Introduction

First described in 1985 by J. Aiden Carney, Carney Complex (CNC) is an extremely rare genetic condition whose symptoms mimic those of many others, emphasising the need for differential diagnoses (DDx).¹

What is carney complex?

Impacting up to 750 people worldwide, CNC is present in its carriers at birth with symptoms manifesting as early as infancy. Global incidence rates of CNC are indiscriminate, with all races and sexes being impacted.^1,2

The most common identifiers of CNC are visual disruption to the pigmentation of skin, cardiac and endocrine tumours, and hormonal hyperactivity.³

What causes carney complex?

While 30% of cases are considered to be caused by newly occurring genetic mutations, the majority are inherited as a result of mutations of PRKAR1A, a gene responsible for tumour suppression. If PRKAR1A is unable to function, tumours can be generated without regulation, resulting in the lesions observed in people with CNC.¹

Differential diagnoses?

A  differential diagnosis is an important clinical procedure where presenting symptoms can be ascribed to a number of conditions, but they are carefully ruled out via testing to ensure the correct, final diagnosis is made.⁴ As many conditions will have similar symptoms to CNC, it is important to rule them out and understand how each is different.

How is carney complex diagnosed?

The symptomatic manifestations of CNC are further categorised into subsets referred to as “LAMB” and “NAME” syndromes. Each of the aforementioned syndromes is an acronym for the specific lesions (a clinical term describing any damage or abnormalities found on tissues) that are presented.^1,5,6

NAME syndrome was first proposed in 1980 to represent a condition with the following traits:⁷

• N - Naevi, a benign mole⁸
• A - Atrial myxoma, benign tumours in the upper chambers of the heart⁹
• M - Myxoid neurofibromata, non-cancerous tumours found on nerve sheaths that aren’t found in the brain or spinal cord¹⁰
• E - Ephelides, sunlight-induced, flat freckles that are typically light-brown or red in colour¹¹

Following this, a patient in 1984 was experiencing an iteration of NAME syndrome that was slightly different; as such, it was called LAMB syndrome:⁵

• L - Lentigines, small, dark spots on the skin with a clear border, surrounded by otherwise unaffected skin¹²
• A - Atrial myxoma
• M - Mucocutaneous myxomas, nodules found in areas like the lips, anal cavity and nostrils⁵
• B - Blue naevi

Then, in 1985, it was proposed that these conditions on myxomas, skin pigmentation and endocrine hyperactivity be unified under the overarching name “Carney Complex”. Additional observations unique to CNC include benign breast tumours (as observed in a fifth of female CNC patients) and a condition called PPNAD.¹

Primary pigmented nodular adrenocortical disease (PPNAD) is a condition that affects the outer layer of the adrenal glands - called the adrenal cortex (AC) - causing them to enlarge and develop small nodules.¹³ The AC is responsible for secreting a hormone called “cortisol”; cortisol helps to control our stress response, metabolism and parts of our immune system.¹⁴ So, when the AC is enlarged as a result of PPNAD, people with CNC can develop a secondary condition called “Cushing’s syndrome”. More than half of the people with CNC have Cushing’s syndrome caused by PPNAD.¹ 

In addition to observable changes in their skin pigmentation and the development of benign tumours, people with CNC who also have Cushing’s may experience additional symptoms caused by raised cortisol levels, such as weight gain, purple stretch marks on the abdomen and weakness in their upper arms, hips or shoulders.¹³

As a result of the myriad of associated symptoms, a definitive diagnosis of CNC is dependent on the confirmed presence of two major criteria (out of a total of 12), which can be detected via molecular testing or imaging. These criteria are as follows:

Symptoms observable on the skin

• Spotty skin pigmentation on the outer border of the lips, eyelids, the corners of the eye and the skin of the vagina or penis  
• Blue nevi

Tumours

• Myxomas on the mucosal or cutaneous layers of skin
• Benign tumours in the heart
• Benign tumours of the breasts
• Bone tumors

Endocrinal symptoms

• PPNAD
• Acromegaly - excess growth of certain body parts, like the hands and feet
• Testicular tumours are called a “Large-Cell Calcifying Sertoli Cell Tumour”
• The presence of cancerous cells in the thyroid 

Miscellaneous

• Benign tumours of the nerve sheath
• Benign tumours in the breast ducts

Non-major criteria

• A first-degree relative with CNC
• Inactivating PRKAR1A gene mutation¹²

How is carney complex treated?

