Five additional Costello syndrome patients with rhabdomyosarcoma: Proposal for a tumor screening protocol

Abstract

We report five new cases of rhabdomyosarcoma (RMS) in Costello syndrome. These cases, combined with those previously reported, increase the number of solid tumors to 17 (10 RMSs, 3 neuroblastomas, 2 bladder carcinomas, 1 vestibular schwannoma, 1 epithelioma), in at least 100 known Costello syndrome patients. Despite possible ascertainment bias, and the incomplete identification of all Costello syndrome patients, the tumor frequency could be as high as 17%. This is comparable to the 7–21% frequency of solid tumors in Beckwith‐Wiedemann syndrome (BWS), and may justify tumor screening. Based on the recommendations for screening BWS patients, we propose a screening protocol consisting of ultrasound examination of the abdomen and pelvis every 3–6 months until age 8–10 years for RMS and abdominal neuroblastoma; urine catecholamine metabolite analysis every 6–12 months until age 5 years for neuroblastoma; and urinalysis for hematuria annually for bladder carcinoma after age 10 years. These recommendations may need to be modified, as new information becomes available. Potential criticism of the tumor screening protocol concerns the lack of evidence for improved outcome, and possible overestimation of the tumor risk. The ability of RMSs to occur at various sites complicates tumor screening, but 8 of the 10 RMSs in Costello syndrome patients originated from the abdomen, pelvis and urogenital area. Prior diagnosis of Costello syndrome is a prerequisite for the implementation of any screening protocol. The diagnosis of Costello syndrome should also be considered in individuals with RMS and physical findings suggestive of Costello syndrome. © 2002 Wiley‐Liss, Inc.

Growth hormone deficiency in Costello syndrome

“…The patients we report have had 3, 3.5, and 7 years of GH treatment with no evidence of neoplasia. They currently undergo regular tumor surveillance screening as recommended by Gripp et al [2002]. Monitoring of GH treatment to maintain insulin like growth factor-1 (IGF-1), a marker of GH action, within physiologic range has been suggested as a tool to minimize risk of neoplasia in this population [Pollak, 2000].…”

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

“…Abdominal and pelvic ultrasound and urine testing for catecholamine metabolites and hematuria were suggested. 48 However, a subsequent report 49 on elevated catecholamine metabolites in individuals with Costello syndrome without an identifiable tumor concluded that screening for abnormal catecholamine metabolites is not helpful. Serial abdominal and pelvic ultrasound screening for rhabdomyosarcoma and neuroblastoma was proposed every 3-6 months until age 8-10 years.…”

“…Urinalysis for hematuria was suggested annually beginning at age 10 years to screen for bladder cancer. 48 Neither of these screening approaches has yet been proven to be beneficial; however, studies are ongoing. The most important factor for early tumor detection remains parental and physician awareness of the increased cancer risk.…”

Endogenous expression of Hras G12V induces developmental defects and neoplasms with copy number imbalances of the oncogene

“…Most patients also have cardiac defects, musculoskeletal anomalies, and neurocognitive impairment (13). Subjects with CS have multiple papillomas and an increased risk of developing rhabdomyosarcomas and bladder carcinomas (14)(15)(16)(17). About 80% of individuals affected with CS have HRAS mutations encoding mutant G proteins with comparatively weak transforming activity, primarily HRAS G12S .…”