Blue Nevi, Familial Multiple

Description

The common blue nevus of Jadassohn-Tieche most frequently presents as a solitary blue 1- to 10-mm dome-shaped papule on the dorsal hand or foot. It is characterized by greatly elongated wavy groups of spindled dermal melanocytes that are oriented parallel to the epidermis. Cellular blue nevi resemble common blue nevi clinically but are usually larger, ranging from 1 to 3 cm in diameter, and occur primarily on the buttocks or sacrum as a solitary blue nodule (summary by Knoell et al., 1998).

Inheritance

Knoell et al. (1998) described familial multiple blue nevi, histologically shown to be of the Jadassohn-Tieche type, occurring in a dominant inheritance pattern over 4 generations, without associated abnormalities. Four females and 1 male were affected. Multiple lesions of the hand and face were illustrated. They reviewed previous reports of other cases of multiple blue nevi but found only one other report of familial occurrence. Blackford and Roberts (1991) described a family in which several blue nevi of the cellular type, numbering up to 12 per person, were present in 6 family members in 3 generations. There were no associated abnormalities and an autosomal dominant inheritance pattern was proposed.

The disorder reported by Knoell et al. (1998) appears to be distinct from blue rubber bleb nevus, or Bean syndrome (112200). Epithelioid blue nevi occur in association with multiple lentigines, atrial myxoma, or mucocutaneous myxoma in the Carney complex (160980).

Molecular Genetics

Somatic Mutations

Van Raamsdonk et al. (2009) reported frequent somatic mutations in the heterotrimeric G protein alpha-subunit (GNAQ; 600998) in blue nevi (83%) and ocular melanoma of the uvea (46%) (see 155720). The mutations occurred exclusively in codon 209 in the Ras-like domain and result in constitutive activation, turning GNAQ into a dominant-acting oncogene. Van Raamsdonk et al. (2009) concluded that their results demonstrated an alternative route to MAP kinase activation in melanocytic neoplasia, providing new opportunities for therapeutic intervention.

Van Raamsdonk et al. (2010) identified somatic mutations affecting residue Q209 of the GNA11 gene (139313) in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. Mutations in the same codon (Q209) of the paralogous GNAQ gene were found in 55% of blue nevi, 45% of primary uveal melanomas, and 22% of uveal melanoma metastases. The sample group included a total of 713 melanocytic neoplasms. Sequencing of exon 4 of both these genes, affecting residue R183, in 453 melanocytic neoplasms showed a lower prevalence of mutations: 2% of blue nevi and 4.9% of primary uveal melanomas. Mice injected with melanocytes transduced with the GNA11 Q209L mutation developed rapidly growing tumors with metastases, whereas injection with GNA11 R183C-transduced cells showed lesser potency. Western blot analysis of melanocytes transduced with GNA11 Q209L showed constitutive activation of the MAPK pathway. Although GNA11 mutations appeared to have a more potent effect on melanocytes than did GNAQ mutations, there was no difference in patient survival among those with GNA11 mutations compared to those with GNAQ mutations.