Introduction

Carney complex (CNC) is a rare, multisystem genetic disorder that affects many parts of the body, involving changes in the skin, heart, and endocrine glands. You can see early signs in the form of skin pigmentation called lentigines, which look like clusters of small, flat, dark-coloured marks near the lips, face, and genital regions. These skin lesions warn you about deeper health issues, and their early appearance during childhood or adolescence can indicate a family history of CNC or suggest spontaneous abnormalities. Some serious manifestations include primary pigmented nodular adrenocortical disease (PPNAD), cardiac myxomas, thyroid and pituitary tumours. The goal of the article is to explore the role of pigmented spots as a dermatological clue in diagnosing CNC.^1,2

Overview of Carney complex 

CNC is an inherited condition that affects the skin, endocrine system, and heart. It is an autosomal dominant disorder, meaning that only one copy of the altered gene is sufficient to cause this condition. CNC results from the mutations in the PRKAR1A gene. The DNA in this gene makes an enzyme that controls how specific proteins behave, like regulating cell growth and hormone production. When the PRKAR1A gene mutates, the enzyme loses control, resulting in an unexpected nature of the cell structure.²

There is a wide range of symptoms and tumour types. Common features in CNC:

• Pigmented skin lesions. For example, lentigines, blue nevi or moles that appear slightly blue on the limbs²
• Cardiac myxomas,  if undetected, can lead to stroke, embolism, or heart failure³ 
• Endocrine tumours, e.g. Cushing’s syndrome due to overactivity of the adrenal gland, or acromegaly from excess growth hormone caused by pituitary adenomas²
• Testicular tumours and thyroid nodules that can affect thyroid function and cause problems with fertility²

In some cases, CNC can develop spontaneously without the parent gene. CNC is not contagious. It is still being researched thoroughly, as new studies have shown that changes in a certain part of the chromosome can also cause CNC.^1,2

Skin manifestations in Carney complex

Early signs of CNC start with the skin. Signs include lentigines, blue nevi and cutaneous myxomas. Lentigines are small, dark brown macules with sharp borders. These distinct features appear in childhood or early adolescence near the face, lips, eyelids, ears, and genital area. These look similar to freckles but are not sensitive to the sun and are persistent throughout the year.^1,3  Lentigines can fade away later in adulthood.

Blue nevi are dark blue/black lesions that are flat or have a slight bump. They appear blue because of the melanin in the dermal melanocytes and multiply, which is one of the signs of CNC. Other skin concerns can present alongside blue nevi, like lentigines or lighter brown spots.^1,3

Cutaneous myxomas are a specific sign of CNC. It looks skin-coloured and is less common. It is a rich tissue made out of mucin. It looks similar to cysts and can emerge on the face, ears, nipples, and torso. It is subtle and harmless. If they cause irritation or get bigger, a minor surgery can be performed to remove them.^1,3

Other pigmented spots include light brown spots called cafe au lait spots. They appear in a newborn baby. It can grow as the child grows.^3,4 These dermatological patterns do not appear randomly; they affect specific parts of the body and can indicate CNC before internal symptoms develop. In all cases, regardless of whether they appear subtle, the location, number of spots, and the combination of skin lesions should be noted. Multiple types in the same area increase the suspicion of CNC and should be monitored. Finding out what type of skin pattern is present will guide genetic testing to determine the proper diagnosis.

Diagnostic value of pigmented spots 

As stated previously, lentigines are the earliest and most visible sign of CNC. When identified early in patients without internal symptoms, it can help to uncover the underlying cause and help lead to a diagnosis of CNC. In other words, if a patient exhibits lentigines without any evidence of hormonal imbalance or cardiac abnormality, this strongly suggests the presence of CNC.^1,3

It is important to note where the lentigines appear. For example, a group of spots can cluster around the eyes, nose, lips, and even inside the mouth. In younger patients, it is especially a concern because of the unique way it is presented. Even in the absence of  family history, these cases can prompt new research into the spontaneous occurrence of CNC.¹

When multiple types of spots appear with lentigines, it immediately meets one of the diagnostic criteria for CNC. In early diagnosis, dermatologists will identify the pigmented spots and the visible patterns, prompting referral to genetics and endocrinology specialists for further evaluation. The process involves close monitoring of the condition, particularly cases associated with cardiac tumours or endocrine irregularities, along with family history. It may lead to more serious complications later on if not observed, which can lead to complex disorders. This also raises suspicion of CNC. Dermatologists and other professionals need to be aware early on to provide the patient with primary care and plan for long-term outcomes.¹

Differential diagnosis for pigmented skin lesions 

As other genetic syndromes also have pigmented skin lesions, it is important to consider and distinguish each one of them for the professional to diagnose correctly. Conditions include: 

