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Genetic and clinical aspects of paediatric pheochromocytomas and paragangliomas
Janaina Petenuci1, Augusto G Guimaraes1, Gustavo F C Fagundes1
1Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil.
Insights
Most pediatric pheochromocytomas and paragangliomas (PPGLs) are hereditary, often linked to VHL gene mutations. This study highlights the genetic landscape and clinical features of PPGL in Brazilian children, impacting management strategies.
Area of Science:
- Pediatric Endocrinology
- Oncology
- Human Genetics
Background:
- Paediatric pheochromocytomas and paragangliomas (PPGLs) have limited and conflicting genetic characterization.
- Understanding the genetic basis of PPGL in children is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the clinical and genetic features of paediatric pheochromocytomas and paragangliomas (PPGLs) in Brazilian children.
- To identify common genetic mutations and their correlation with clinical presentation in this pediatric cohort.
Main Methods:
- Conducted a study on 25 children diagnosed with PPGL.
- Employed Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and targeted next-generation sequencing panels for genetic analysis.
- Collected clinical data including age at diagnosis, follow-up duration, tumor type, laterality, and metastatic status.
Main Results:
- Identified germline pathogenic variants in 72% of cases: VHL (44%), SDHB (16%), SDHD (8%), and RET (4%).
- Children with VHL mutations were younger and more likely to have bilateral pheochromocytoma.
- SDHB variants were associated with abdominal paragangliomas, while SDHD variants presented with head and neck paragangliomas. Metastatic PPGL occurred in 16% of cases.
Conclusions:
- The majority of paediatric PPGLs in this cohort are hereditary and multifocal.
- VHL and other pseudohypoxic cluster 1 genes are the most frequently mutated.
- These genetic findings have significant implications for the surgical management and surveillance of children with PPGL.
Objective:
Few and conflicting reports have characterized the genetics of paediatric pheochromocytomas and paragangliomas (PPGLs). This study aimed to investigate the clinical and genetic features of Brazilian children with PPGL.
Patients And Methods:
This study included 25 children (52% girls) with PPGL. The median age at diagnosis was 15 years (4-19). The median time of follow-up was 145 months. The genetic investigation was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification and/or target next-generation sequencing panel.
Results:
Of the 25 children with PPGL, 11 (44%), 4 (16%), 2 (8%), 1 (4%) and 7 (28%) had germline VHL pathogenic variants, SDHB, SDHD, RET and negative genetic investigation, respectively. Children with germline VHL missense pathogenic variants were younger than those with SDHB or SDHD genetic defects [median (range), 12 (4-16) vs. 15.5 (14-19) years; P = .027]. Moreover, 10 of 11 cases with VHL pathogenic variants had bilateral pheochromocytoma (six asynchronous and four synchronous). All children with germline SDHB pathogenic variants presented with abdominal paraganglioma (one of them malignant). The two cases with SDHD pathogenic variants presented with head and neck paraganglioma. Among the cases without a genetic diagnosis, 6 and 2 had pheochromocytoma and paraganglioma, respectively. Furthermore, metastatic PPGL was diagnosed in four (16%) of 25 PPGL.
Conclusions:
Most of the paediatric PPGL were hereditary and multifocal. The majority of the affected genes belong to pseudohypoxic cluster 1, with VHL being the most frequently mutated. Therefore, our findings impact surgical management and surveillance of children with PPGL.
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