Genetics & Genomics

Renal Cell Cancer Syndromes: Identification and Management of Patients and Families at Increased Risk

Melissa Paquin

Tracy Fasolino

hereditary renal cell cancer syndromes, mutation, autosomal dominant, genetics
CJON 2020, 24(4), 356-359. DOI: 10.1188/20.CJON.356-359

There are many inherited renal cell cancer syndromes that increase an individual’s risk of developing renal cell cancer. The age of onset for these renal cell cancer syndromes ranges from infancy to age 65 years. Clinical manifestations vary widely, and multiple body systems can be involved and present unique challenges to the healthcare team. With the advancement of genetic panels, clinicians can screen individuals with known hereditary syndromes for genetic mutations. This article offers clinically relevant information specific to various major renal cell cancer syndromes.


  • Most renal cell cancer syndromes are autosomal dominant and increase an individual’s risk of developing renal cell cancer and other malignancies. 
  • A wide range of clinical manifestations include benign and malignant histology. 
  • Heightened surveillance and preemptive management of individuals with known renal cell cancer syndromes can improve outcomes and quality of life. 

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    Individuals with inherited renal cell cancer syndromes develop kidney cancer at an earlier age with notable features of heterogeneous, multifocal, and bilateral tumors. Several of the syndromes have renal cell cancer as a primary feature, including von Hippel-Lindau syndrome and Birt-Hogg-Dubé syndrome, whereas others, such as Lynch syndrome and Cowden syndrome, have renal cell cancer as a secondary feature. Most hereditary renal cell cancer syndromes are autosomal dominant, meaning that only one copy of the mutated gene is needed to be present to express the disease. The mutated gene predisposes affected individuals to tumor development, often with early-onset malignancy (da Costa et al., 2017). Children of parents with autosomal dominant diseases have a 50% chance of inheriting the syndrome. Each hereditary renal cell cancer syndrome manifests with different clinical symptoms and is correlated with varying risks of developing renal cell cancer. This article presents clinically relevant information on hereditary renal cell cancer syndromes associated with renal cell cancer, with a focus on the incidence, background, and clinical implications (see Table 1).

    Hereditary Renal Cell Cancer Syndromes

    von Hippel-Lindau Syndrome

    von Hippel-Lindau syndrome is the most common hereditary renal cell cancer syndrome. It is characterized by visceral cysts and benign tumors that have the potential to become malignant. Individuals with von Hippel-Lindau syndrome have a 40% chance of developing renal cell cancer (Gupta et al., 2017). However, the loss of VHL gene function alone is not enough for patients to develop renal cell cancer. Other gene mutations in conjunction with VHL, including BAP1, PBRM1, JARID1C, SETD2, and KDM6A, have been found in patients with renal cell cancer, indicating that multiple gene mutations are involved with renal cell cancer development (Gossage et al., 2014). SDHB and TMEM127 alterations have been linked to VHL mutations, but their connection to renal cell cancer is unclear (Gupta et al., 2017). Additional research is necessary to determine the exact relationship among SDHB, TMEM127, VHL, and renal cell cancer.

    Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer

    Lynch syndrome, synonymous with hereditary nonpolyposis colorectal cancer, is a condition that predisposes individuals to an increased risk of colorectal cancer, endometrial cancer, upper tract urothelial cancers, and other types of cancers (Lynch et al., 2015). A number of germline mutations are associated with Lynch syndrome, specifically in the mismatch repair genes. These genes are responsible for correcting mismatched nucleotides when DNA is copied in preparation for cell division. Germline mutations in the MLH1, MSH2, MSH6, and PMS2 genes (members of the MMR gene family) are the most common cause of Lynch syndrome (Ziada-Bouchaar et al., 2017). In addition, deletions in the EPCAM gene, a gene that codes for a cell adhesion protein, can result in silencing of the MSH2 gene, which can lead to EPCAM-associated Lynch syndrome.

