The First Vietnamese Patient of LEOPARD Syndrome due to a PTPN11 Mutation: A Case Report and Review of the Literature

LEOPARD syndrome is a rare congenital anomaly that involves several organs. Patients with this syndrome develop multiple lentigines resembling a leopard’s hide. LEOPARD is an acronym of the major features constituting the syndrome including lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary valve stenosis, anomalies of genitalia, retardation of growth, and deafness. The syndrome is rare, and only 200 cases have been reported yet worldwide. We present the case of an 8-year-old female patient who visited the Ho Chi Minh City Hospital of Dermato-Venereology because of multiple brownish-black “dots” on her face and body. On examination, she also showed abnormalities in the maxillofacial bones, vertebrae, shoulders, sternum, and teeth, as well as deaf-mutism and growth retardation, which are typical of LEOPARD syndrome. Genetic analysis revealed a PTPN11 gene mutation in this case. To the best of our knowledge, this is the first case of LEOPARD syndrome reported in Vietnam.

Association of PTPN11 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors.

e21596 Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Mutations of PTPN11 (Protein Tyrosine Phosphatase, Non-receptor type11) have been reported to be associated with higher response rate and prolonged survival in advanced Renal Cell Carcinoma, Glioblastoma. The association between PTPN11 mutation and the efficacy of ICIs for melanoma is unknown. Methods: Genomic and survival data of melanoma patients administrated with ICIs were retrieved from publicly accessible data (Melanoma.Allen2015.WES.110) and the association between PTPN11 mutation and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between PTPN11 mutation with TMB was also analyzed in this public immunotherapy-treated cohort(Melanoma.Allen2015.WES.110), Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 466 patients with Skin Cutaneous Melanoma (SKCM) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and PTPN11 mutation status was further analyzed by CIBERSORT. Statistical significance was set at p = 0.05. Results: 3.6% (4/110) patients in the clinical cohort harbored PTPN11 mutation. Survival analysis in the public cohort demonstrated that PTPN11 mutation resulted in significantly longer OS (33.6 vs 8.5 months; HR, 0.16; p = 0.037) and an increasing trend on PFS without significantly difference (9.1 vs 2.8 months; HR, 0.3; P = 0.078) in melanoma patients treated with ICIs. Moreover, PTPN11 mutation is associated with higher TMB in public cohort (p = 0.01). Furthermore, the correlation analysis between immune infiltration and PTPN11 mutation status in melanoma shows that M1 macrophages increased significantly (p = 0.0014), CD8 T cells, plasma B cells and activated NK cells also show an upward trend (p = 0.17, p = 0.17 and p = 0.19) while the resting NK cells decreased significantly (p = 0.016)in melanoma patients with PTPN11 mutation. Conclusions: This study shows that PTPN11 mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages and the down regulation of resting NK cells may be a potential mechanism for the better efficacy of ICIs in patients with PTPN11 mutation.

PATH-22. COMPREHENSIVE ANALYSIS OF DIVERSE LOW-GRADE NEUROEPITHELIAL TUMORS WITH FGFR1 ALTERATIONS REVEALS A DISTINCT MOLECULAR SIGNATURE OF ROSETTE-FORMING GLIONEURONAL TUMOR

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.

LEOPARD Syndrome with PTPN11 Gene Mutation in Three Family Members Presenting with Different Phenotypes

LEOPARD syndrome (LS) is a rare autosomal dominant disorder that is characterized by multiple lentigines and various congenital anomalies. The clinical diagnosis of LS requires molecular confirmation. The most frequently reported mutations in LS patients are in the protein tyrosine phosphatase nonreceptor type 11 gene, PTPN11. Herein, we report the cases of three family members from two generations who are affected by LS and all carry the PTPN11 mutation c.836A > G (p.Tyr279Cys), identified by next-generation sequencing, while exhibiting different phenotypes.

A First Case Report of Subependymoma in PTPN11 Mutation-Associated Noonan Syndrome

Noonan syndrome (NS) is an autosomal dominant disorder in some cases caused by PTPN11 mutations. Since somatic mutations in PTPN11 are seen in several tumor types, NS which causes germline PTPN11 mutations are also increase the risk of hematologic malignancies and brain solid tumors. However, the report of brain tumors in Noonan syndrome remains rather rare. Here, we report the first case of an 11-year-old Thai boy with Noonan syndrome who presented with symptoms related to hydrocephalus secondary to subependymoma in the fourth ventricle, and PTPN11 mutation was identified in this patient.