Carney complex
CNC; "NAME" syndrome (naevi, atrial myxoma, myxoid neurofibroma, ephelides โ older); "LAMB" syndrome (lentigines, atrial myxoma, mucocutaneous myxoma, blue naevi โ older)
Carney complex is a rare autosomal dominant multiple-neoplasia syndrome caused by germline loss-of-function mutations of PRKAR1A on chromosome 17q24.2 โ the regulatory subunit of cAMP-dependent protein kinase A. Affected patients develop a striking constellation of cutaneous, cardiac and endocrine tumours from late childhood onwards: spotty pigmentation (lentigines particularly on the face, lips, conjunctivae and genital mucosa), blue naevi (often multiple cellular and epithelioid types), cutaneous and cardiac myxomas, primary pigmented nodular adrenocortical disease (PPNAD) causing Cushing syndrome, large-cell calcifying Sertoli-cell tumour of the testis and growth-hormone-producing pituitary adenomas. The dermatologist or plastic surgeon is often the first to recognise the syndrome through the spotty mucocutaneous pigmentation pattern, and prompt referral matters โ the cardiac myxomas account for the majority of premature mortality and are highly amenable to surgical excision once detected.
Genetics
- Germline loss-of-function mutations of PRKAR1A on chromosome 17q24.2 โ encodes the regulatory subunit type 1ฮฑ of cAMP-dependent protein kinase A; loss leads to PKA hyperactivation.
- Autosomal dominant; high (~95%) penetrance by age 50.
- Approximately 70% of probands have a detectable PRKAR1A mutation; a smaller subset map to a second locus on chromosome 2p16 (CNC2).
- Cascade testing of first-degree relatives.
Mucocutaneous features
- Spotty pigmentation โ multiple small (1โ5 mm) brown lentigines concentrated on:
- Centrofacial skin (lip vermilion, periocular, ears).
- Conjunctival sclera and lacrimal caruncle.
- Genital and anal mucosa.
- Differential โ Peutz-Jeghers syndrome (lentigines on lips and oral mucosa, GI hamartomatous polyps, GI cancer risk; STK11 mutation) and LEOPARD/Noonan syndrome (lentigines, hypertrophic cardiomyopathy, RASopathy).
- Blue naevi โ multiple, often cellular or epithelioid blue naevi; "epithelioid blue naevus" is so closely associated with Carney complex that its presence in any patient should prompt a search for the syndrome.
- Cutaneous myxomas โ pedunculated or flesh-coloured papules on the face (especially eyelids, ears), neck and trunk; often multiple.
- Cafรฉ-au-lait macules in some patients.
Cardiac myxomas โ the leading cause of mortality
- Lifetime risk >50%; often multiple and recurrent.
- Distinct from sporadic atrial myxoma โ younger age, multiple chambers, ventricular involvement, recurrence after resection.
- Complications โ arrhythmia, heart failure, embolism (stroke), sudden cardiac death.
- Annual transthoracic echocardiogram from infancy; lower threshold for surgical resection.
Endocrine tumours
- Primary pigmented nodular adrenocortical disease (PPNAD) โ bilateral adrenal nodular hyperplasia causing ACTH-independent Cushing syndrome; lifetime risk ~25โ60%.
- Large-cell calcifying Sertoli-cell tumour โ testicular tumour; calcified on USS; surveillance from age 5.
- Growth-hormone-secreting pituitary adenoma โ acromegaly / gigantism; lifetime risk ~10โ15%.
- Thyroid follicular adenoma / carcinoma โ increased risk.
- Psammomatous melanotic schwannoma โ paraspinal nerve roots; rare malignant transformation.
- Breast ductal adenoma / fibroadenoma in women.
Diagnosis (modified Carney criteria)
Diagnosis requires:
- Two or more major criteria, OR
- One major criterion + an affected first-degree relative, OR
- One major criterion + a pathogenic PRKAR1A mutation.
Major criteria โ spotty mucocutaneous pigmentation in typical distribution; blue naevi; cutaneous / cardiac myxoma; PPNAD or paradoxical Liddle test; acromegaly; large-cell calcifying Sertoli-cell tumour; psammomatous melanotic schwannoma; pituitary adenoma; thyroid follicular tumour.
Surveillance & management
- Multidisciplinary care โ endocrinology, cardiology, dermatology, clinical genetics; lifelong.
- Annual transthoracic echocardiogram from infancy.
- Annual physical examination and skin / mucosal surveillance.
- Annual urinary free cortisol or dexamethasone suppression test (PPNAD).
- Annual testicular ultrasound from age 5.
- IGF-1 / pituitary MRI if acromegaly suspected.
- Annual thyroid ultrasound.
- Surgical excision of cardiac myxomas.
- Bilateral adrenalectomy for symptomatic PPNAD.
- Cosmetic management of cutaneous lentigines (laser).
- Genetic counselling and cascade testing.
References
- Stratakis CA et al. Clinical and molecular features of the Carney complex. J Clin Endocrinol Metab; 2001.
- Bertherat J et al. Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A) โ clinical and molecular study. J Clin Endocrinol Metab; 2009.
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