Continuing Education Activity

Nevus anemicus is an uncommon, congenital vascular malformation resulting in hypopigmented cutaneous macules and/or patches that characteristically do not become erythematous in response to trauma, heat, or cold. Nevus anemicus typically presents as an isolated lesion with no other systemic manifestations. Nevus anemicus is attributed to the increased sensitivity of cutaneous blood vessels to catecholamines such as epinephrine (adrenaline) and norepinephrine (noradrenaline). This hypersensitivity results in permanent vasoconstriction leading to hypopigmentation. This activity reviews the evaluation and treatment of nevus anemicus and addresses the importance of an interprofessional team approach to its evaluation.

Objectives:

• Explain when to include nevus anemicus on a differential diagnosis.
• Identify conditions that should be ruled out before the diagnosis of nevus anemicus is made.
• Explain how to rule out conditions that can mimic nevus anemicus.
• Describe the need for a well-integrated, interprofessional team approach to improve care and ensure appropriate evaluation of patients with nevus anemicus.

Introduction

Nevus anemicus is an uncommon, congenital vascular malformation resulting in hypopigmented cutaneous macules and/or patches that characteristically do not create erythema in response to trauma, heat, or cold.[1][2][3][4]

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. Nevus anemicus may be associated with various genetic syndromes, which include: neurofibromatosis type 1 (NF1), tuberous sclerosis, and phakomatosis pigmentovascularis (PPV) type II to IV. All phakomatosis pigmentovascularis types are characterized by the presence of nevus flammeus (port wine stain). In additional, phakomatosis pigmentovascularis type II has Mongolian spots (congenital dermal melanocytosis), phakomatosis pigmentovascularis type III has nevus spilus, and pigmentovascularis type IV has nevus spilus and Mongolian spots. When present in neurofibromatosis type 1, nevus anemicus tends to affect younger neurofibromatosis type-1  patients compared to neurofibromatosis type-1  patients who do not have nevus anemicus (mean age ten years versus 17 years, respectively). It should be noted that the presence of nevus anemicus in neurofibromatosis type-1 patients does not increase the risk of other neurofibromatosis type-1 manifestations such as optic gliomas. Nevus anemicus is not present in Legius syndrome, which mimics neurofibromatosis type 1 by the presence of cafe au lait macules and intertriginous freckling. Other rarely reported associations with nevus anemicus include telangiectatic nevus (with abnormal vasodilation) and Becker nevus.

Epidemiology

The prevalence of nevus anemicus in dermatology research control groups has been estimated to be 1% to 2%. Its prevalence may be underestimated due to underrecognition of its subtle clinical presentation, especially in lighter skin types. Nevus anemicus has a slight female preponderance.

Pathophysiology

Nevus anemicus is attributed to the increased sensitivity of cutaneous blood vessels to catecholamines such as epinephrine (adrenaline) and norepinephrine (noradrenaline). This hypersensitivity results in permanent vasoconstriction leading to hypopigmentation. Nevus anemicus has also been described as a "pharmacologic nevus" due to this catecholamine sensitivity. It has been speculated that nevus anemicus is a mosaic disorder resulting from post-zygotic mutations. Interestingly, nevus anemicus has been reported to be resistant to dermatophyte infections such as Trichophyton rubrum, which was postulated to be due to the reduced blood flow and lower temperature of the lesional skin. Nevus anemicus may also be spared during generalized contact dermatitis. This phenomenon may be explained by the lack of expression of endothelial E-selectin and epidermal intercellular adhesion molecule-1 (ICAM-1) and HLA-DR within nevus anemicus skin, which interferes with the recruitment of circulating T lymphocytes that cause contact dermatitis.[5][6][7]

Histopathology

Skin biopsy of a nevus anemicus lesion will show normal findings including an uninvolved epidermis with normal melanocyte number and distribution. There have been reports of nonspecific findings such as a mononuclear cell perivascular infiltrate in the dermis. Although biopsy of nevus anemicus lesions in nondiagnostic, it may be helpful in ruling out other lesions on the leukoderma differential diagnosis. Note that vitiligo shows absent melanocytes and melanin granules in well-established lesions, while the border of expanding lesions shows a decreased number of melanocytes and melanin.

History and Physical

Nevus anemicus presents as congenital hypopigmented patches with a well-defined border. They are asymptomatic and typically seen on the upper trunk, although they have also reported on the face and extremities. The distribution of hair, formation of sweat, and skin sensation are unaffected by nevus anemicus. Lesions have an average diameter of 5 cm to 10 cm but may be large enough to span significant portions of the trunk and are thus called "giant nevus anemicus" in such instances. Lesions may have islands of sparing of normal skin within the lesion or satellite hypopigmented macules around the lesion. Other lesional morphologies include linear lesions or coalescing macules resembling a cluster of grapes.

The history and physical exam are paramount in the diagnosis of nevus anemicus since there are no characteristic histopathologic findings. The onset of the lesion is also important since nevus anemicus is a congenital lesion often present at birth while other hypopigmented or depigmented lesions such as vitiligo often develop later in life. Nevus anemicus lesional skin characteristically does not create reactive erythema in response to heat, cold, or trauma. This can be examined 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 can be performed by pressing a glass slide on the border of the lesion, which will cause the lesion border to blend with the normal surrounding skin 

Evaluation

Use of a Wood's lamp which is an ultraviolet light with a wavelength of 365 nm is helpful in diagnosis. 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, showing normal skin and thus ruling out other hypopigmented or depigmented lesions such as vitiligo. Electron microscopy of nevus anemicus shows normal findings, while nevus depigmentosus has 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, which would show the characteristic "spaghetti and meatballs" appearance of Malassezia furfur hyphae and spores respectively.

Treatment / Management

No treatment is required for nevus anemicus. Cosmetic camouflage makeups may be helpful, especially for lesions affecting the face.[8][9]

Differential Diagnosis

• Hypochromic nevi

• Nevus depigmentosus

• Vitiligo

Pearls and Other Issues

The diagnosis of nevus anemicus requires practitioners to rule out other conditions on the leukoderma differential diagnosis. These includes but is 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). Vitiligo is characterized by well-demarcated depigmented macules and patches with irregular borders which may have a surrounding rim of hyperpigmentation or erythema, along with white hairs within the lesion. Nevus depigmentosus presents as hypopigmented patches within the first three years of life but will not show the characteristic lack of redness in response to trauma, heat, or cold which is 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. The latter two lesions do not have the congenital onset seen in nevus anemicus.

Enhancing Healthcare Team Outcomes

The diagnosis of nevus anemicus is not simple. Healthcare workers including the primary care provider and nurse practitioner should refer patients with skin lesions to the dermatologist. The diagnosis of nevus anemicus requires practitioners to rule out other conditions on the leukoderma differential diagnosis.  Once nevus anemicus is diagnosed, no treatment is required. Cosmetic camouflage makeups may be helpful, especially for lesions affecting the face.