A Case of Synchronous Malignancy with Novel Missense Mutation in a Child: Is This Li-Fraumeni Syndrome or a Novel Case Masquerading as Li-Fraumeni Syndrome??

Abstract

We report the case of an 11-month-old child who presented with a change in voice, increased weight, and hirsutism, who was also found to have elevated levels of serum cortisol and testosterone, showing three synchronous malignancies in the liver, left adrenal gland, and posterior mediastinum. Clinical exome sequencing report revealed germline TP53 (P177A) and MLH3 (V741P) mutations with NMYC positive neuroblastoma. At the outset, this may look like a Li-Fraumeni syndrome (LFS) with TP53 germline mutation but lacks other features to be termed as LFS or Li-Fraumeni-like syndrome. The gene mutation variant found in this case (P177A) is a novel missense mutation which has never been reported, and the MLH3 gene mutation variant V741P has not been previously associated with any of the malignancies seen in this child.

Keywords

Adrenocortical malignancy - hepatoblastoma - mismatch repair gene - neuroblastoma - synchronous malignancy

• References

• 1 Pivnick EK, Furman WL, Velagaleti GV, Jenkins JJ, Chase NA, Ribeiro RC. Simultaneous adrenocortical carcinoma and ganglioneuroblastoma in a child with Turner syndrome and germline p53 mutation. J Med Genet 1998; 35: 328-32
• 2 Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D. et al. The genetic landscape of high-risk neuroblastoma. Nat Genet 2013; 45: 279-84
• 3 Tang YJ, Yu TT, Ma J, Zhou Y, Xu M, Gao YJ. Composite adrenocortical carcinoma and neuroblastoma in an infant with a TP53 germline mutation: A case report and literature review. J Pediatr Hematol Oncol 2019; 41: 399-401
• 4 Moertel CG, Dockerty MB, Baggenstoss AH. Multiple primary malignant neoplasms. I. Introduction and presentation of data. Cancer 1961; 14: 221-30
• 5 Behjati S, Maschietto M, Williams RD, Side L, Hubank M, West R. et al. A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing. PLoS One 2014; 9: e96531
• 6 Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E. et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009; 27: e108-9
• 7 Frank TS. Hereditary cancer syndromes. Arch Pathol Lab Med 2001; 125: 85-90
• 8 Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ. et al. Beyond Li-Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009; 27: 1250-6
• 9 Courtney R, Ranganathan S. Simultaneous adrenocortical carcinoma and neuroblastoma in an infant with a novel germline p53 mutation. J Pediatr Hematol Oncol 2015; 37: 215-8
• 10 Rossbach HC, Baschinsky D, Wynn T, Obzut D, Sutcliffe M, Tebbi C. Composite adrenal anaplastic neuroblastoma and virilizing adrenocortical tumor with germline TP53 R248W mutation. Pediatr Blood Cancer 2008; 50: 681-3
• 11 Seidinger AL, Fortes FP, Mastellaro MJ, Cardinalli IA, Zambaldi LG, Aguiar SS. et al. Occurrence of neuroblastoma among TP53 p.R337H Carriers. PLoS One 2015; 10: e0140356
• 12 Porter DE, Holden ST, Steel CM, Cohen BB, Wallace MR, Reid R. A significant proportion of patients with osteosarcoma may belong to Li-Fraumeni cancer families. J Bone Joint Surg Br 1992; 74: 883-6
• 13 Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A. et al. A systematic p53 mutation library links differential functional impact to cancer mutation pattern and evolutionary conservation. Mol Cell 2018; 71: 178-90, e8
• 14 IARC TP53 Search. http://p53.iarc.fr/TP53GeneVariations.aspx. Available from: [Last accessed on 2019 Jul 18]
• 15 Liu HX, Zhou XL, Liu T, Werelius B, Lindmark G, Dahl N. et al. The role of hMLH3 in familial colorectal cancer. Cancer Res 2003; 63: 1894-9
• 16 All genes-Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM) & Dian Diagnostics. http://www.genomed.zju.edu.cn/LOVD3/gene. Available from: [Last accessed on 2019 Jul 18]
• 17 Casey DL, Kushner BH, Cheung NK, Modak S, LaQuaglia MP. et al. Local control with 21-Gy radiation therapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 2016; 96: 393-400