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

Abstract

In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize 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 recommends 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 tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83–e90. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations

“…Malignant tumors present at various sites and at different ages, with the overall risk estimated to be ~3%, however given the wide range of site and age, no specific tumor screening guidelines are currently recommended. There have been no genotype–phenotype correlations on tumors and Sotos syndrome [Villani et al, ]. Benign tumors have been reported, though infrequently, with only two cases of teratomas being reported to date, neither of which were associated with HI [Leonard, ].…”

Costello syndrome: Clinical phenotype, genotype, and management guidelines

“…As expected for such a rare disorder, there is no evidence on which to base a screening protocol, in terms of effect on mortality and morbidity. Based on literature recommendations, physical examination plus abdominal and pelvic ultrasounds are suggested every 3 months until age 8–10 years, and annual urinalysis from age 10 (Table ; Gripp et al, ; Villani et al, ). Screening for neuroblastoma has been complicated by the demonstration of abnormal urinary catecholamines in the absence of neuroblastoma in patients with CS; as a result, this is no longer recommended (Bowron, Scott, Brewer, & Weir, ).…”

De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

“…In this study, we performed exome sequencing on children with cancer and additional features pointing toward genetic predisposition. 36 Interestingly, many syndromes, such as Weaver syndrome (MIM: 277590), 37,38 Rubinstein Taybi syndrome (MIM: 180849), 39,40 and Sotos syndrome (MIM: 117550), 41,42 caused by variants in other chromatin-remodeling genes have been described to cause both ID and a mildly increased risk of cancer. Because only two out of 17 individuals in our cohort developed cancer, and both were recruited through a childhood cancer predisposition study 36 (introducing an ascertainment bias), it is unclear whether the variants in KDM3B are causative of the cancer in these children.…”