more information about genomic testing, see Presentation: Patient with Carney complex.

A diagnosis of Carney complex can be established in a patient with two or more major diagnostic criteria listed above in the clinical features section and/or by identification of a heterozygous constitutional (germline) pathogenic variant.

Carney complex is an autosomal dominant condition with almost complete penetrance. Around 30% of cases may occur as a consequence of a de novo pathogenic variant. A parent with a pathogenic variant has a 50% chance of passing the variant on to their child. Rare cases of gonadal mosaicism in a parent could result in affected children with unaffected parents.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management of patients with Carney complex is intricate due to its rarity and multisystem manifestations. Care should be delivered via a multidisciplinary team, which may include (but is not limited to) adult and/or paediatric endocrinologists, cardiologists, cardiac surgeons, endocrine surgeons, oncologists, dermatologists and specialist nurses.

For clinicians

• GeneReviews: Carney Complex
• Genomics England: Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Bouys L and Bertherat J. ‘Management of endocrine disease: Carney complex: Clinical and genetic update 20 years after the identification of the CNC1 (PRKAR1A) gene’. European Journal of Endocrinology 2021: volume 184, issue 3, pages R99–R109. DOI: 10.1530/EJE-20-1120

For patients

• Association for Multiple Endocrine Neoplasia Disorders (AMEND)
• National Organization for Rare Disorders: Carney complex
• The Pituitary Foundation