Familial aggregation of small congenital nevomelanocytic nevi

Rhodes, Arthur R.; Slifman, Nancy R.; Korf, Bruce R.; Opitz, John M.; Reynolds, James F.

doi:10.1002/ajmg.1320220215

Cited by 13 publications

(4 citation statements)

References 25 publications

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“…As this is a sporadic condition and had been described in one twin of monozygotic pairs, 18,19 it was proposed 25 years ago to be due to a postzygotic mutation in utero, and therefore to represent a mosaic disorder. 20 However, reports of occasional familial cases [21][22][23] later led to the hypothesis that multiple CMN were due to paradominant inheritance with allelic loss, 24 and later still to a patchy manifestation of a polygenic trait. 25 In the interim, many variants were described in single samples of CMN from cohorts of patients, including TP53, 26 NRAS, [26][27][28][29][30] BRAF, [31][32][33][34][35] GNAQ 29 and MC1R.…”

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confidence: 99%

Does the gene matter? Genotype–phenotype and genotype–outcome associations in congenital melanocytic naevi

et al. 2019

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Summary Background Genotype–phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management. Objectives To characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype–phenotype and genotype–outcome associations. Methods We conducted a large cohort study in which we undertook MC1R genotyping from blood, and high‐sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%]. Results Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild‐type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild‐type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF‐mutant multiple CMN, however, this genotype is rare. Conclusions CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70–80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases. There has been debate about genotypic association with different sizes of CMN, and no data on genotype–outcome. What does this study add? NRAS mosaicism was found in 68%, BRAF in 7% and double wild‐type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN, but was nearly universal in projected adult size > 60 cm. BRAF is often associated with a distinct multinodular clinical/histological phenotype. Adverse outcomes did not differ between genotypes on current numbers.

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confidence: 99%

Does the gene matter? Genotype–phenotype and genotype–outcome associations in congenital melanocytic naevi

et al. 2019

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“…Another caveat in this study that must be taken into consideration is the finding of Rhodes and colleagues 26 that siblings of patients with CNN have a higher probability (12.5%) of having CNN than the general population (1.1%). Since some of the patients seen in this study were referred by relatives of patients who did have pigmented lesions of various types as their main complaints, it is possible that this may have caused some bias in this survey because of familial clustering of CNN and/or CNLN.…”

Section: Commentsmentioning

confidence: 80%

Congenital‐Nevus‐Like Nevi, Nevi Spili, and Café‐Au‐Lait Spots in Patients with Malignant Melanoma

Kopf

Levine

Rigel

et al. 1985

The Journal of Dermatologic Surgery and Oncology

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The prevalence of congenital-nevus-like nevi (CNLN) in a group of 105 adults who had malignant melanoma (MM) was compared with that in a control group of 601 adults not afflicted by MM. Total cutaneous examinations were performed on both groups. The control group presented with complaints other than pigmented lesions. In this series, 10 (9.5%) of the group with MM had clinically diagnosed CNLN 1.5 cm or larger in diameter. These CNLN were not in contiguity with the MM sites. The 9.5% prevalence of CNLN in the group with MM was significantly higher (p less than 0.005) than the 2.5% CNLN observed in the control population. None of the patients in either group had large congenital nevocytic nevi (greater than or equal to 20 cm). In addition, in the group with MM, 5 patients (4.8%) had nevi spili (NS) and 13 (12.4%) had café-au-lait spots (CLS). The prevalence rates for these two types of pigmented lesions were not significantly different from those observed in the nonmelanoma control group (2.3% for NS; 13.8% for CLS). The relative risk for developing MM is 4.1 in people with CNLN compared with those without CNLN, which indicates that these nevi may be markers for individuals prone to develop malignant melanoma.

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“…Small CMN have been reported to aggregate in families [ 46 ], and there is evidence for a similar phenomenon for larger varieties of CMN [ 11 ]. A polygenic paradominant mode of inheritance has been proposed for two cases of familial giant CMN [ 47 ].…”

Section: Familial Aggregationmentioning

confidence: 96%