What is Carney Complex?

Causes and symptoms
Protein kinase A (PKA)
Epidemiology
Diagnosis and treatment
References
Further reading

Carney complex (CNC) is a rare familial lentiginosis syndrome caused due to mutations in the PRKAR1A gene. Patients may develop a range of endocrine and non-endocrine malignancies and numerous skin abnormalities.

Skin pigmentary abnormalities, multiple endocrine tumors, and schwannomas are the characteristic features of CNC. It follows the autosomal dominant pattern of inheritance.

Causes and symptoms

PRKAR1A mutations and cyclic AMP-dependent protein kinase (PKA) signaling pathway alterations cause the Carney complex. The CNC1 locus on chromosome 17q22–24, which contains the PRKAR1A gene, which encodes the R1 subunit of PKA, and the CNC2 locus on chromosome 2p16, are the two distinct loci of CNC discovered by genetic linkage research.

Germline inactivating mutations in the PRKAR1A gene, located on the long arm of chromosome 17 at the 17q24.2–24.3 locus (CNC1 locus), are found in 37% of sporadic CNC patients and more than 70% of familial CNC patients, with nearly 100% penetrance.

Genetic linkage analysis of tumors has found a second problematic locus on chromosome 2p16 in most of the remaining instances of CNC (CNC2 locus). Despite this, the relevant gene at this locus is yet to be discovered.

The most common characteristics of CNC include: spotty skin pigmentation (café-au-lait spots, lentigines, blue nevi, and freckling); myxomas of the heart and breast; and primary pigmented nodular adrenal cortical disease (PPNAD) linked with an unusual type of Cushing syndrome (CS).

CNC is unusual in that it involves such a wide range of organs. CNC is a multiple endocrine neoplasia (MEN) syndrome (with MEN-1 and -2) and a cardiocutaneous syndrome (such as Noonan syndrome and associated diseases).

Cardiovascular myxomas are the most prevalent non-cutaneous tumors seen in CNC. PMS (psammomatous melanotic schwannomas) is an uncommon nerve sheath tumor reported in CNC patients (up to 10%).

Compared to spontaneous, non-CNC-associated myxomas, these tumors are usually more aggressive. The former, unlike the latter, can occur in any heart chamber and at any moment. They can begin at any age (including infancy) and without regard to gender (sporadic myxomas are more common in elderly women and almost invariably arise as single one-time tumors in the left atrium). In the past, cardiac myxomas accounted for more than half of the disease-specific mortality among CNC patients.

Growth hormone-secreting pituitary adenomas, PPNAD (corticotropin-independent CS secondary to primary pigmented nodular adrenocortical disease), thyroid gland disease, and testicular tumors are some examples of endocrine gland involvement. Abnormal skin pigmentation may be present at birth.

After the fourth decade, lentigines tend to disappear, while some may survive until the eighth decade. Cardiac and cutaneous myxomas are the most prevalent tumors in children; PPNAD appears after age five, while thyroid nodules emerge around puberty.

Cardiac myxomas affect people of all ages in the same way. PPNAD can appear as early as the first five years of life; however, it is more common in the second and third decades.

In the third and fourth decades of life, acromegaly is common. Individuals with CNC have a 50-year average life expectancy. Complications with cardiac myxomas (cardiomyopathy, cardiac arrhythmia, and surgical intervention), metastatic or intracranial PMS, thyroid carcinoma, and metastatic pancreatic and testicular tumors are the most common reasons for mortality in individuals with CNC.

After puberty, girls with CNC develop breast myxomas, which are commonly bilateral. Nipple myxomas can affect both men and women at any age. In females with CNC, ovarian cysts and malignancies of the ovarian surface epithelium have been documented.

A myxomatous tumor of the bone characterizes osteochondromyxoma, a rare component of CNC. They frequently emerge at a young age (before age 2).

Protein kinase A (PKA)

Protein kinase A (PKA) is a cAMP-dependent serine-threonine kinase that regulates cellular functions such as transcription, metabolism, cell cycle progression, and apoptosis.

PKA comprises two regulatory and two catalytic subunits that form a heterotetramer. PKA's regulatory (R1, R1, R2, and R2) and catalytic subunits (Cα, Cβ, Cγ, and PRKX) are divided into four isoforms, each with its location and specificity. Targeting proteins that relocate PKA to specific locations in the cell, near-certain substrates, are part of the PKA signaling pathway.

The cell-type-specific expression of the different PKA regulatory and catalytic isoforms and/or splice variants, the different PKA substrates, and the subcellular location of PKA all influence the result of PKA signaling. CNC is the first disease linked to a mutation in the PKA heterotetramer identified in humans.

Epidemiology

CNC is a rare disease with unknown prevalence. 63% of the patients in the largest genotyped series were females, while 37% were males.

More than 750 cases of Caucasians, African–Americans, and Asians from three continents have been recorded by the NIH-Mayo clinic, centers in the United States, and the Cochin Hospital in France. North and South America, Europe, Japan, China, and India are among them.

Diagnosis and treatment

Clinical surveillance in patients with CNC for early diagnosis of syndrome manifestations varies by age group because most endocrine tumors do not appear clinically until the second decade of life.

Beginning at six months, pre-pubertal juvenile patients should get yearly echocardiography. Abnormalities in growth rate and annual pubertal staging should be closely monitored because they could indicate an elevated level of the hormones.

Each complication/tumor should be handled independently in CNC. Cardiac myxomas should be surgically removed. Pituitary adenomas that produce SH and/or GH can be treated medically with somatostatin analogs or surgically removed.

Although surgical excision of cutaneous and mammary myxomas is sometimes required, it is not always necessary because these tumors are fully benign. PMS is more difficult to treat because many of these tumors are found near nerve roots, which are usually inoperable.

At least once a year, any patient diagnosed with CNC should be actively monitored for clinical symptoms. This form of follow-up has been found in studies to enhance prognosis.

References

• Wei K, Guo H W, Fan SY, et al. (2019). Clinical features and surgical results of cardiac myxoma in Carney complex. Journal of Cardiac Surgery, 34(1), 14-19. doi:10.1111/jocs.13980. https://onlinelibrary.wiley.com/doi/10.1111/jocs.13980
• Kamilaris CD, Faucz FR, Voutetakis A, et al. (2019). Carney complex. Experimental and Clinical Endocrinology & Diabetes, 127(02/03), 156-164. doi:10.1055/a-0753-4943. https://pubmed.ncbi.nlm.nih.gov/30428497/
• Stratakis CA, Raygada M. Carney Complex. 2003 Feb 5 [Updated 2018 Aug 16]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1286/
• Stratakis CA (2016). Carney complex: A familial lentiginosis predisposing to a variety of tumors. Reviews in Endocrine and Metabolic Disorders, 17(3), 367-371. doi:10.1007/s11154-016-9400-1. https://link.springer.com/article/10.1007/s11154-016-9400-1
• Correa R, Salpea P, & Stratakis CA (2015). Carney complex: an update. European Journal of Endocrinology, 173(4), M85-M97. doi:10.1530/EJE-15-0209. https://academic.oup.com/ejendo/article-abstract/173/4/M85/6660773?redirectedFrom=fulltext

Further Reading

• All Multiple Endocrine Neoplasia Content
• Multiple Endocrine Neoplasia
• Multiple Endocrine Neoplasia Type 1 (MEN1)
• Multiple Endocrine Neoplasia Type 2A (MEN2A)
• Multiple Endocrine Neoplasia Type 2B (MEN2B)