Fatal leukodystrophy in Costello syndrome: a case report.

BACKGROUND: Costello syndrome (CS) is a rare genetic condition characterized by dysregulation of the signaling pathway, phenotypic alteration due to fetal macrosomia or growth retardation, facial abnormalities, loose skin, cardiovascular abnormalities, and a variable degree of intellectual disability. CASE PRESENTATION: We describe the case of a 20-month-old male patient with fetal macrosomia and polyhydramnios, presenting psychomotor development delay and growth limitation during the first months of life. CS was diagnosed at four months of age after detecting a variant of the HRAS gene c.35G > C (p.G12A). A clinical description of his condition was recorded throughout his life, including cardiovascular diseases, endocrine disorders, and recurrent infections. At 20 months of age, after presenting events of marked hypotonia and generalized seizures, brain magnetic resonance revealed symmetrical lesions of the infra- and supratentorial white matter in both cerebral hemispheres, which resulted in the diagnosis of cerebral leukodystrophy. The patient had a rapid and progressive deterioration that eventually led to death. CONCLUSIONS: This is the first report of a case of CS in Peru. In addition, this is a case that presented with multisystemic conditions culminating in leukodystrophy, which is a rare event according to the literature.

Epithelial-myoepithelial carcinoma ex-pleomorphic adenoma of the parotid gland: report of a rare case with immunohistochemical and genetic analyses.

Epithelial-myoepithelial carcinoma (EMCa) is a rare low-grade salivary malignancy. It is rare for EMCa to occur as the carcinomatous component of carcinoma ex-pleomorphic adenoma (PA). We examined one additional case of EMCa ex-PA, immunohistochemically and genetically. The patient was an 83-year-old female, who suffered from swelling of the right parotid region. Histologically, the tumor contained a hyalinized nodule, which displayed elastosis. The main tumor exhibited a bi-layered structure, involving inner ductal cells and clear outer myoepithelial cells. Immunostaining indicated that the inner cells were positive for epithelial membrane antigen, whereas the outer cells were positive for p40. On the genetic level, the carcinoma harbored no HRAS gene mutations, whereas fluorescence in situ hybridization (FISH) of the Pleomorphic Adenoma Gene1 showed splitting signals in the carcinomatous component. We diagnosed this case as EMCa ex-PA. It is necessary to differentiate EMCa ex-PA from myoepithelial carcinoma and clear cell carcinoma, and FISH is useful for such purposes.

Computational Exploration of Single-Nucleotide Polymorphisms in the Human hRAS Gene: Implications and Insights.

Background A group of genes called oncogenes includes the Harvey rat sarcoma virus (hRAS) gene. Along with hRAS, Kirsten rat sarcoma viral oncogene homolog (kRAS) and neuroblastoma RAS viral oncogene homolog (nRAS) genes belong to the Rat sarcoma (Ras) family of oncogenes. These three genes result in Rho guanosine triphosphate hydrolases (GTPases) as their protein product. Instructions for producing the protein hRAS, which is mainly involved in controlling cell division, are provided by the hRAS gene. The hRAS protein transfers signals from outside through a process called signal transduction. Because the hRAS protein is a GTPase, it changes the chemical guanosine-5'-triphosphate (GTP) into guanosine diphosphate (GDP). GTP and GDP molecules operate as switches to turn on and off the hRAS. This study aimed to anticipate the structure and stability of the protein resulting from missense single-nucleotide polymorphisms (SNPs) in the human hRAS genes. Methodology To investigate the possible negative effects associated with these SNPs, bioinformatic analysis is typically essential. The following tools were employed for forecasting harmful SNPs: Scale-Invariant Feature Transform (SIFT), Protein Analysis Through Evolutionary Relationships (PANTHER), non-synonymous SNP by Protein Variation Effect Analyzer (PROVEAN), and non-synonymous SNP by Single Nucleotide Polymorphism Annotation Platform (SNAP). Results The present study identified a total of 11 SNPs using the SIFT approach, which were shown to have functional significance. Only two of these 11 SNPs were determined to be tolerable, whereas nine were shown to be detrimental. Among the 11 SNPs analyzed, seven (Q61H, Q99H, K117R, A121D, A146V, R169W, R169Q) were classified as possibly damaging,and four (G13V, Q22K, Q61K, Q13V) were categorized as probably benign according to the predictions made by PANTHER tools. Therefore, the seven SNPs were identified as high-risk SNPs. Conclusions Given that SNPs have the potential to be candidates for cellular alterations brought on by mutations that are associated with cancer, this study provides vital information about how SNPs might be utilized as a diagnostic marker for cancer.

HRas and Myc synergistically induce cell cycle progression and apoptosis of murine cardiomyocytes.

