Skin lesions are consistently reported in the majority of the CNC patients (above 80%), the most common being lentigines (in 70– 75% of cases). Other pigmented lesions, most frequently blue nevi and café- au- lait spots, with or without lentigines, are seen in approximately 50% of CNC patients. The effort to systemize the knowledge on the cutaneous lesions in CNC patients is driven by their high diagnostic value— presented early in life and easily recognizable, the skin manifestations are an early sign that directs dermatologists’ attention towards underlying endocrine or other pathology. In an attempt to outline the most specific and sensitive skin abnormalities in CNC, several research groups have published exhaustive analyses that add to an improved diagnostic and preventive approach. The major challenge appears to be in distinguishing the disease- associated prominent lesions from the more common non- CNC- specific, age- or sun- related skin alterations.
Lentigo is a hamartomatous melanocytic lesion, clinically similar but histologically different from freckles. Morphologically, lentigines are flat, poorly circumscribed, brown- to- black macules, usually less than 0.5 cm in diameter, but these may differ in different ethnic groups. In African Americans, for example, lentigines may be slightly raised, dark papules, similar to nevi. In contrast to the common freckles, on histological examination lentigines show basal cell layer hyperpigmentation associated with an increased number of melanocytes (hyperplasia), the majority of which appear hypertrophic. This distinguishes them from freckles (ephelides), which present with a regular number of melanocytes and are pigmented as a result of melanin disposition in the sur rounding keratinocytes.
Lentiginosis is one of the manifestations of CNC that can occur early; lentigines usually acquire their typical intensity and distribution during the peripubertal period. They typically in volve the centrofacial area, including the vermilion border of the lips, and the conjunctiva, especially the lacrimal caruncle and the conjunctival semilunar fold; intraoral pigmented spots have also been reported. In contrast to age- related skin lesions, CNC- associated lentigines tend to fade after the fourth decade of life, but may be detectable as late as the eighth decade.
The next very common skin manifestation in CNC is a lesion known as blue nevus, which is infrequent in the general population. Blue nevi can be seen as small (usually <5 mm), blue to black- coloured marks with a circular or star- shaped appearance. Their distribution is variable; most often they occur on the face, trunk, and limbs, and less frequently on the hands or feet.
An interesting subtype of blue nevus, which is exceedingly rare as a sporadic lesion in the general population but is sometimes seen in patients with CNC, is the epithelioid blue nevus. Epithelioid blue nevus usually presents with intensive pigmentation and poorly circumscribed proliferative regions containing two cell types: heavily pigmented globular and fusiform cells; and lightly pigmented, polygonal spindle melanocytes with a single prominent nucleolus. In contrast to blue nevi, epithelioid blue nevi display no dermal fibrosis. After comprehensive comparative analysis and based on the fact the epithelioid blue nevi have also been reported in patients with none of the other features of CNC, epithelioid blue nevi are not considered pathognomonic for CNC but simply associated with the disease.
Blue nevi and lentigines in CNC are often accompanied by café- au- lait spots, which are otherwise rarely present as an isolated skin manifestation of CNC. Like lentigines, café- au- lait spots can be present at birth. In general, café- au- lait spots in CNC are less in tensely pigmented than those seen in McCune– Albright syndrome and they are more similar to those seen in the neurofibromatosis syndromes.
The third most common skin manifestation of CNC— cutaneous myxoma— is reported in between 30% and 55% of the studied patients. Cutaneous myxomas rarely exceed 1 cm in diameter and often affect the eyelids, ears, and nipples, but may also be seen on other areas of the face, ears, trunk, and perineum. They usually appear as asymptomatic, sessile, small, opalescent, or dark pink papules and large, finger- like, pedunculated lesions. They are typically diagnosed early in life, most often during the teenage years (mean age, 18 years). In the majority of patients (>70%) cutaneous myxomas show multiple appearance and a tendency to recur. The frequency of myxoma may be underestimated because clinical diagnosis may be uncertain at times; hence, histological examination is strongly recommended when in doubt. Histopathologically, myxomas are characterized by a location in the dermis or, occasionally, more superficially in the subcutaneous tissues, sharp circumscription (sometimes encapsulation), relative hypocellularity with abundant myxoid stroma, prominent capillaries, lobulation (larger lesions), and occasional presence of an epithelial component. It is estimated that approximately 80% of CNC patients with life- threatening cardiac myxoma present with cutaneous myxoma earlier in life; therefore, cutaneous myxoma can serve as good marker for the disease with high prognostic significance.
Other CNC- related skin abnormalities include melanocytic and atypical nevi, and the so- called Spitz nevus. Occasionally, depigmented lesions can be present at birth or, more often, develop in early childhood. These manifestations, although usually not considered specific, may be suggestive for the disease or may accompany other CNC signs of importance for the diagnosis.
