A Novel Variant in the TP53 Gene Causing Li-Fraumeni Syndrome - Case Report

Sep 28, 2026

Li–Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer disorder linked to germline pathogenic variants in the TP53 gene and increased risk of early-onset malignancies. This case describes a 15-month-old girl presenting with clitoromegaly and pubic hair, in whom adrenal imaging identified a large left tumor and adrenalectomy confirmed adrenocortical carcinoma. Family history prompted whole-genome sequencing, revealing a novel likely pathogenic TP53 frameshift variant segregating across five generations. Variant assessment supported strong clinical validity for autosomal dominant LFS. Guided surveillance enabled timely identification of a second tumor (primary osteosarcoma) and early detection of breast and cervical cancer in her mother, underscoring the need for multidisciplinary monitoring and referral to expert centers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Abstract

1. Introduction

2. Case Report

2.1. Presentation

children Case Report A Novel Variant in the TP53 Gene Causing Li–Fraumeni Syndrome Dimitrios T. Papadimitriou 1,2, *, Constantine A. Stratakis 3, Antonis Kattamis 4,5, Stavros Glentis 4,5, Constantine Dimitrakakis 6, George P. Spyridis 7, Panagiotis Christopoulos 8, George Mastorakos 1, Nikolaos F. Vlahos 9 and Nicoletta Iacovidou 10, * Citation: Papadimitriou, D.T.; Stratakis, C.A.; Kattamis, A.; Glentis, S.; Dimitrakakis, C.; Spyridis, G.P.; Christopoulos, P.; Mastorakos, G.; Vlahos, N.F.; Iacovidou, N. A Novel Variant in the TP53 Gene Causing Li–Fraumeni Syndrome. Children 2023, 10, 1150. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/children10071150](10.3390/children10071150) Academic Editor: Gianvincenzo Zuccotti Received: 4 June 2023 Revised: 26 June 2023 Accepted: 29 June 2023 Published: 30 June 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Endocrine Unit, Second Department of Obstetrics and Gynecology, Aretaieion Hospital, 11528 Athens, Greece 2 Pediatric–Adolescent Endocrinology and Diabetes, Athens Medical Center, 15125 Marousi, Greece 3 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 4 Division of Pediatric Hematology and Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, 11527 Athens, Greece 5 `Aghia Sophia' Children's Hospital ERN-Genturis Center, 11527 Athina, Greece 6 First Department of Obstetrics and Gynecology, Alexandra University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece 7 Surgical Pediatric Oncology, Mitera Children's Hospital, 15123 Marousi, Greece 8 Pediatric Gynecology Unit, Aretaieion Hospital, 11528 Athens, Greece 9 Second Department of Obstetrics and Gynecology, Aretaieion Hospital, 11528 Athens, Greece 10 Neonatal Department, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece * Correspondence: [info@pedoendo.net](info@pedoendo.net) (D.T.P.); [niakobid@med.uoa.gr](niakobid@med.uoa.gr) (N.I.) Abstract: 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. Keywords: TP53 gene; Li–Fraumeni synd

FAQs

What genetic change was identified as the cause of Li–Fraumeni syndrome in this family?

Whole-genome sequencing found a novel likely pathogenic TP53 frameshift variant: c.892delGinsTTT (p.Glu298PhefsX48; NM_000546.6).

How did the index patient present clinically, and what diagnosis was confirmed?

The index case, a 15-month-old girl, presented with clitoromegaly and pubic hair. Adrenal ultrasound detected a large left adrenal tumor, and total adrenalectomy confirmed adrenocortical carcinoma.

What impact did proper LFS guidance and surveillance have on cancer detection?

It enabled timely diagnosis of a second tumor (primary osteosarcoma) in the patient and early detection of breast and cervical cancer in her young mother.

Sep 28, 2026

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