Aim: Adult mammalian cardiomyocytes are incapable of significant proliferation, limiting regeneration after myocardial injury. Overexpression of the transcription factor Myc has been shown to drive proliferation in the adult mouse heart, but only when combined with Cyclin T1. As constitutive HRas activity has been shown to stabilise Cyclin T1 in vivo, we aimed to establish whether Myc and HRas could also act cooperatively to induce proliferation in adult mammalian cardiomyocytes in vivo. Methods and results: Using a genetically modified mouse model, we confirmed that constitutive HRas activity (HRas G 12 V ) increased Cyclin T1 expression. HRas G 12 V and constitutive Myc expression together co-operate to drive cell-cycle progression of adult mammalian cardiomyocytes. However, stimulation of endogenous cardiac proliferation by the ectopic expression of HRas G 12 V and Myc also induced cardiomyocyte death, while Myc and Cyclin T1 expression did not. Conclusion: Co-expression of Cyclin T1 and Myc may be a therapeutically tractable approach for cardiomyocyte neo-genesis post injury, while cell death induced by HRas G 12 V and Myc expression likely limits this option as a regenerative therapeutic target.

Woolly hair nevus caused by somatic mutation and Costello syndrome caused by germline mutation in HRAS: Consider parental mosaicism in prenatal counseling.

Germline mutations in HRAS cause Costello syndrome (CS), while mosaic mutations in HRAS show a variability of phenotypes, ranging from mild features such as keratinocytic epidermal nevus (KEN), sebaceous nevus (SN), woolly hair nevus (WHN) with KEN, to severe manifestations of CS with cutis laxa. We report two individuals. The first was a 2-year-old boy with woolly hair nevus (WHN) without any other cutaneous involvement, in whom somatic HRAS mutation (c.34G>A; p.Gly12Ser) was identified in his affected scalp and hair follicle specimens. This is the first reported WHN type 1 (no cutaneous involvement) patient caused by somatic HRAS mutation. The other individual was a 12-year-old girl with CS caused by germline HRAS mutation (c.34G>A), that manifested with coarse face, palmoplantar keratoderma, deep palmar and plantar creases, hyperpigmented patches, asymmetry and deformity of lower limbs, atopic dermatitis, as well as mental retardation. Of note, a linear hyperpigmented plaque was observed in her father's lumbosacral region. Although the father refused to provide semen and skin tissue for further examination, this reminds us of possible mosaicism in parents of individuals with germline de novo HRAS mutation and underlines the importance of parental evaluation for prenatal counseling.

Genetic analyses of a secondary poroma and trichoblastoma in a HRAS-mutated sebaceous nevus.

A sebaceous nevus is a congenital skin hamartoma caused by postzygotic HRAS or KRAS mosaic mutations. With age, affected individuals may develop secondary tumors within a sebaceous nevus. RAS mutations are harbored from the onset of sebaceous nevus, and further mutations can be expected to be required in order to explain the initiation of secondary tumors. However, genetic analyses of the secondary tumors have not been conducted. Herein, we describe the rare coexistence of a poroma and a trichoblastoma arising in a sebaceous nevus. This is the first report of an investigation of multiple genes in a secondary tumor in an SN. First, HRAS c.37G>C, which is the common mutation in sebaceous nevus, was detected in all three lesions (sebaceous nevus, poroma, and trichoblastoma). Next, to elucidate the potential second-hit mutations in the secondary poroma and trichoblastoma, we applied a panel sequencing for skin cancers that was newly developed in our institution. Our comparison of the mutational profile of 95 skin cancer-related genes in each of the three lesions newly revealed TP53 p.R158P in the poroma and NOTCH2 p.G329S in the trichoblastoma. TP53 p.R158P has been determined as a pathogenic mutation in other tumors, and NOTCH2 p.G329S was a novel mutation. We identified two novel mutations that may have contributed to the pathogenesis of the secondary tumor's development. The roles of the mutations remain unclear.

Fetal costello syndrome with neuromuscular spindles excess and p.Gly12Val HRAS mutation.

Costello syndrome (CS) is a rare multiple congenital disorder caused by activating germline mutations in HRAS gene and is characterized by coarse facial features, severe feeding difficulties, failure to thrive, mild to severe intellectual disability, severe postnatal growth retardation, cardiac abnormalities or cancer predisposition. Phenotypic spectrum associated with HRAS mutations is broad, ranging from attenuated CS phenotype to neonatal and lethal forms with limited genotype-phenotype correlations. Congenital myopathy with neuromuscular spindle excess has been rarely described in the literature. We report a new severe fetal case of CS with distal arthrogryposis due to neuromuscular spindle excess, confirmed by the detection of the p.Gly12Val mutation in HRAS gene. This case emphasizes the fact that HRAS is the only gene responsible for neuromuscular spindle excess, underlines a correlation between p.Gly12Val mutation and severe CS phenotype and points out the importance of a muscle biopsy performed according to the suitable procedure in neuromuscular disorders for any fetal arthrogryposis.