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CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma Jennifer M. Kalish1, Leslie Doros2, Lee J. Helman3, Raoul C. Hennekam4, Roland P. Kuiper5, Saskia M. Maas6, Eamonn R. Maher7, Kim E. Nichols8, Sharon E. Plon9, Christopher C. Porter10, Surya Rednam9, Kris Ann P. Schultz11, Lisa J. States12, Gail E. Tomlinson13, Kristin Zelley14, and Todd E. Druley15 Abstract A number of genetic syndromes have been linked to increased cancer predisposition specialists. At this time, these recommenda- risk for Wilms tumor (WT), hepatoblastoma (HB), and other tions are not based on the differential risk between different embryonal tumors. Here, we outline these rare syndromes with at genetic or epigenetic causes for each syndrome, which some least a 1% risk to develop these tumors and recommend uniform European centers have implemented. This differentiated approach tumor screening recommendations for North America. Specifi- largely represents distinct practice environments between the cally, for syndromes with increased risk for WT, we recommend United States and Europe, and these guidelines are designed to renal ultrasounds every 3 months from birth (or the time of be a broad framework within which physicians and families can diagnosis) through the seventh birthday. For HB, we recommend work together to implement specific screening. Further study is screening with full abdominal ultrasound and alpha-fetoprotein expected to lead to modifications of these recommendations. Clin serum measurements every 3 months from birth (or the time of Cancer Res; 23(13); e115–e22. Ó2017 AACR. diagnosis) through the fourth birthday. We recommend that See all articles in the online-only CCR Pediatric Oncology when possible, these patients be evaluated and monitored by Series. Introduction tumors, typically Wilms tumors (WT), are reported in a number of these disorders with variable frequencies ranging from 1% to Overgrowth syndromes represent a heterogeneous group of 90%. Clinically identified malformations and syndromes account disorders that result in differing presentations based on the for almost 18% of WT (1). In addition, several syndromes have an developmental pathways and organ systems affected. Renal increased risk for hepatoblastoma (HB). Previously, screening guidelines have been largely based on those developed for Beck- with–Wiedemann syndrome (BWS) and WT1-related disorders. 1Division of Human Genetics, Children's Hospital of Philadelphia and the Depart- As part of the 2016 AACR Childhood Cancer Predisposition ment of Pediatrics at the Perelman School of Medicine, University of Pennsyl- Workshop, an international committee of geneticists, oncologists, 2 vania, Philadelphia, Pennsylvania. Cancer Genetics Clinic, Children's National radiologists, and genetic counselors reviewed and made recom- Medical Center, Washington, DC. 3Center for Cancer Research and Pediatric Oncology Branch, National Cancer Institute, Rockville, Maryland. 4Department mendations for the management of children with the syndrome- of Pediatrics, University of Amsterdam, Amsterdam, the Netherlands. 5Princess associated WT and other tumors present in these syndromes, and Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. 6Department offered recommendations for tumor screening based on current of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands. published data and clinical practice. These recommendations 7Department of Medical Genetics, University of Cambridge, and Cambridge were designed to be uniform for each tumor type being screened 8 NIHR Biomedical Research Centre, Cambridge, United Kingdom. Department of and to offer screening in cases with a 1% or greater risk when early Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. 9Depart- detection is minimally invasive and significantly improves ment of Pediatrics/Hematology-Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas. 10Department of Pediatrics, Emory Univer- outcome. sity, Atlanta, Georgia. 11Division of Cancer and Blood Disorders, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota. 12Division of Radi- Genetic Summary ology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 13Division of Pediatric Hematology-Oncology and Greehey Children's Cancer Research Beckwith–Wiedemann syndrome (BWS) is a rare overgrowth Institute, The University of Texas Health Science Center at San Antonio, San syndrome classically characterized by pre- and postnatal consti- Antonio, Texas. 