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Histopathology. A, Epidermal hyperplasia and a dense dermal population of atypical lymphocytes with focal epidermotropism. B, Epidermotropism and Pautrier microabscesses at higher power. C, CD4 immunostain highlighting most of the atypical lymphoid infiltrate. D, CD8 immunostain highlighting few reactive T-lymphocytes (hematoxylin-eosin stain; original magnification: A, 340; B, 3600; C, D, 3100).
Contexts in source publication
Context 1
... CD4:CD8 ratio was greatly increased, at least 4:1, in the atypical infiltrate. Epidermal spongiosis was absent (Fig 2). Immunohistochemical staining for CD7 demonstrated diminished staining in a subset population. ...
Context 2
... microabscesses were present. The CD4:CD8 ratio was greatly increased, at least 4:1, in the atypical infiltrate. Epidermal spongiosis was absent (Fig 2). Immunohistochemical staining for CD7 demonstrated diminished staining in a subset population. T-cell receptor gene rearrangement polymerase chain reaction was negative for clone; however, SHOC2 gene (c.4A[G, p.S2G), discovered in 2009, causes NS/LAH. 3 SHOC2 is a scaffold protein that tethers RAS, RAF-1, and protein phosphatase 1c, thereby promoting MAPK signaling. Mutations in the SHOC2 gene, as seen in NS/LAH, enhance MAPK activation. 3 NS/LAH is characterized by several similar characteristics to Noonan syndrome and other related RASopathies, ...
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Citations
... The role of Shoc2 in cancer progression has been explored as well. Even though there is not enough evidence to suggest that NSLH Shoc2 mutations cause pediatric cancers, instances of neuroblastoma and cutaneous T-cell lymphoma have been reported in patients heterozygous for the c.4A>G Shoc2 variant (5,74). Several studies have suggested that Shoc2 could be an independent prognostic marker for breast, lung, and other cancers (75) or have evaluated Shoc2's feasibility as a therapeutic target for pancreatic, lung, and colorectal tumors (76)(77)(78). ...
The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary mutations in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these mutations affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. We found that, in cells expressing the Shoc2 NSLH mutants, the AKT signaling pathway triggers the PAK activation, followed by phosphorylation and Raf-1/MEK1/2 /ERK1/2 signaling axis activation. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide evidence for the Shoc2 role as a "gatekeeper" in controlling the selection of downstream effectors within the EGFR signaling network.
The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-Regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary variants in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these variants affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. In cells expressing the Shoc2 NSLH mutants, we found that the AKT signaling pathway triggers the PAK activation, followed by phosphorylation of Raf-1/MEK1/2 and activation of the ERK1/2 signaling axis. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide additional evidence for the role of Shoc2 as a “gatekeeper” in controlling the selection of downstream effectors within the EGFR signaling network.
RASopathies are a set of clinical syndromes that have molecular and clinical overlap. Genetically, these syndromes are defined by germline pathogenic variants in RAS/MAPK pathway genes resulting in activation of this pathway. Clinically, their common molecular signature leads to comparable phenotypes, including cardiac anomalies, neurologic disorders and notably, elevated cancer risk. Cancer risk in individuals with RASopathies has been estimated from retrospective reviews and cohort studies. For example, in Costello syndrome, cancer incidence is significantly elevated over the general population, largely due to solid tumors. In some forms of Noonan syndrome, cancer risk is also elevated over the general population and is enriched for hematologic malignancies. Thus, cancer surveillance guidelines have been developed to monitor for the occurrence of such cancers in individuals with some RASopathies. These include abdominal ultrasound and urinalyses for individuals with Costello syndrome, while complete blood counts and splenic examination are recommended in Noonan syndrome. Improved cancer risk estimates and refinement of surveillance recommendations will improve the care of individuals with RASopathies.
Noonan syndrome is a common developmental disorder characterized by distinctive facial dysmorphism, short stature, congenital heart defects, pectus deformity, and developmental delay. It is related to the abnormal activation of genes involved in the RAS-MAPK signaling pathway, more than a dozen of which can be affected. However, mutations of the RRAS2 gene are rare, with only 6 different RRAS2 variants in 13 patients reported to date. In this case report, whole-exome sequencing revealed a novel heterozygous variant in the RRAS2 gene NM_012250: c.212G > A, p.(Gly71Glu). Phenotypically, our patient had typical Noonan syndrome-related clinical manifestations consistent with published reports, such as short stature, facial dysmorphism, short neck, patent foramen ovale, moderate global developmental delay, and hearing impairment. In addition, our patient also had a distal middle finger deformity and hair defect, which have not been reported in previous cases. We analyzed the clinical characteristics of all patients with Noonan syndrome caused by RRAS2 variants and reviewed the literature. This discovery expands the genetic and phenotypic spectrum of Noonan syndrome.
