What is the Carney complex?

By Cristiano Antonino On Nov 27, 2022

Carney complex is a rare disease characterised by a set of alterations that can be summarised as follows: skin lesions associated with tumours that may involve both endocrine and non-endocrine organs

It is therefore a multiple endocrine neoplastic syndrome (i.e. a disease in which several endocrine glands are simultaneously affected by tumours).

The gene responsible for the syndrome has been identified on chromosome 17 and is called PRKAR1A.

It is probably an oncosuppressor, i.e. a gene that normally controls and prevents tumours from developing; however, when it is mutated, it does not function, cannot perform its function and therefore cannot stop a tumour from developing.

Epidemiology of the Carney complex

To date, 338 patients with Carney’s complex are known (43% are male, 57% are female).

Most of these patients (70%) belong to affected families while the remainder have, at least apparently, no affected relatives.

Complicating the identification of affected relatives is the considerable clinical heterogeneity of Carney’s complex.

The alterations that characterise this pathology do not always occur all at once in the same individual; therefore, within a family, the most diverse combinations can occur, making correct diagnostic classification difficult.

In addition, generational leaps may occur whereby one may lose memory of any affected ancestors; this could lead to a case being mistakenly identified as sporadic when, on the contrary, it has a familial connotation.

However, an accurate family history often allows one to identify relatives or ancestors who had particular skin spots (freckles) or signs and/or symptoms clearly attributable to endocrine diseases.

Certain testicular neoplasms (which are frequently found in this disease) can lead to obstruction of the seminiferous tubules or even necessitate surgical removal of the testicles, leading, in both cases, to a significant reduction in fertility in the male affected by Carney.

This, of course, makes transmission of the disease through affected males statistically less likely as the latter are frequently infertile.

Symptoms

Carney’s complex is a developmental disorder in that the lesions that characterise it often occur during the period of puberty; the average age at which Carney complex is diagnosed is around 20 years.

Carney complex is characterised by the following changes:

Pigmented skin spots (lentigines)

The most frequent clinical sign of Carney’s complex are skin spots (lentigines) that develop gradually during growth.

Usually, although altered skin pigmentation may already be present at birth, lentigines take on the characteristic distribution, density and intensity of Carney’s complex in the peripuberal period; finally they tend to fade after the age of 40.

Typical distribution sites are the lips, conjunctiva and vaginal or penile mucosa.

In addition to lentigines, other skin lesions that may be found (although more rarely) in Carney’s complex are blue nevi, milk-caffeine spots or hypopigmented lesions.

Myxomas

These are neoplasms (more or less benign) that can affect the heart or more rarely other organs.

The most frequent are cardiac myxomas, which are often multicentric, may affect one or all of the cardiac chambers and usually appear in youth.

Often, after an initial surgical removal, they can recur and require multiple surgeries.

Cutaneous myxomas, on the other hand, are rarer and usually involve the eyelid, external auditory canal and nipples.

Other sites described are the genitals, oropharynx and mammary glands where myxomas are often bilateral.

Nodular pigmented adrenal dysplasia

This is the most frequent (25% of cases) of the endocrine tumours found in Carney’s complex.

However, this percentage may underestimate the frequency of this lesion; certain tests (such as the dexamethasone test also known as the Liddle test) may help identify patients with this type of lesion.

Calcific Sertoli large cell tumour

This is a rare testicular tumour that in Carney’s complex is often multicentric and bilateral; it frequently presents with calcifications.

However, although less frequently, other types of tumours can also be found in the testicles.

Pituitary tumours (Acromegaly, Hyperprolactinaemia)

Acromegaly is a clinical picture resulting from an excess secretion of growth hormone (GH).

If this abnormal secretion occurs before the bone cartilage has fused (i.e. before puberty), it leads to a significant increase in growth rate and to the attainment of exaggerated final heights (gigantism).

If, on the other hand, excess secretion of growth hormone occurs after the completion of puberty, acromegaly occurs.

This condition is characterised by the presence of bone deformities especially in the hands and feet.

Thyroid nodules

Thyroid nodules are a very common finding in Carney’s complex; they can be benign (adenomas) or malignant (carcinomas).

Usually these nodules show up on thyroid ultrasound as hypoechogenic lesions.

Psammomatous melanocytic schwannomas

These are rare tumours of the peripheral nervous system which, although potentially affecting the entire nervous system, are mainly located in the gastro-intestinal tract (oesophagus and stomach).

In Carney’s complex, these tumours are characterised by their dark colour (due to the presence of melanin), multicentricity and the presence of calcifications.

Other neoplasms found, more rarely, in the Carney complex are ductal adenoma of the breast and osteochondromyxoma (a rare tumour of the bone).

Given the genetic heterogeneity, it is important to use uniform criteria to make a diagnosis of Carney’s complex

A diagnosis of Carney’s complex is made when at least 2 major criteria or 1 major and 1 minor criterion are present:

Major criteria

skin spots (lentigines)
myxoma
cardiac myxoma
mammary myxomatosis
nodular pigmented adrenal dysplasia or paradoxical response to Liddle’s test
acromegaly
calcific Sertoli large cell tumour or testicular calcifications
thyroid nodules or tumours
psammomatous melanocytic schwannomas
blue nevi
ductal adenoma of the breast
osteochondromyxoma

Minor criteria

affected first-degree relatives
PRKAR1A gene mutation

What to do

Given the clinical complexity, a patient suffering from Carney’s complex must undergo a series of periodic check-ups throughout life.

An adult patient should have an echocardiogram, and the dosage of urinary free cortisol and somatomedin C (IGF-1) annually.

In males it is also advisable to look for testicular tumours by means of an ultrasound of the testicles, while in females a pelvic and breast ultrasound is recommended.

In both sexes, a thyroid ultrasound is useful on a regular basis.

In the case of children suffering from Carney’s complex, it is advisable to perform frequent echocardiograms in the first six months of life and then one every year; children who have already undergone surgery to remove a myxoma should still continue to be monitored as myxomas can recur.

Whereas, since the other alterations of the Carney complex usually occur after puberty, it is not necessary to perform all the other examinations every year; these should only be performed at the beginning when the diagnosis is made.

In children with testicular tumours, however, it is also indicated to perform appropriate hormonal and auxolological examinations (assessing growth rate and bone age), especially if gynaecomastia is already present.

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