A Novel Variant in the <i>TP53</i> Gene Causing Li–Fraumeni Syndrome
Dimitrios T. Papadimitriou,
Constantine A. Stratakis,
Antonis Kattamis,
Stavros Glentis,
Constantine Dimitrakakis,
George P. Spyridis,
Panagiotis Christopoulos,
George Mastorakos,
Nikolaos F. Vlahos,
Nicoletta Iacovidou
Affiliations
Dimitrios T. Papadimitriou
Endocrine Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, 11528 Athens, Greece
Constantine A. Stratakis
Section on Endocrinology & Genetics, The Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20814, USA
Antonis Kattamis
Division of Pediatric Hematology and Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, 11527 Athens, Greece
Stavros Glentis
Division of Pediatric Hematology and Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, 11527 Athens, Greece
Constantine Dimitrakakis
First Department of Obstetrics and Gynecology, Alexandra University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece
Li–Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline pathogenic variants in the tumor protein p53 (TP53) gene and elevated risk of a broad range of early-onset malignancies. Patients with LFS are at risk of a second and third primary tumor. A 15-month-old girl consulted for clitoromegaly and pubic hair. Adrenal ultrasound detected a large left adrenal tumor. Left total adrenalectomy confirmed adrenocortical carcinoma. Family history revealed multiple highly malignant neoplasms at an early age across five generations, and a genetic dominant trait seemed probable. Whole-genome sequencing was performed. Multiple members of the family were found positive for a novel likely pathogenic variant (c. 892delGinsTTT, p. Glu298PhefsX48, NM_000546.6) in the TP53 gene, causing the loss of normal protein function through non-sense-mediated mRNA decay. According to the PSV1 supporting criteria and the Auto PVS1 online tool this frameshift variant: hg19/17-7577045-TC-TAAA:NM_000546.6 has a very strong, definitive clinical validity for LFS with autosomal dominant inheritance. Proper guidance resulted in timely diagnosis of a second tumor (primary osteosarcoma) in the index case and in the early detection of breast and cervical cancer in her young mother. Patients with cancer predisposition syndromes like LFS require close multidisciplinary cancer surveillance and appropriate referral to expert centers.
