Introduction

Carney complex (CNC) is a rare genetic disorder that can be inherited and affects multiple parts of the body, such as the skin, the heart, and the endocrine system. The CNC impacts the endocrine system by causing tumours or hormonal imbalances in the thyroid, pituitary gland, and adrenal gland.¹ Carney complex has high clinical variability, even within the same family, which can make diagnosis harder. Carney complex is also referred to as NAME (nevi, atrial myxoma, myxoid neurofibromas, ephelides) syndrome or LAMB (lentigines, atrial myxomas, blue nevi) syndrome, which refers to the symptoms that the patient might exhibit. Carney complex must be diagnosed accurately and quickly, as many of the symptoms can be life-threatening. To diagnose the Carney complex, multiple methods can be used. These include methods such as clinical signs, family history, imaging and genetic testing. A multi-disciplinary team will often use multiple methods to ensure an accurate diagnosis. Carney complex can be diagnosed as early as two years old, but is most commonly diagnosed around early adulthood. It can also be diagnosed as late as someone being in their 50s.² The CNC mutation is considered autosomal dominant, meaning that only one gene needs to be mutated for the condition to be present. Because it is autosomal, the mutation is not linked to sex chromosomes. The CNC mutation is commonly found on the PRKAR1A gene³ due to either an inactivation or deletion of part or all of the gene. This mutation disrupts the PKA signalling pathway, which plays a key role in various cell processes including cell growth and hormone secretion. 

Symptoms of carney complex 

Skin findings

The Carney complex is characterised by the presence of multiple benign tumours (neoplasia), endocrine overactivity and spotty skin pigmentation. These skin pigmentations can occur all over the body, as well as on mucous membranes, such as the mouth or eyes. Skin pigmentation from the Carney complex manifests in different forms and is very common, with over 80% of patients reporting pigment spots or skin growths. One of the most common features is lentigines, which are flat, brown or black spots typically appearing around the mouth and eyes (Figure A). Lentigines often present before puberty, but increase in colour and number during puberty.² 

Blue nevi are another type of non-cancerous skin lesion seen in the Carney complex. While rare in the overall population, they are relatively frequent in individuals with CNC. Blue nevi appear as defined, blue bump or mole usually less than 5mm in size, and typically found on legs, arms or the trunk.⁵ 

Cafe-au-lait, flat patches of skin ranging from light to dark brown, are also commonly observed.

Cutaneous myxomas (Figure B) are the third most common skin finding in the Carney complex. These small, non-cancerous skin lesions that tend to recur and are often found on eyelids, ear canals, ears and nipples, though they can occur anywhere on the body.^1,2

Cardiac myxomas 

These lesions can occur not only on the skin but also internally, with the heart being a common site. Cardiac myxomas are the leading cause of mortality in individuals with Carney complex.² Although non-cancerous, myxomas are found in approximately 40% of patients, and can be located in any of the four chambers of the heart. They often require surgical removal. If left untreated, the lesion can obstruct blood flow, leading to stroke or embolism (blockage). As these myxomas can recur, patients require frequent monitoring through screening via echocardiography (Figure C). Due to the fatality of these lesions, prompt diagnosis of Carney Complex is essential to enable timely and safe removal of these lesions. The presence of these myxomas also aids in diagnosing Carney complex, as these tumours can occur anywhere in the heart and affect males and females equally. This contrasts with sporadic (non-CNC-related) cardiac myxomas, which are more commonly found in older females and predominantly occur on the left side of the heart.² 

Tumours in carney complex

Endocrine tumours are also commonly found in Carney Complex. The most common tumour is Primary Pigmented Nodular Adrenocortical Disease (PPNAD) (Figure D), which affects the adrenal glands. PPNAD causes excessive cortisol production, often leading to Cushing syndrome.⁶ Hormone abnormalities are frequent in CNC, with up to 75% of people with CNC have elevated levels of growth hormone, insulin-like growth factor 1 and prolactin. Notably, these abnormalities can occur without any visible tumour on imaging like magnetic resonance imaging (MRI). In addition, affected individuals often demonstrate abnormal hormone responses to stimulation or suppression tests. For example, growth hormone levels remain high despite glucose administration, which normally suppresses its secretion. Blood tests are used to measure hormone levels for diagnosis. True pituitary tumors occur in about 12% of CNC cases.² These pituitary adenomas can overproduce growth hormone, resulting in acromegaly, a condition characterised by abnormal enlargement of bones and soft tissues.⁷ Moreover, lesions can also appear on the testicles or thyroid glands in CNC patients, increasing their risk of developing cancer later in life. 

Imaging

Clinicians use various types of imaging to help diagnose and monitor CNC. Echocardiography is a specialised ultrasound of the heart, uses sound waves to produce an image. This method is particularly effective for detecting cardiac myxomas, as well as monitoring their progression, making it one of the first tests ordered when CNC is suspected. Early detection of CNC through this method helps prevent serious complications (Figure 4).⁸ 

Additionally, MRI or computed tomography (CT) scan can also be used. MRI scan uses magnetic fields to create detailed images of soft tissues, making it ideal for detecting pituitary tumours. CT scans, which utilise X-rays to generate cross-sectional images are useful for assessing other parts of the body, such as the adrenal gland, for the presence of tumours. 

Genetic testing 

Genetic testing is recommended when Carney Complex (CNC) is suspected based on clinical symptoms. A clinician will advise testing if a patient meets the clinical criteria for CNC. CNC is most commonly caused by a mutation in the PRKAR1A gene. There are two main methods used for genetic testing in CNC suspected cases:. 

• Sanger sequencing 

This technique sequences the exact DNA nucleotide sequence of a single gene. This is highly accurate but is limited to one gene at a time, making it ideal for confirming mutations in PRKAR1A gene⁹

• Next Generation Sequencing (NGS)

NGS analyses multiple genes or the entire genome, often used when Sanger sequencing does not detect a mutation, but clinical suspicion remains high. This is because CNC may sometimes result from mutations in other genes or broader genetic changes.

If there is no known family history of CNC mutation, additional genetic screening may be required to detect the initial mutation.¹⁰ Genetic testing may also be recommended for family members, even if they have no symptoms. It is important to note that a negative genetic test result does not definitively exclude CNC, since some mutations may evade detection with current methods or reside in genes not yet identified. Genetic testing also helps differentiate CNC from other diseases, such as McCune-Albright disease shares similar symptoms but has different genetic causes. Thereby, identifying the specific genetic mutation allows for a definitive diagnosis and appropriate management.

Summary 

Overall, Carney Complex can cause a wide range of symptoms, many of which are not immediately visible. To accurately and quickly diagnose CNC, clinicians use a combination of tests, including various types of imaging, blood tests and genetic testing. Diagnosing and managing CNC requires a team of specialists working together to build a comprehensive profile of the patient’s condition.