14Division of Oncology, Children's Hospital of Philadelphia, tutional and organ overgrowth, macroglossia, omphalocele/ 15 Philadelphia, Pennsylvania. Division of Pediatric Hematology and Oncology, umbilical hernia, facial nevus flammeus, hemihyperplasia, and Washington University, St. Louis, Missouri. embryonal tumors (2). WT and HB are the most common tumor Corresponding Author: Jennifer M. Kalish, Children's Hospital of Philadelphia, types reported; however, additional tumors have been reported, 3501 Civic Center Boulevard, CTRB Room 3028, Philadelphia, PA 19104. Phone: including neuroblastoma, rhabdomyosarcoma, pheochromocy- 215-590-1278; Fax: 267-425-7499; E-mail: [email protected] toma, and adrenocortical carcinoma (3). Most cases of BWS doi: 10.1158/1078-0432.CCR-17-0710 are mosaic, and clinical features typically vary between patients Ó2017 American Association for Cancer Research. with rare familial forms identified. Many cases of isolated www.aacrjournals.org e115 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2017 American Association for Cancer Research. CCR PEDIATRIC ONCOLOGY SERIES hemihyperplasia (IHH) are considered a more subtle presenta- depressed nasal bridge, anteverted nares, low-set and posteriorly tion of BWS leading to a spectrum of features due to a variety of rotated ears, glabellar nevus flammeus, low anterior hairline), structural, genetic, or epigenetic abnormalities localized to chro- microcephaly, forehead hirsutism, cleft lip and palate, retinal mosome 11, termed the "11p Overgrowth Spectrum." IHH can abnormalities, flexion anomalies of upper limbs with radial head have other non-11p causes as well. Several different clinical dislocation and ulnar deviation of fingers ("BOS posture"), lower scoring systems have been presented to clarify the clinical diag- limb anomalies, structural brain anomalies, and seizures (10– nosis of BWS (2, 4). The incidence of BWS is one in 10,500 births 15). About 40% of patients die in early childhood, typically from (2), but with inclusion of the subtle cases with IHH, the incidence unexplained bradycardia, obstructive apnea, or pulmonary infec- is likely higher. BWS is caused by the dysregulation of growth tions. Hoischen noted that in those who survive past infancy, genes encoding both proteins and regulatory RNAs (H19, IGF2, distinctive facial features may fade over time (13). Females and CDKN1C) on chromosome 11p15 that are imprinted and, outnumber males approximately 3:1, with no evidence for dif- therefore, normally expressed in a parent-of-origin–specific man- ference in viability (13). ner. At least 85% of BWS cases are not inherited, and most are due Multiple studies have demonstrated the transforming capacity to epigenetic changes on chromosome 11p15, most commonly of ASXL1 mutations, suggesting ASXL1 is a tumor-suppressor gene gain of methylation at one imprinting control region, IC1 (H19/ (13, 15–19). Thus, there is an increased tumor risk in patients with IGF2:IG-DMR), or loss of methylation at a second imprinting BOS. Two patients presented with bilateral WT with confirmed control region, IC2 (KCNQ1OT1:TSS-DMR). Paternal uniparental ASXL1 mutations: one diagnosed at age 2 years and the other at isodisomy (pUPD11) for part or all of chromosome 11 (where age 6 years. In the 43 cases reported by Russell and colleagues both copies of this region of chromosome 11 are derived from the (2015), two patients developed WT and one had nephroblasto- father) can also cause BWS. More rarely, mutations on the mater- matosis leading to a renal neoplasm incidence of 7% (15). The nally derived copy of CDKN1C, paternally inherited duplications small number of reported patients with BOS and high infant of the 11p15 region, or chromosomal rearrangements cause mortality rate indicates that the true cancer risk may be higher hereditary BWS. Given the complexity of the genetics, we recom- than reported. WT screening guidelines as used for BWS have mend that any determination of recurrence risk for the parents or previously been recommended and the AACR workshop com- adults with BWS or testing of relatives be performed by a genetics mittee concurred with that recommendation (15). health care professional. Mulibrey (muscle, liver, brain, and eye) nanism is a rare, Recent data from a large cohort of European patients with BWS autosomal recessive growth disorder with prenatal onset that suggest there is a correlation between tumor risk and the genetic or includes severe growth retardation, distinct dysmorphic features, epigenetic cause of BWS, and it has been recommended that tumor constrictive pericarditis, hepatomegaly, male infertility, insulin screening should be based on the genetic or epigenetic cause (3, 5). resistance, and metabolic deficiencies (20, 21). Approximately Overall incidence of tumor risk is 5% to 10%, which represents an 130 cases