Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

Abstract

Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multisystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (<1%) of certain specific individual malignancies (e.g., rhabdomyosarcoma). Tumors do contribute to both morbidity and mortality, especially later in life. A single whole-body MRI should be considered at transition to adulthood to assist in determining approaches to long-term follow-up. Clin Cancer Res; 23(12); e46–e53. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

“…Of note, maternal imprinting with silencing of the maternal allele occurs for SDHD and SDHAF2, and thus, only mutations inherited from the father will cause disease [10,11]. Some of the genetic syndromes associated with PPGL can be diagnosed based on clinical criteria [Multiple Endocrine Neoplasia type 2 (MEN2), Von Hippel Lindau syndrome (VHL), Neurofibromatosis type 1 (NF1), Multiple Endocrine Neoplasia type (MEN1) and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)], see Table 1 [12][13][14][15][16][17][18], and recommendations for the surveillance of healthy carriers of pathogenic variants in these syndromes are already published [19][20][21][22][23][24][25][26][27][28][29][30][31], Table 2. Surveillance recommendations were lacking at the initiation of this work for genes discovered from year 2000 and onwards: SDHA, SDHB, SHDC, SDHD, SDHAF2 (together abbreviated SDHx), as well as TMEM127, and MAX [10,[32][33][34][35][36][37][38].…”

Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk

“…The group of RASopathies are described in detail below (1)(2)(3). Among these are neurofibromatosis type 1 (NF1); cancer surveillance in persons with NF1 is discussed in the CCR Pediatric Oncology Series article by Evans and colleagues (4).…”

Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions

“…The risk is particularly high for juvenile myelomonocytic leukemia (JMML), a disease inextricably linked with RAS activation, as mutations in RAS pathway genes (somatic or germline) can be found in at least 90% of cases (25). NF1 is caused by mutations in the NF1 gene and associated with a high risk of solid tumors, including brain tumors, peripheral nerve sheath tumors, and rhabdomyosarcoma (8). Although less frequently encountered, patients with NF1 have a greater than 200-fold increase in the risk for JMML, as well as increased risk of ALL and AML (26).…”

“…There are currently no guidelines for individuals with CBL syndrome. Recommendations from the AACR Pediatric Cancer Working Group for surveillance for solid tumors in children with NF1 are addressed in a companion article (8), which is part of this CCR Pediatric Oncology Series.…”

“…For a more comprehensive description of the leukemia-predisposing conditions, the readers are referred to Table 1 and several excellent recent reviews (2-7), some of which describe management suggestions for affected children (3) and adults (7). For recommendations regarding surveillance for solid tumors in those syndromes in which leukemia occurs among a spectrum of other cancers, see other articles in this CCR Pediatric Oncology Series (8)(9)(10)(11).…”