Nevus Anemicus

Etiology

Nevus anemicus typically presents as an isolated lesion with no other systemic manifestations. It is unclear if isolated nevus anemicus lesions have a genetic component. However, some genetic syndromes, such as neurofibromatosis type 1 (NF1), tuberous sclerosis, and phakomatosis pigmentovascularis types II to IV, may be linked to nevus anemicus.

All types of phakomatosis pigmentovascularis are characterized by the presence of nevus flammeus (port-wine stain). Researchers have observed nevus anemicus in close proximity to capillary abnormalities of the port-wine stain type, which are believed to be caused by somatic recombination. Phakomatosis pigmentovascularis type II includes Mongolian spots (congenital dermal melanocytosis), type III includes nevus spilus, and type IV includes both nevus spilus and Mongolian spots.

In individuals with NF1, nevus anemicus tends to appear at a younger age compared to those without it (mean age 10 versus 17). Importantly, the presence of nevus anemicus in NF1 patients does not increase the risk of other NF1-related manifestations, such as optic gliomas. Conversely, Legius syndrome, which resembles NF1 with features such as café-au-lait spots and intertriginous freckling, does not include nevus anemicus.[6][7]

Other rarely reported associations with nevus anemicus include telangiectatic nevus (characterized by abnormal vasodilation) and Becker nevus. When nevus anemicus and reticular telangiectatic vascular malformations occur together, they form nevus vascularis mixtus, also known as mixed vascular nevus. Dyke-Davidoff-Masson–type brain abnormalities (hypoplasia of the middle and large cerebral vessels leading to hemicerebral hypoplasia) have also been associated with nevus anemicus.[8][9]

Epidemiology

The prevalence of nevus anemicus in dermatology research control groups is estimated to be 1% to 2%.[10] The subtle clinical presentation of nevus anemicus, particularly in lighter skin types, often leads to underrecognition and potential underestimation of its prevalence. Nevus anemicus may be present at birth or first observed in early childhood, with no indicated ethnic predilection. Early reports suggested a higher prevalence in females, but in the context of NF1, the incidence is equal in both males and females.[11]

Pathophysiology

The increased sensitivity of cutaneous blood vessels to catecholamines such as epinephrine (adrenaline) and norepinephrine (noradrenaline) is the cause of nevus anemicus. This hypersensitivity results in permanent vasoconstriction, leading to hypopigmentation. Further explanations for the pathophysiology of nevus anemicus include the following:

• The catecholamine sensitivity has led to the description of nevus anemicus as a "pharmacologic nevus." Intralesional injections of bradykinin, acetylcholine, serotonin, nicotine, 5-hydroxytryptamine, and histamine do not induce the anticipated vasodilation or erythema in the afflicted area. Nevertheless, erythema may occur following an intradermal injection of the alpha-adrenergic blocking agent pilocarpine or an axillary sympathetic block of the affected limb. These results suggest that the most appropriate classification for nevus anemicus is a pharmacologic nevus, resulting from increased vascular sensitivity to catecholamines. This conclusion is further supported by autograft exchange transplantation studies demonstrating donor site dominance.[12] 

• Nevus anemicus is speculated to be a mosaic disorder resulting from post-zygotic mutations.

• Nevus anemicus has been reported to be resistant to dermatophyte infections, such as Trichophyton rubrum, which is postulated to be due to the reduced blood flow and lower temperature of the lesional skin.

• Generalized contact dermatitis may also spare nevus anemicus from harm. The lack of expression of endothelial E-selectin, epidermal intercellular adhesion molecule-1 (ICAM-1), and human leukocyte antigen-DR isotype (HLA-DR) within nevus anemicus skin may explain this phenomenon, as it interferes with the recruitment of circulating T lymphocytes that cause contact dermatitis.[13][8][14]

Histopathology

A skin biopsy of a nevus anemicus lesion will reveal normal findings, including an uninvolved epidermis with a normal number and distribution of melanocytes. Nonspecific findings, such as a perivascular infiltrate of mononuclear cells in the dermis, have been reported. Although a biopsy of nevus anemicus lesions is nondiagnostic, it may help rule out other lesions in the leukoderma differential diagnosis. In well-established vitiligo lesions, melanocytes and melanin granules are absent, while the border of expanding lesions shows a decreased number of melanocytes and melanin. Electron microscopy does not detect abnormalities in the vascular structure of nevus anemicus lesions.

History and Physical

Nevus anemicus presents as congenital hypopigmented patches with well-defined borders. These asymptomatic patches are typically observed on the upper trunk but have also been reported on the face and extremities. The distribution of hair, sweat formation, and skin sensation are not affected by nevus anemicus. The average diameter of lesions ranges from 5 to 10 cm, but they can span significant portions of the trunk, a condition known as "giant nevus anemicus." Lesions may feature islands of normal skin within the affected area or be surrounded by satellite hypopigmented macules. Other morphologies include linear lesions or coalescing macules resembling a cluster of grapes. A mosaic form, characterized by numerous anemic nevi, may present a reticulate or net-like pattern. 

