Early-Onset Melanocytic Nevi: Cutaneous, Developmental, Psychological, and Endocrine Associations

Melanocytic nevi (MN), or moles, are found in almost every child and constitute a common reason for pediatric dermatology consultations and visits. These moles can be present from birth (“congenital”) or can be “acquired.”1 Beyond the well-established risk of melanoma,2 other disorders associated with MN during infancy and early childhood remain largely unknown. For instance, the embryologic development and ectodermal origin of the skin and neural tissues, along with the more dramatic presentation of congenital melanocytic nevi (CMN) syndrome, suggest a connection between nevi and neurologic or developmental disorders;2 children with MN may experience psychological burdens, such as depression and anxiety; growth and hormonal issues, such as premature thelarche, have also been reported in patients with CMN syndrome.3 Because most studies present data in case series or small cohorts, we aimed to explore these relationships using a large dataset.This population-based cohort study used the TriNetX Network to analyze deidentified electronic health records from 80 US health care organizations and was exempt from institutional review board approval. The study included subjects diagnosed with MN (International Classification of Diseases, 10th Revision, code D22) in early childhood (<3 years old) and controls without MN diagnosis by the same age. Participants with a history of malignancy were excluded. Cohorts were 1:1 propensity-score matched using greedy nearest-neighbor method for age, sex, race, socioeconomic status, health utilization, gestational status, and congenital abnormalities. Definitions of variables are listed in Supplemental Table 3. The primary outcomes were subsequent diagnoses clinically relevant to MN within 10 years of the tracking period. Subjects were right-censored if lost to follow-up or at the end of the study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards regression model, with the Bonferroni-adjusted log-rank test P < .005 considered statistically significant. Data source, data collection, and statistical analysis are detailed in Supplemental Information.A total of 30 021 patients with MN and 2 113 232 controls were identified between January 1, 2013, and February 19, 2024. Both cohorts had 30 005 participants after matching (Table 1). Most diagnoses of MN were initially made in the outpatient settings (59.5%, Supplemental Table 4). Patients with MN did not show an overall increased risk of mortality, but had significantly higher risks of malignancies, including melanoma (HR 16.39; 95% CI 7.08–37.91) and nonmelanoma skin cancer (HR 4.25; 95% CI 2.72–6.65). Early MN diagnosis also correlated with higher risks of vitiligo, depression, anxiety, and precocious puberty, but a lower risk of eczema (Table 2).This is the first study to use a large patient database to examine the associations between early-onset MN and various associations in children.The increased risks of melanoma and nonmelanoma skin cancer such as basal cell carcinoma are supported by the literature.1 Exposure to melanocytic antigens could trigger autoimmunity and may lead to vitiligo.4 Previous studies reported that the number of nevi was lower in patients with eczema, possibly resulting from proinflammatory cytokines in atopic skin that inhibit melanocyte growth.5,6 Although no previous studies have investigated the reverse relationship, the lower incidence of eczema in the MN cohort may be because of skin immunity and genetic factors, such as upregulation of antiinflammatory markers by melanocyte genes.7We found no strong association between the presence of MN and developmental disorders, including developmental delay, autism spectrum disorder, and attention-deficit/hyperactivity disorder. However, increased risks of depression and anxiety, which children with visible skin disorders frequently struggle with,8 were noted in our MN cohort.Although specific endocrine disorders have been described in children with CMN syndrome,3 we only observed an increase in precocious puberty.In summary, beyond the risk of malignant transformation, psychological challenges in children with MN, such as low esteem and emotional problems, demand clinicians’ attention. The frequently raised concerns of developmental disorders by parents appeared to lack strong evidence of association with nevi in this study. Because stigmatization can cause significant stress and social impact, it is essential to provide accurate information about nevi. Children and families should be reassured that nevi are unique characteristics rather than abnormalities.Limitations include the validity of diagnostic coding and its limited use in nonurgent settings, lack of distinct codes to differentiate the nature and sizes of MN, and residual confounding. Further research is required to elucidate the mechanisms that underline these associations in children with early-onset MN.