In October 2016, the American Association for Cancer Research (AACR) held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. In June 2017 issue of the Clinical Cancer Research, the expert panel summarised clinical and genetic aspects of the syndromes and reviewed data to make recommendations that patients with these disorders are offered cancer surveillance.
Paediatric Neurofibromatosis 1
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 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 leukaemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumour as well as substantial risks of non-invasive 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).
Tumours 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.
Paediatric Neurofibromatosis 2 and related disorders
For over 80 years, neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis were inextricably tied together under generalised neurofibromatosis. In 1987, the localization of NF1 to chromosome 17q and NF2 (bilateral vestibular schwannoma) to 22q led to a consensus conference at Bethesda, Maryland. The two main neurofibromatoses, NF1 and NF2, were formally separated. More recently, the SMARCB1 and LZTR1 genes on 22q have been confirmed as causing a subset of schwannomatosis.
Childhood presentation of NF2 (often with meningioma) in particular predicts a severe multitumour disease course.
Malignancy is rare in NF2, particularly in childhood; however, there are substantial risks from benign and low-grade central nervous system tumours necessitating MRI surveillance to optimize management.
At least annual brain MRI, including high-resolution images through the auditory meatus, and a clinical examination and auditory assessment are required from diagnosis or from around 10 to 12 years of age if asymptomatic.
Spinal imaging at baseline and every 2 to 3 years is advised with more frequent imaging if warranted on the basis of sites of tumour involvement.
The malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumour in SMARCB1. Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition.
Gorlin syndrome and rhabdoid tumour predisposition syndrome
Gorlin syndrome and rhabdoid tumour predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumours. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life.
Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including PTCH1 and SUFU.
SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended.
Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended.
Rhabdoid tumours (RTs) usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumours or extracranially, especially in the kidney, as malignant rhabdoid tumours. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type.
The outcome following a diagnosis of any of these tumours is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations.
Von Hippel–Lindau and hereditary pheochromocytoma/paraganglioma syndromes
Von Hippel–Lindau disease (vHL) is a hereditary tumour predisposition syndrome that places affected individuals at risk for multiple tumours, which are predominantly benign and generally occur in the central nervous system or abdomen.
Although the majority of tumours occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumour detection and their sequelae.
Although multiple tumour screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. The expert panel proposed a new vHL screening paradigm similar to existing approaches, with important modifications for some tumour 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 tumour spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumours.
The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes, 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 tumours early and to decrease morbidity and mortality from HPP-related tumours.
PTEN, DICER1, FH, and their associated tumour susceptibility syndromes
PTEN hamartoma tumour syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumour predisposition syndromes that include benign and malignant neoplasms affecting adults and children.
PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years.
DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumours, and multinodular goiter and thyroid carcinoma as well as brain tumours including pineoblastoma and pituitary blastoma.
Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma.
For each of these syndromes, the expert panel provided a summary of the key syndromic features, discussed the underlying genetic events, and recommended specific screening.
RASopathies and other rare genetic conditions with increased cancer risk
The expert panel summarised clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance.
For all syndromes, the panel recommended increased awareness and prompt assessment of clinical symptoms.
Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered.
Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome.
Also, the high brain tumour risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs.
For most syndromes, surveillance may be needed for non-malignant health problems.
Rednam SP, Erez A, Druker H, et al. Von Hippel–Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res; 23(12); e68–e75.
Schultz KAP, Rednam SP, Kamihara J, et al. PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res; 23(12); e76–e82.
Villani A, Greer M-L C, Kalish JM, et al. Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk. Clin Cancer Res; 23(12); e83–e90.