Background/objectives: Schimmelpenning-Feuerstein-Mims syndrome (SFMS) is a rare genodermatosis from the group of epidermal nevus syndromes with a wide range of clinical manifestations, including linear nevus sebaceous, ophthalmological disorders, cardiovascular abnormalities, nervous system and musculoskeletal system lesions. Benign and malignant neoplasms, precocious puberty, lymphedema and malformations of the lymphatic system may also be present. The main cause of the syndrome are postzygotic mutations in the RAS pathway, namely in the HRAS, KRAS , and NRAS genes. The aim of our work was to analyze previously described and genetically confirmed clinical cases of SFMS in order to reveal genotype-phenotype correlations. Methods: A systematic literature review (SLR) was conducted in several databases, including PubMed and ResearchGate to search for clinical cases of SFMS with genetic testing data from 1946 to 2025. The criterion for inclusion was considered to be the reference to SFMS or its synonyms in article titles with no limitations on language or date of publication. Also, no restrictions on patient age, ethnicity, presence/absence of photo-materials were applied. Only original articles reporting clinical case or case series with detection of postzygotic mutations in the HRAS , KRAS or NRAS genes were included. Results: Currently, 50 patients with SFMS and identified pathogenic variants in the HRAS ( n = 17), KRAS ( n = 30), or NRAS ( n = 3) genes have been described in the literature. Analyzing presented phenotypic features of genetically confirmed cases of SFMS depending on the affected gene, we found that ophthalmological and central nervous system anomalities were more common for the KRAS-mut patients ( p < 0.05). In contrast, patients with HRAS mutations were more likely to have skeletal abnormalities ( p < 0.05). Benign and malignant tumors were diagnosed with equal frequency in both genetic groups, but renal tumors were strongly associated with KRAS mutations. Conclusion: The data obtained indicates the necessity of genetic testing for all patients suspected of SFMS to determine the individual risk of comorbidities and to form a personalized plan for dynamic follow-up. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251085872 , identifier CRD420251085872.

Background/Objectives: Metastatic colorectal cancer remains a fatal disease, with a 5-year survival rate lower than 15%. The most common metastatic sites are the lungs and the liver, while skin metastases are very rare and often indicate a poor prognosis with a lower survival rate. Methods. Herein, we present the clinical case of a 62-year-old female patient with rectal cancer metastases to the skin of the anogenital and abdominal regions, diagnosed 2 years after completion of treatment of the underlying disease. Results: Histological examination of the skin lesions revealed adenocarcinoma, and expression of the same immunohistochemical markers was also found in the primary tumor and in the cutaneous metastases. However, next-generation sequencing demonstrated differences in the mutational profiles of the primary tumor and metastasis to the skin. Somatic mutations in the APC, TP53, and PTPN11 genes were revealed in primary rectal adenocarcinoma, but another pathogenic TP53 mutation and a frameshift variant in the DYNC1I1 gene were found in cutaneous metastases. The patient underwent several courses of FOLFOX6 chemotherapy in combination with bevacizumab, but the treatment was unsuccessful. An analysis of 50 clinical cases from the literature concerning various manifestations of cutaneous metastases of rectal cancer showed a median survival of 8.5 months from the time of detection of the skin lesions. Conclusions: In this regard, careful skin examination of patients with rectal cancer and timely detection of cutaneous metastases are essential steps in the follow-up of patients who have undergone treatment of the primary tumor.

Background/Objectives: Cowden syndrome (or PTEN hamartoma tumor syndrome) (CS/PHTS) belongs to a group of inherited disorders associated with the development of multiple hamartomas. The clinical presentation of patients may include dysmorphic facial features, macrocephaly, developmental delay, and multiple benign and malignant tumors of various localizations. At the same time, only thyroid cancer is thought to have an increased risk in childhood. Skin lesions in CS/PHTS occur in 90–100% of patients and include multiple tricholemmoma, papilloma, acral keratosis, pigmentation changes, as well as rarer forms like vascular malformations, fibromas, neuromas, melanoma, and basal cell carcinoma. Methods: Next-generation sequencing and Sanger sequencing were used to search for PTEN genetic variants. A histological and immunohistochemical examination of tumor biopsies and skin lesions was performed. Results: A total of 13 patients from six families with CS/PHTS, including 10 children, were described. Seven pediatric patients belonged to families with paternal transmission of the PTEN pathogenic variants, while three others were de novo cases. Atypical manifestations in CS/PHTS were diffuse large B-cell lymphoma in one adult, a renal cell carcinoma, three germ cell tumors, and a linear epidermal nevus in pediatric patients. A literature review of the identified pathogenic variants in the PTEN gene was performed, assessing their clinical significance and analyzing the traditional and modified diagnostic criteria as applied to the pediatric population. Conclusions: Taking into account the low incidence of CS/PHTS, the data presented significantly expand our current understanding of this disease and guide physicians to consider a wider range of possible malignant neoplasms in pediatric patients with CS/PHTS.

