TMEM127 (Transmembrane Protein 127)

RET membrane immunoreactivity also distinguished PPGLs carrying non-disrupting TMEM127 variants from variants of uncertain significance (VUS) with likely damaging effects. These results point to high RET membrane expression as a biomarker for pathogenic TMEM127 and suggest that RET IHC may also assist in interpreting the functional impact of PPGLs carrying TMEM127 VUS.

Functional imaging confirmed a contralateral adrenal lesion, raising considerations regarding oncological safety versus adrenal preservation. This case highlights the complexity of hereditary pheochromocytoma/paraganglioma syndromes and illustrates how evolving genetic testing can influence surgical decision-making.

Our study highlights the variability in PPGL-associated mutation carrier prevalence across genes and ancestries. The findings underscore potential disparities in genetic risk that may not have been fully captured by clinical cohorts.

In this review, we provide a brief up-to-date clinical overview of HPPS and describe recently proposed tumor surveillance regimens. We then detail our updated consensus pediatric-focused tumor surveillance recommendations from the 2023 AACR Childhood Cancer Predisposition Workshop.

Germline testing was performed in less than half of patients with PPGL, and 30% who underwent tested carried a pathogenic mutation, reinforcing the importance of genetics evaluation. Older age, Medicare coverage, and head and neck paragangliomas were associated with lower rates of genetic testing, presenting opportunities to improve education and equity in the management of patients with PPGL.

Genetic testing documented a germline pathogenic variant (c.410-2A>C) in the TMEM-127 gene, a rare pheochromocytoma etiology that typically presents as unilateral adrenal lesion with rare metastatic behavior. The authors underline less frequent findings described in the literature - bilaterality and metastatic behavior - and emphasize the absence of aggressive prognostic markers at initial clinical presentation.

The identification of a germline mutation in patients with apparently sporadic PPGLs could lead to an early diagnosis of multiple or more aggressive tumors, or other neoplastic syndromes, in patients. Furthermore, this information may improve the development of targeted primary and secondary prevention programs tailored to these high-risk groups.

In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, both in cases of synchronous and metachronous bilateral disease, when performed as second operation.

With the identification of frequent variations and the detection of novel variations, the findings of this study have contributed to the variant spectrum. Genetic testing conducted in family members is presented as real-life data, showcasing the implications in terms of counseling, monitoring, and treatment through case examples.

A study of the level of transcription of the genes associated with PHEO (RET, TMEM127, MAX, FGFR, MET, MERTK, BRAF, NGFR, Pi3, AKT, MTOR, KRAS, MAPK) was conducted, a statistically significant decrease in the level of transcription of the KRAS and BRAF genes and increase in the level of transcription of the TMEM127 gene in comparison with control samples have been detected. This case demonstrates the need for timely recognition of NF-1 for further appropriate patient's follow up and show the effectiveness of a multidisciplinary approach to the diagnosis and treatment of NF-1-associated catecholamine-secreting tumors.

In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

Personalized management of patients with PPGL might benefit from considering sexual and ancestral differences. Further studies with better clinically aligned cohorts from various origins are required to better dissect ancestral influences on PPGL development.