Peutz-Jeghers syndrome (PJS)

The lentigines present in PJS are around the lips and inside the mouth. It is associated with stomach polyps, which cause bleeding and stomach pains. It causes a heightened risk of cancer.⁵

LEOPARD syndrome

In LEOPARD syndrome, the lentigines multiply and can accompany some congenital heart defects, deafness, and hypertelorism. It has an inherited autosomal dominant pattern like CNC. Endocrine tumours are not typical in LEOPARD syndrome. It can feature heart problems like arrhythmias. It is more commonly known to be part of the RASothapies group.^6,7

Neurofibromatosis type 1 (NF1)

The cafe au lait spots are the main sign of NF1 and stem from early childhood. The spots are more widespread in NF1 than in CNC. Nerve and brain tumours are typical in NF1 and closely resemble learning difficulties and feature bone abnormalities. Later in childhood, axillary freckling occurs near the genital area and armpits. The spots increase as the patient grows older.⁸

Laugier-Hunziker syndrome (LHS)

LHS presents with lentigines like CNC in the same facial areas, and uncommonly in the genital region. LHS has no genetic cause and appears in adulthood. It has no involvement with the heart or endocrine system, and the lentigines are benign. It can present with vertical black lines on the finger nails and toe nails, known as  melanonychia, further distinguishing LHS from CNS.⁹

Several clinical clues help spot differences in other syndromes. CNC presents with lentigines that appear on the face and are associated with hormone-producing tumours that affect the adrenal, thyroid and pituitary glands. Family history or the presence of cardiac myxomas supports the diagnosis of CNC and other skin symptoms.

Role of genetic testing and diagnosis 

To confirm the diagnosis of CNC, the PRKAR1A gene is tested. PRKAR1A is a tumour suppressor gene, and once it mutates, the gene can lead to abnormal cell growth in multiple organs. Once the common features of CNC are identified, such as lentigines in certain regions and a personal/family history of endocrine tumours or cardiac problems, CNC is thought to be diagnosed. The pathogenic mutation is tested by sequencing and deletion/duplication analysis of the PRKAR1A gene.¹⁰

There are guidelines that doctors use to decide whether a patient has CNC. The original criteria involve the main features, which are lentigines, heart tumours, endocrine tumours, genital tumours, and skin myxomas. These are features professionals can uncover before genetic testing.^1,10,11

Early detection of visible signs enables timely testing and interventions to prevent disease progression. The skin signs can be used as screening markers for at-risk family members. This can be done through dermatological findings and genetic testing to enable disease monitoring and early treatment to be commenced. 

Currently, the clinical guidelines have been updated to incorporate modern diagnostic tools to provide a more accurate diagnosis.^1,10 Carney complex is inherited in an autosomal dominant form with high penetrance. Genetic testing is very helpful in practice for family screening and in unclear situations.

Clinical management and monitoring

While pigmented spots in CNC do not need treatment, their presence is a great indicator of the requirement for further investigation. It can be concealed with cosmetics. Importance lies in conducting a system evaluation, as the presence of spots could indicate internal organ involvement.^1,10

If CNC is suspected based on the skin findings, the following evaluations should occur:

• An echocardiogram to screen for heart tumours, which can be  asymptomatic and fatal^1,2
• Hormonal testing, which includes adrenocorticotropic hormone, growth hormones, and thyroid hormones^1,2 
• Imaging tests to look at the adrenal and thyroid glands, the testes and the ovaries for tumours^1,2

Monitoring is essential as tumour recurrences and hormonal imbalances can fluctuate or arise over time. Critical management for CNC its symptoms and to avoid complications involves consulting^1,2 

• A dermatologist to monitor the skin
• A specialist in endocrinology to manage hormonal stages and unusual activity
• A cardiologist for regular screening of the heart and potential tumours/tremors/myxomas 
• A specialist in genetics to test genes, assess family history, and decide if any counselling is needed for the family^1,2,11

Summary 

Pigmented spots known as lentigines can be the first sign of CNC, especially if located on the face and genital area. Since these signs are visible, it is important to follow up with a professional to proceed with further investigation to assess for internal manifestations of the disease, such as heart and endocrine tumours. Even the most subtle signs of the condition can help with early diagnosis - this is especially true if frequent check-ups with a dermatologist occur. Once the signs are recognised, genetic testing, screening, and monitoring can be performed to help people who are also at risk of CNC. Care coordination is essential in a patient's journey from diagnosis to treatment, and follow-up is properly handled. Healthcare workers can provide patient-centred care by adhering to these concepts of skill, strategy, ethics, duties, interprofessional communication, and care coordination. This will ultimately improve patient outcomes and team performance.