Given the absence of characteristic histopathologic findings, history and physical examination are paramount in diagnosing nevus anemicus. The history of lesion onset is also important since nevus anemicus is a congenital lesion often present at birth. In contrast, other hypopigmented or depigmented lesions, such as vitiligo, often develop later in life.

Nevus anemicus lesional skin characteristically does not develop reactive erythema in response to heat, cold, or trauma. This can be confirmed by vigorously rubbing the lesion and surrounding skin or by applying ice or heat, which will accentuate the lesion by causing reactive erythema in the surrounding skin while the nevus anemicus lesion maintains a persistent pallor. Diascopy, performed by pressing a glass slide on the border of the lesion, will cause the lesion border to blend with the normal surrounding skin. Occasionally, other vascular anomalies, such as capillary malformations (port-wine stains), are observed in close proximity.

Evaluation

A Wood lamp, which emits UV light with a wavelength of 365 nm, is helpful in diagnosing nevus anemicus. The lamp does not accentuate the hypopigmentation of nevus anemicus but does accentuate the hypopigmentation and depigmentation seen in nevus depigmentosus and vitiligo, respectively. A skin biopsy may be performed, which may reveal normal skin, thereby ruling out other hypopigmented or depigmented lesions such as vitiligo.

Electron microscopy findings of nevus anemicus are normal, whereas nevus depigmentosus shows a normal number of melanocytes but decreased melanization with melanosome aggregation in melanocytes. If tinea versicolor is suspected, potassium hydroxide (KOH) examination of lesional skin should be performed, revealing the characteristic "spaghetti and meatballs" appearance of Malassezia furfur hyphae and spores, respectively.

The pathogenesis of naevus anemicus is well-supported by the paucity of blood vessels in the center of the lesion, which is accompanied by a compensatory flare in the surrounding skin and blending with the surrounding on contact dermoscopy, similar to diascopy. Therefore, identifying these distinctive dermoscopic characteristics is beneficial in developing an early clinical diagnosis.[1]

Treatment / Management

Nevus anemicus is typically asymptomatic and benign, requiring no treatment in most cases. The primary significance of this condition lies in differentiating it from other hypopigmented skin conditions, ensuring patients avoid unnecessary interventions. Patients should be reassured of the harmless nature of nevus anemicus. Cosmetic camouflage makeup may be helpful, especially for lesions affecting the face.[15][11](B2)

In rare cases where cosmetic treatment is desired, options are limited due to the condition's vascular nature. Laser therapy, commonly used for other skin pigmentations, is ineffective for nevus anemicus. Educating patients about the condition and providing support for any psychological distress caused by its appearance are essential aspects of management.

Differential Diagnosis

The diagnosis of nevus anemicus requires healthcare professionals to rule out other conditions in the leukoderma differential diagnosis. These include, but are not limited to, vitiligo, pityriasis alba, nevus depigmentosus, tinea versicolor, tuberous sclerosis, halo nevus, piebaldism, Hansen disease (leprosy), and physical leukodermas (mechanical, chemical, or thermal). Achromic nevus, postinflammatory hypopigmentation, progressive macular hypomelanosis, and scarring can also be mistaken for nevus anemicus.

Diascopy, which involves applying pressure to the lesion and the adjacent unaffected skin with a glass slide, can differentiate nevus anemicus from other pale lesions. In contrast to true depigmenting disorders, a Wood lamp examination does not accentuate nevus anemicus and may render the lesion inapparent. The lesion remains unaffected by the application of friction, cold, or heat. Therefore, scratching a line across both the lesion and the adjacent skin will induce erythema in the normal skin but not within the nevus anemicus lesion.

Vitiligo is characterized by well-demarcated depigmented macules and patches with irregular borders. These areas may have a surrounding rim of hyperpigmentation or erythema and may also include white hairs within the lesion.

Nevus depigmentosus presents as hypopigmented patches within the first 3 years of life but does not exhibit the characteristic lack of redness in response to trauma, heat, or cold seen in nevus anemicus.

Pityriasis alba is most often diagnosed in patients with associated atopic dermatitis, while tinea versicolor presents as hypopigmented macules after increased episodes of diaphoresis. Unlike nevus anemicus, the last 2 lesions do not have a congenital onset.

Prognosis

The prognosis for nevus anemicus is excellent, as it is a benign and typically asymptomatic condition. The appearance of nevus anemicus remains stable throughout life, with no documented progression to malignancy or other serious skin disorders. While the hypopigmented patches may persist indefinitely, they do not cause discomfort or functional impairment. 

Complications

Patients with nevus anemicus do not experience systemic complications or health risks associated with the lesion. However, the presence of nevus anemicus in a child with multiple café-au-lait macules should raise suspicion of NF1. The prevalence of nevus anemicus in NF1 is approximately 50%, as evidenced by 2 prospective studies.[11][10]