Von Hippel–Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Abstract

Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes (SDHA, SDHB, SDHC, SDHD, SDHA, and SDHAF2), although other genes also have been described (MAX and TMEM127). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors.

Evidence for genetic anticipation in vonHippel-Lindau syndrome

“…However, their surveillance protocol would have missed at least one patient in our cohort due to either the intervals between scans being too long or organ-specific surveillance being initiated too late. The Clinical Cancer Research (CCR) Paediatric Oncology Series recently published recommended surveillance guidelines for vHL by Rednam et al 42 based on patient data and expert opinion with an emphasis on paediatric manifestations (table 1). These CCR guidelines focus on the paediatric population with earlier surveillance and shorter time intervals 42.…”

“…The Clinical Cancer Research (CCR) Paediatric Oncology Series recently published recommended surveillance guidelines for vHL by Rednam et al 42 based on patient data and expert opinion with an emphasis on paediatric manifestations (table 1). These CCR guidelines focus on the paediatric population with earlier surveillance and shorter time intervals 42. Our observation of an earlier AOO in younger generations suggests that surveillance guidelines may need to account for generational differences in AOO.…”

“…Further studies need to be done to determine the underlying molecular mechanism for GA in vHL. Manifestations for patients in our cohort would have been identified using the vHL surveillance protocol proposed by Rednam et al 42 which initiates surveillance at an earlier age, but would not have all been identified using the more widely accepted vHL Alliance protocol (table 1). Our observation of anticipation suggests that surveillance guidelines and modelling of AOA have to take into account GA, as one cannot assume that probability of developing a manifestation in vHL is constant between generation to generation.…”

Next Generation Sequencing and Pediatric Brain Tumors: Detection of Cancer Predisposition Syndromes in Patients and Their Families

“…The benefit of such programs has been established for common CPS such as familial breast and ovarian cancer [4], hereditary colorectal cancer [5], neurofibromatosis [16,17], or multiple endocrine neoplasia [18,19]. Also, for very rare CPS such as DICER1 syndrome or hereditary paraganglioma/pheochromocytoma syndrome, surveillance recommendations exist [20][21][22] and recent data show advantages for patients with TP53 variants under screening protocols [23,24]. A benefit of screening for rare pediatric CPS is assumed but needs to be evaluated in ongoing studies [25].…”

Screening guidelines and recommendations for patients at high risk of developing endocrine cancers

“…Affected individuals carry an increased risk of developing renal cell carcinomas, retinal tumors, pheochromocytomas, tumors of the central nervous system and endocrine tumors of the pancreas. While many of these tumors are benign, PNETs develop in 10% to 17% of vHL patients and is a major cause of mortality 63 . PNETs associated with vHL are typically multifocal, low‐grade, well‐differentiated, nonfunctioning tumors with an early age of onset typically in the third decade of life 64 .…”