Aside from the cardiac risk posed, none of the major symptoms of CNC are lethal, so there is no established “cure” per se for CNC. Instead, people with the condition are regularly tested to detect and monitor existing tumours, ensuring that they are benign.¹⁵ Despite being difficult to remove with surgery, as they reappear often and in different locations, cardiac myxomas are operated on.¹⁶ 

Cushing’s syndrome (resulting from CNC) is often treated by removing the adrenal glands, but can sometimes be managed with medication. If a person with CNC has thyroid nodules, fine-needle aspiration is a recommended treatment, with surgery becoming necessary if the lesion is infected.² 

Peutz-jeghers syndrome

Another rare condition, Peutz-Jeghers syndrome (PJS), is characterised by the presence of polyps in the gastrointestinal tract (polyposis) and irregular skin pigmentation in areas that are similarly affected by CNC.¹⁷

What’s more, both PJS and CNC are most commonly diagnosed when patients are in their early twenties, with inheritance being dependent on one parent carrying the impacted gene.^18,19

It is these symptomatic similarities that cause PJS to be considered in the DDx of CNC.

How is peutz-jeghers syndrome different from carney complex?

Unlike CNC, PJS presents with a higher risk of malignancy. This means that the polyps, tumours and other symptoms are much more likely to develop into cancerous or otherwise infected lesions. As the threat of developing cancer is much higher, people with PJS will experience different treatment and management plans. Some of these differences are:

• The removal of polyps larger than 1 cm
• Regular (every two to three years) colonoscopies or endoscopies
• Bi-annual breast exams for female patients
• Annual exams to detect cancers in the liver, pancreas, lungs and other organs¹⁷

While CNC is initially detected due to the appearance of the major criteria listed above, PJS often manifests for the first time as a bowel obstruction, which can cause excessive bleeding and part of the intestine to slide into itself.

Lastly, both conditions are caused by the mutation of different genes, with PJS development being attributed to a mutation in the STK11 gene.¹⁸

Multiple endocrine neoplasia

While PJS is characterised by the growth of gastrointestinal polyps (something not commonly observed in CNC), multiple endocrine neoplasia (MEN) encompasses a range of conditions pertaining to endocrine tumours.²⁰

There are four specific syndromes categorised as MEN conditions, with MEN1 being the most common. Neoplasia is a term that defines the uncontrolled growth of tumours (benign or otherwise), with the thyroid, pancreas and pituitary gland being the most affected areas.^{21, 22}

The observable symptoms of MEN can differ depending on where tumours are present; for example, tumours on the parathyroid glands cause high levels of calcium in your blood, which in turn can cause feelings of nausea or thirst.²³

How is multiple endocrine neoplasia different from carney complex?

The areas impacted by endocrine neoplasia increase the risk of mortality for people with MEN, giving them a lower life expectancy than CNC. As a result, early detection is crucial via genetic testing. Additionally, a person with MEN may undergo a parathyroidectomy as a part of their treatment, something not commonly observed in CNC patients.²⁴

Ultimately, while people with CNC may develop endocrine tumours (namely, adrenal myxomas), the risk of them becoming malignant is significantly lower than that of people with MEN.²²

Summary

CNC is an incredibly rare condition that encompasses the growth of (predominantly) benign tumours alongside observable inconsistencies in skin pigmentation, such as freckles or moles. Although the tumours are benign, the presence of cardiac myxomas can pose a risk of potentially fatal heart problems. 

Despite being a rare condition, other genetic syndromes like PJS and MEN bear some symptomatic similarities with CNC, as the former presents with observable skin lesions and the latter with endocrine tumours. However, the genetic mutations, treatment methods and overall patient experience highlight the differences between these unique conditions, further emphasising the clinical significance of differential diagnoses to ensure patient care is to standard.