Carney complex

Overview

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.

Clinical features

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
- corticotrophima (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.

Genetics

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. 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.

Inheritance and genomic counselling

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.

Management

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.