The median age of diagnosis is 20 years. Clinical manifestations increase over time, such that the penetrance is 70%-80% by age 40. By early adulthood, patients with CNC may have life-threatening complications as a consequence of cardiac myxomas and/or endocrine abnormalities. Diagnostic cutaneous findings are present in over half of CNC patients, and cutaneous findings at least suggestive of CNC are present in 80% of patients. Cutaneous manifestations thus can be used for early detection of the disease and may prevent its most dangerous complications.
Common skin findings that are in the diagnostic criteria (see Diagnostic Pearls section) include lentigines, cutaneous or mucosal myxomas, and multiple blue nevi. Other common cutaneous findings in CNC that are not diagnostic criteria but are suggestive of the diagnosis include intense freckling, café-au-lait spots, multiple fibrous tumors, lipomas, and angiofibromas. Spitz nevi and nevus spilus may be seen in CNC.
Lentiginosis is one of the earliest clinically detectable signs of CNC. Lentigines generally appear during the first 2 decades of life, become more apparent during puberty, and may fade during adulthood. They are not associated with sun exposure. Although lentigines can be found anywhere on the body, the centrofacial area tends to be the most common. Appearance on the vermillion lips, eyelid margins, and lacrimal caruncle are quite uncommon and therefore a clinical clue in diagnosing CNC. Conjunctival pigmentation has also been recognized in CNC.
Blue nevi are present in 40% of patients with CNC. They are typically small and multiple, often occurring on the face, trunk, limbs, and less commonly, hands and feet. Epithelioid blue nevi are not exclusively seen in CNC but suggest the possibility of this diagnosis. Café-au-lait spots are usually present, and may be present from birth.
Cutaneous myxomas are found in less than half of CNC patients; however, their presence strongly points to CNC when discovered.
Systemic findings of diagnostic value to CNC include endocrine tumors and nonendocrine tumors. Endocrine tumors typically involve the adrenal glands, pituitary glands, and testicles. Primary pigmented nodular adrenocortical disease (PPNAD) occurs in 25%-45% of CNC cases, leading to Cushing syndrome and overproduction of cortisol. Acromegaly from pituitary adenomas occurs in 10%-15% of CNC cases, most commonly in the third and fourth decades. Large-cell calcifying Sertoli cell tumors (LCCSCT) occur in 75% of male CNC patients, leading to gynecomastia in prepubertal boys, and various ovarian cancers have been found in women. Thyroid nodules occur in 75% of CNC patients, and thyroid cancers occur in less than 10%.
Nonendocrine tumors are most often found in the heart, breast, bone, and nervous system. About 3%-10% of cardiac myxomas are associated with CNC. Cardiac myxomas develop at an early age in multiple cardiac chambers, usually the atria bilaterally, and require echocardiography for identification. Cardiac myxomas account for 20% of the deaths of these patients.
Psammomatous melanotic schwannomas are most commonly seen in the gastrointestinal tract but can be found anywhere in the central nervous system (CNS) and peripheral nervous system. Breast myxomas and myxoid fibroadenomas are found in 14% of female CNC patients, usually after puberty. Osteochondral myxomas are painless bone tumors associated with 1% of CNC cases, typically presenting before the age of 2 years and primarily affecting nasal sinuses and long bones.
Related topic: atrial myxoma
Q87.89 – Other specified congenital malformation syndromes, not elsewhere classified
733491005 – Carney complex
Differential Diagnosis & Pitfalls
- McCune-Albright syndrome – Characterized by perioral and mucosal pigmentation, café au lait macules, endocrine hyperactivity, precocious puberty, and polyostotic fibrous dysplasia.
- LEOPARD syndrome – Characterized by multiple disseminated lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness. Lesions appear in infancy and increase over time. Allelic mutations to Noonan syndrome.
- Peutz-Jeghers syndrome – Characterized by mucosal and cutaneous lentigines, multiple gastrointestinal polyps, and visceral tumors (pancreas, ovary, testes).
- Cronkhite-Canada syndrome – Characterized by lentigines (buccal mucosa, face, palmoplantar), alopecia, nail dystrophy, and intestinal polyps.
- Noonan syndrome – Characterized by a webbed neck, hypertelorism, short stature, undescended testicles, low posterior hairline, cardiovascular anomalies, lymphedema, dystrophic nails, and curly hair. Allelic mutations to LEOPARD syndrome.
- Touraine centrofacial lentiginosis – Characterized by lentigines (central face and lips, spares mucosa, none elsewhere), bone abnormalities, dysraphia, endocrine disorders, and neurologic disease.
- Inherited patterned lentiginosis – Characterized by lentigines (central face, hands, feet, buttocks, spares mucous membranes); no other associated systemic abnormalities. Reported in Black Americans and a kindred in China.
- Segmental and agminated lentiginosis – May have no associated systemic manifestations.
- Generalized lentigines
- Arterial dissection with lentiginosis
- Laugier-Hunziker syndrome – Characterized by pigmentation of the nails associated with buccal and lip hyperpigmentation.
- Cantú (hyperkeratosis-hyperpigmentation) syndrome – Characterized by hypertrichosis, osteochondrodysplasia, and cardiomegaly.
- Cowden disease – Characterized by multiple facial trichilemmomas, oral mucosal papillomas, and acral keratotic papules. Allelic mutations to Bannayan-Riley-Ruvalcaba syndrome.
- Bannayan-Riley-Ruvalcaba syndrome – Characterized by multiple subcutaneous lipomas and vascular malformations, lentigines of the penis and vulva, verrucae, and acanthosis nigricans. Allelic mutations to Cowden syndrome.