Background: Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder caused by pathogenic variants in the NF1 gene. Although genotype–phenotype correlation studies are increasing, robust clinically relevant correlations have remained limited. Methods: We conducted a retrospective analysis of data obtained from a cohort of 204 Hungarian individuals, with a mean age of 16 years (age range: 1–33 years). The data were collected over 15 years. Results: Among the cohort of 204 patients, 148 subjects fulfilled ≥2 criteria established by the National Health Institute. Genetic testing was performed in 70 patients, with an 82.8% detection rate, of which 13 patients were excluded. Among the remaining 45 pathogenic variants, 17 (37.7%) frameshift, 11 (24.4%) nonsense, 8 (17.8%) splice-site, 4 (8.9%) missense mutations, and 5 (11.11%) copy number variations (CNVs) were detected. Café-au-lait macules were present in all patients (100%). Intracranial malformations were the second most common feature (55.6%), followed by Lisch nodules (35.6%), neurofibromas (33.3%), and skeletal abnormalities (31.1%). Conclusions: In our cohort, patients with splice-site variants (8/45, 17.8%) demonstrated a notably more severe phenotype compared to findings reported in other studies, with a high prevalence of plexiform neurofibromas (37.5%), intracranial findings (62.5%), skeletal abnormalities (50%), Lisch nodules (50%), and even pseudarthrosis (25%). Correlating with the literature, missense variants represented a mild phenotype, while patients with microdeletion syndrome revealed a more severe phenotype.

In the following paper, the Authors aim to describe the complex relationship between pigmentation, UV addiction and vitamin D and their evolutionary connections based on recent advances in research. It has been long suggested that prolonged UV exposure can induce addiction and a dependence-like state in some individuals, with β-endorphin released from keratinocytes in response to UV. An evolutionary benefit of UV addiction may be the promotion of vitamin D synthesis following chronic UV exposure. Vitamin D synthesis was also an evolutionary driver of the lighter skin in the Northern Hemisphere, so presumably the UV-induced addictive pleasant sensation may have once similarly facilitated the maximisation of vitamin D synthesis by increasing time spent under the sun. However, excessive UV exposure increases the risk of many skin cancers, so it is important to better understand vitamin D, pigmentation and the pleasurable effects that follow UV radiation.

Café-au-lait macules (CALMs) are common hyperpigmented macules that can present in solitary or multiple forms. Approximately 2-3% of healthy newborns are affected by café-au-lait spots; however, their multiplex appearance may indicate an underlying genetic syndrome. The authors provide a comprehensive overview of the differential diagnosis of café-au-lait macules (CALMs) and their associated conditions, including the clinical features and genetic background of each syndrome. Among the discussed conditions are RASopathies, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), Legius syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines (LEOPARD syndrome), Costello syndrome, and Watson syndrome. Furthermore, the review includes phakomatoses such as tuberous sclerosis and McCune-Albright syndrome, alongside constitutional mismatch repair deficiency syndrome (CMMRD) and other syndromes that exhibit a weaker association with CALMs. The publication emphasizes the importance of a multidisciplinary approach for patients presenting with multiple CALMs, as well as highlights the significance of early diagnosis and genetic counseling for establishing an appropriate therapeutic plan and improving prognosis.