Background. Phacomatosis pigmentokeratotica (PPK) is an orphan genodermatosis from the epidermal nevus syndrome group. This disease is caused by somatic mosaicism predominantly in the HRAS gene. Pathognomonic PPK sign is combination of congenital linear nevus sebaceus of Jadassohn and speckled lentiginous nevus. Second one may debut much later. In some cases, there are signs of nervous system damages, skeletal disorders, visual impairments. Case description. Description of a patient with PPK and novel for this disease mosaic variant G469A in the BRAF gene is presented. Clinical picture included typical signs of the syndrome and immunological disorders unusual for patients with PPK. Possible genotype-phenotype correlations were analyzed based on 16 previously published observations of genetically verified PPK. Conclusion. The syndrome rarity, its course variability, and patients genetic testing features determine the difficulties in PPK diagnosis. The disease should be considered not only in terms of dermatological signs, but also regarding comorbid disorders. The dynamic follow-up should include consultations of pediatric oncologist, neurologist, ophthalmologist, endocrinologist, orthopedist, cardiologist, and immunologist.

Cancer predisposition syndromes (CPSs) account for 8.5–18% of all childhood cancer cases. Most of them are inherited in an autosomal dominant pattern; consequently, there is a 50% risk of transmission to offspring. Early detection of CPSs is crucial for choosing patient treatment strategies and for counseling in the family. This study enrolled 886 pediatric patients with hematologic and solid neoplasms from prospective and retrospective cohorts (2018–2025). Clinical exome or multigene panel sequencing was used to analyze blood DNA. Overall, 186 pathogenic/likely pathogenic (PLP) variants in cancer-associated genes were identified in 176/886 (20%) of patients, and the most frequently mutated were the NF1 (n = 35) and TP53 (n = 18) genes. Among the 186 PLP variants, 126/886 (14.2%) were causative for pediatric neoplasms, while 56/886 (6.3%) were heterozygous mutations associated with adult-onset CPSs affecting DNA repair. The highest total mutation rate was revealed in retinoblastoma (80%), peripheral nerve sheath tumors (60%), and pheochromocytoma/paraganglioma (47%), while the lowest rate was found in hematologic malignancies (4.6%) and neuroblastoma (12%). The wide range and high frequency of deleterious variants in pediatric patients, especially in those with solid tumors, highlights the importance of multigene panel sequencing for the accurate determination of CPSs.

Mosaic RASopathies are rare conditions caused by postzygotic mutations in RAS/MAPK signaling pathway genes arising during embryonic development. They are mainly characterized by a combination of epidermal nevi with extra-cutaneous manifestations. Choosing between different entities can be challenging because of their substantial clinical and genetic overlap. Our aim was to demonstrate the importance of genetic background in accurate diagnosis and further prognostic assessment of disease progression by analyzing genotype–phenotype correlations within this clinical group. The study enrolled 18 patients (10 males, 8 females) aged from 1 month to 21 years with congenital nevi of craniofacial localization and variable extracutaneous abnormalities. DNA isolated from peripheral blood lymphocytes and affected tissues (nevus, tumor) was analyzed using a targeted next-generation sequencing (NGS) panel covering RAS/MAPK pathway genes, followed by Sanger sequencing. Eight patients were diagnosed with Schimmelpenning–Feuerstein–Mims syndrome caused by postzygotic mutations in the HRAS (n=4) or KRAS (n=4) genes. Seven patients were clinically diagnosed with phacomatosis pigmentokeratotica, and mosaic mutations were identified in the HRAS (n=4), KRAS (n=2), or BRAF (n=1) genes. Two patients with similar phenotypes carried somatic mutations in the PIK3CA and FGFR2 genes, respectively, and in one case no mutation was detected in the affected skin. We compared the spectrum of extracutaneous anomalies depending on the mutation in a specific gene by combining our data with data from other clinical cases of mosaic RASopathies described in the literature. In summary, 53 cases with HRAS postzygotic mutations and 41 cases with KRAS mutations were involved in the analysis of genotype–phenotype correlations. Hypophosphatemic rickets and malignant tumors were associated with mutations in the HRAS gene, while ophthalmological, neurological, cardiovascular, and renal disorders were more common in KRAS-mutant patients. Thus, genetic testing of affected tissue is essential for accurate diagnosis of these mosaic disorders. Taking into account clinical manifestations and the identified genotype–phenotype correlations may further assist in prognosis and patient management.