Nevus Anemicus As an Additional Diagnostic Marker of Neurofibromatosis Type 1 in Childhood

Abstract

Diagnosis of neurofibromatosis type 1 (NF1) can be established when at least two out of seven defined clinical findings are present. However, a definite clinical diagnosis may be challenging, especially in young children. Therefore, we tried to identify additional clinical signs suggestive of NF1. We observed that nevi anemici (NA) occur with increased frequency in NF1 patients. To establish NA as an additional diagnostic criterion for NF1 we evaluated their exact frequency in children potentially affected by NF1. During a 6-month period we examined 100 NF1 patients and documented patients' age and sex as well as presence, location, and characteristic features of NA. We were able to show that NA are present in 28% of NF1 patients, which is well above the 5% prevalence of NA in the general population. It is not known why NA appear with increased frequency in NF1. We hypothesize that an imbalance between α- and β-adrenergic receptors, resulting in increased α-adrenergic vasoconstriction might be the underlying cause of NF1-associated NA. Based on our own observations and previously published studies, we propose that NA in children with suspected NF1 might facilitate definite diagnosis and improve clinical management.

Novel and Unusual Retinal Findings in Two Patients with Neurofibromatosis Type 1

“…A choroidal nevus is a benign melanocytic tumor primarily found in white patients with a prevalence of approximately 5% in the United States and a less than 1% risk for malignant transformation [6]. Although NF1 has widely been associated with various types of cutaneous nevi, choroidal nevi have not been previously associated with this syndrome in the literature [18]. Known retinal manifestations of NF1 include retinal astrocytic hamartoma, combined hamartoma of the retina and retinal pigment epithelium, capillary hemangiomas, and choroidal nodules [3, 19].…”

Nevus anemicus and RASopathies

“…Anemic nevi are hypothesized to result from vasoconstriction induced by localized hypersensitivity of cutaneous arteriolar α1-adrenergic receptors (AR) to catecholamines. 2 , 3 , 11 Because RAS-MAPK (rat sarcoma protooncogene family mitogen-activated protein kinase) activation results from α1-AR activation and RAS itself is negatively regulated by neurofibromin, local absence of neurofibromin in smooth muscles of the skin arterioles could potentiate the effect of α1-AR–mediated vasoconstriction resulting in anemic nevi. 1 , 2 , 3 …”

“…Another hypothesis, more specific to NF1, suggests that non–RAS-related properties of neurofibromin, such as the regulation of G-protein–coupled adenylate cyclase, might interfere with α1-AR. 3 Finally, in cultured fibroblasts from NF1 patients, loss of β-AR has been shown to induce increased α-adrenergic stimulation. 12 In arterioles, this might cause anemic nevi.…”

“…In 2013, Marque et al published the frequent occurrence of anemic nevi in 77 of 151 patients clinically diagnosed with NF1, but not in 7 patients with SPRED1 (sprouty-related, EVH1 domain–containing protein 1), 2 with PTPN11 (protein tyrosine phosphatase nonreceptor type 11), and 1 with RAF1 (rapidly accelerated fibrosarcoma-1) mutations. 2 In a later study in 100 genetically confirmed NF1 patients, anemic nevi were found in 28 children with NF1, 3 much higher than the estimated 1%-5% in the general population. 2 Anemic nevi were suggested as an additional diagnostic marker of NF1, facilitating differentiation from other genodermatoses with café au lait macules (CALMs) and lentigines.…”

“… 2 Anemic nevi were suggested as an additional diagnostic marker of NF1, facilitating differentiation from other genodermatoses with café au lait macules (CALMs) and lentigines. 1 , 2 , 3 Anemic nevi are congenital pale macules or patches, which become more prominent by warming or rubbing of the skin and disappear with diascopy or wood lamp examination. 1 , 2 …”