Rössler Jochen

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis for patients with high-grade and metastatic disease is still very poor, and survivors are burdened with long-lasting side effects. Therefore, more effective and less toxic therapies are needed. Surface proteins are ideal targets for antibody-based therapies, like bispecific antibodies, antibody-drug conjugates, or chimeric antigen receptor (CAR) T-cells. Specific surface targets for RMS are scarce. Here, we performed a surfaceome profiling based on differential centrifugation enrichment of surface/membrane proteins and detection by LC-MS on six fusion-positive (FP) RMS cell lines, five fusion-negative (FN) RMS cell lines, and three RMS patient-derived xenografts (PDXs). A total of 699 proteins were detected in the three RMS groups. Ranking based on expression levels and comparison to expression in normal MRC-5 fibroblasts and myoblasts, followed by statistical analysis, highlighted known RMS targets such as FGFR4, NCAM1, and CD276/B7-H3, and revealed AGRL2, JAM3, MEGF10, GPC4, CADM2, as potential targets for immunotherapies of RMS. L1CAM expression was investigated in RMS tissues, and strong L1CAM expression was observed in more than 80% of alveolar RMS tumors, making it a practicable target for antibody-based therapies of alveolar RMS.

Aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD) are the characteristic findings of Adams–Oliver syndrome (AOS). The variable clinical spectrum further includes cardiac, neurologic, renal, and ophthalmological findings. Associated genes in AOS are in the Notch and the CDC42/Rac1 signaling pathways. Both autosomal‐dominant and autosomal‐recessive inheritances have been reported, the latter with pathogenic variants in DOCK6 or EOGT . The EOGT ‐associated recessive type of AOS has been postulated to present a more favorable prognosis. We here report a 12‐year‐old girl from a refugee family of Iraq with consanguineous parents. She was born with a severe phenotype of AOS presenting a large ACC of the scalp with an underlying skull defect, which was often infected and inflamed. Afterward, additional ulceration developed. Furthermore, the girl showed microcephaly, TTLD on both hands and feet, and neurological findings: spastic paresis, epilepsy and suspicion of intellectual deficit. Molecular genetic analysis (next‐generation sequencing) revealed a novel frameshift mutation in the EOGT gene in Exon 13 in homozygous constellation: c.1013dupA p.(Asn338Lysfs*24). A biopsy within an ulceration at the scalp ACC showed a cutaneous squamous cell carcinoma (cSCC) with local invasive growth into the dura, the meninges, and the cortex. Treatment including surgical resection and focal irradiation was not curative and the girl deceased 6 months after initial diagnosis. This report on a patient with AOS and an autosomal‐recessive EOGT gene variant dying of a local aggressive cSCC at an ACC lesion shows that close monitoring of ACC is essential.