NS04 - New-Onset Heart Murmur as Initial Presentation of Li-Fraumeni Syndrome

Introduction/Purpose: Li-Fraumeni syndrome (LFS) is a multi-cancerous predisposition syndrome with an increased risk of malignancies spanning from childhood to adulthood (1). The lifetime risk of cancer in patients with LFS is greater than 60% in males and greater than 90% in females. The majority of LFS presents as adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft tissue sarcomas (1). We present a 32-year-old female with a new-onset heart murmur and dyspnea.

Due to the diverse spectrum of tumors, LFS can present in a wide variety of ways. LFS is noted in individuals who have inherited one mutated form of TP53. TP53 is responsible for cell cycle progression, DNA repair, cellular senescence, and apoptosis. Most tumor suppressor genes, such as RB, BRCA1, and APC, become inactivated through deletions or truncated mutations. P53 is unique as it is observed to undergo missense mutations, leading to tumorigenesis (2). De novo or inherited changes in the core DNA-binding protein create an inactive, yet stable protein that accumulates with time in the tumor cells. This build-up decreases a cell’s protection against mutations (3). Patients with LFS are predisposed to the development of malignant tumors as one additional “hit” in the normal allele leads to dysfunction of the TP53 allele (4). Patients with this genetic predisposition have a 25% greater chance of developing a malignant tumor by the age of 50 when compared to the general population (5). Loss of TP53 function allows DNA to go unrepaired, thus allowing mutations to accumulate in oncogenes in higher numbers and at a higher rate.

The presenting symptoms of LFS can occur with a variety of symptoms and locations. In patients with a family history that includes a young age of diagnosis or multiple malignancies, an in-depth history with multiple generations is important to ensure early and broad screening is performed. Diagnostic criteria for LFS consist of a proband with a germline pathogenic variant in TP53. Additionally, patients with all three of the following meet the criteria for LFS: a proband with a sarcoma diagnosed before 45 years of age, a first degree relative with any cancer diagnosed before age 45, and a first or second degree relative with any cancer diagnosed before age 45 or a sarcoma diagnosed at any age (6).

Methods or Case Description: A 32-year-old woman presented to her family physician with new-onset dyspnea on exertion and lower extremity edema. A new-onset heart murmur was noted on physical examination. A subsequent echocardiogram demonstrated a mass in the right atrium with preserved left ventricular ejection fraction. This finding was followed by a cardiac MRI which demonstrated a right-sided mass that extended from the right adrenal cortex into the inferior vena cava and right atrium.

Surgery was then delayed due to a case of asymptomatic COVID-19. Upon repeat scans, the patient was deemed not to be a surgical candidate due to the progression of the mass, which had extended and now consisted of an upper abdominal retroperitoneal adenopathy with enlarged posterior mediastinal lymph nodes in the inferior chest. Subsequent biopsy confirmed the diagnosis of adrenocortical carcinoma (ACC). The patient was also noted to have signs of hirsutism due to elevated testosterone and 17 OH hydroxyprogesterone levels which were attributed to her adrenal tumor.



Subsequently, the patient began experiencing an increasing headache for which an MRI of the brain was performed. This demonstrated an extra-axial mass along the sphenoid bone which was biopsied. Five days later, the patient developed a severe headache along with nausea, vomiting, and confusion. She then experienced a seizure in the emergency department. Repeat imaging revealed a subdural hematoma and the patient underwent a craniotomy and tumor resection in the left temporal lobe. Histopathology of the brain mass was consistent with giant cell glioblastoma multiforme WHO Grade 4 IDH1 (R132H) negative, MGMT negative.



Her family history is positive for LFS in her mother. The patient’s mother was positive for TP53 mutations and presented with colon and renal cancers. Both the patient and her mother underwent genetic testing for LFS. They demonstrated heterozygosity for a TP53 (c.818G >A p.ARG273 His). The patient underwent chemotherapy and radiation treatments; however, she succumbed to the progression of the disease two years after the initial presentation.

Outcomes: LFS is a rare autosomal-dominant inherited syndrome that has an initial presentation in younger patients with a TP53 mutation. 41% of patients develop tumors by age 18 with a mean age of 25 years of age (7). Many of these patients develop adrenocortical carcinoma, as with our patient. However, it was unique in this case that the development of adrenocortical carcinoma did not present until adulthood. Mutations have been detected with high frequency in children with ACC, but literature focused on ACC in adults with TP53 mutations has not been investigated (8). This patient experienced hormonal changes secondary to the tumor, such as hirsutism. She also presented with dyspnea and a new-onset heart murmur due to the tumor's extension through the inferior vena cava and into the right atrium. The patient’s presentation of ACC in adulthood, as opposed to during childhood, demonstrates the importance of expanding literature analysis in patients with LFS to improve screening and treatment protocols.

The three most common brain tumors seen with LFS include choroid plexus carcinoma, medulloblastoma, and glioma (9). Genomic analysis has demonstrated that gliomas in patients with LFS are diffuse astrocytic neoplasms that are stratified into molecular groups due to different IDH mutations (9). However, IDH1 mutations have been noted most frequently in secondary GBMs but are typically absent in primary GBMs (10). MGMT Methylation is a DNA repair enzyme that functions to protect cells against alkylating agents that lead to G:C to A:T mutations (11). They are often found in patients with secondary GBM lesions rather than primary GBMs or low-grade gliomas (12). This patient was both IDH1 and MGMT negative, providing support for the diagnosis of a primary GBM lesion. Analysis of biomarkers is vital to determining the origin of tumors and developing treatments that target specific aspects of the tumor.

Following the diagnosis of LFS, patients should be strenuously monitored. This is important for the early detection and treatment of malignancies. Evaluations should include annual full-body MRIs, breast MRIs, brain MRIs, colonoscopies, and dermatological exams (13). MRI is used for screening due to an increased susceptibility to radiation. Additionally, therapeutic radiation treatments should be avoided due to increased sensitivity to ionizing radiation (14). Prophylactic bilateral mastectomy is an option to reduce the risks of breast cancer. It is advised that patients avoid and minimize exposures to carcinogens, tobacco, and sunlight, as each of these factors increases the risk of cumulative pathogenic variants. Patients should be educated about different signs and symptoms of cancers as well.

Conclusion: Due to an increased lifetime risk of cancer and the diverse tumors associated with this syndrome, it is challenging from a multidisciplinary standpoint. Enhancing care is best done by interprofessional approaches including genetics, oncology, radiology, surgery, and psychiatry. To improve prognosis and quality of life in patients with this disposition, a set of clear clinical guidelines and protocols is vital to tailor to the specific needs of individual cases.