    Tuberous Sclerosis Complex

    Tuberous sclerosis complex is a rare, multisystem disease characterized by multiple benign tumors in the brain, spinal cord, kidneys, heart, and other areas because of a mutation in the tumor suppression gene TSC1 or TSC2. Each of these genes codes for proteins involved in cell proliferation. Typically, individuals with tuberous sclerosis complex present with benign renal tumors (Leech et al., 2015). However, when both copies of the gene are mutated, an individual has a greater chance of developing malignant renal tumors.

    Birt-Hogg-Dubé Syndrome

    Birt-Hogg-Dubé syndrome is an extremely rare, complex disorder characterized by deletion of the folliculin gene (FCLN) (Centini et al., 2018). The FLCN gene transports instructions to produce folliculin, a protein whose precise function is not known but that seems to interact with proteins involved in cell growth, energy production, and metabolism. As a tumor suppressor gene, FLCN aids in apoptosis, but mutations predispose individuals to cancer development.

    Hereditary Leiomyomatosis and Renal Cell Cancer

    Hereditary leiomyomatosis and renal cell cancer, also known as Reed syndrome, is characterized by the presence of one or more of the following: cutaneous leiomyomas (average age of occurrence is 25 years); uterine leiomyomas, or fibroids (average age of occurrence is 30 years); and renal cell cancer (National Cancer Institute, 2020). The pattern of renal cell cancer in hereditary leiomyomatosis and renal cell cancer differs from other inherited renal cell cancer syndromes in that the tumors tend to be solid, unilateral, and more aggressive (Skala et al., 2018). Hereditary leiomyomatosis and renal cell cancer is caused by a germline mutation in the FH gene, which codes for an enzyme that catalyzes the conversion of fumarate into L-malate during the Krebs cycle (Arenas Valencia et al., 2017). Fumarase, or fumarate hydratase, allows the cells to use oxygen and generate energy. Excesses of fumarate may interfere with cellular oxygen levels, yielding chronic hypoxia that can lead to tumor formation and the tendency to develop leiomyomas and renal cell cancer.

    Cowden Syndrome

    Cowden syndrome is a relatively rare condition that predisposes individuals to developing renal tumors and is characterized by multiple noncancerous growths (called hamartomas) at various sites. Nearly all patients with Cowden syndrome will present with benign growths on the skin, on the mouth, and along the inner lining of the gastrointestinal tract by the end of their 20s (Eng, 2016). Mutations in four genes, PTEN, SDHB, SDHD, and KLLN, have been identified in people with Cowden syndrome. Of interest is the tumor suppressor gene PTEN, which codes for a protein involved in cell proliferation (Breuksch et al., 2018). In addition, SDHB and KLLN have been found to contribute to Cowden syndrome even in the absence of a PTEN mutation. However, individuals with a KLLN mutation have a higher risk of developing renal cell cancer compared to individuals with a SDHB mutation.

    Implications for Nurses

    Hereditary renal cell cancer syndromes account for about 5% of all kidney cancers, although this number is probably underestimated (Kallinikas et al., 2017). The number of families identified with hereditary conditions leading to renal cell cancer continues to increase as germline genetic testing is being used more frequently. Renal cell cancer can either be a major or a minor feature of the cancer susceptibility syndrome. Most renal cell cancer is sporadic, but it can be related to defined hereditary renal syndromes or less common gene mutations. In fact, mutations in the MET, MITF, and SDH genes also have a strong association with an increased risk of renal cell cancer.

    Early age of onset, unusual or pathognomonic pathology, and multiple tumors in a patient with renal cell cancer raise concern for hereditary renal cell cancer syndromes. Accurate, ongoing, and complete assessment of family history is the first step in identifying individuals who may be at risk for hereditary renal cell cancer syndromes. Nurses can inquire about the type of kidney cancer as well as the presence of other indicators of hereditary risk, particularly dermatologic and other unusual findings. Families with unusual histories should be referred for further evaluation and possible genetic testing by a credentialed genetics professional.

    The identification of known mutation carriers enables the implementation of aggressive and often complex surveillance in those likely to benefit and prevents unnecessary aggressive surveillance in those who do not have an inherited risk. The complexity of screening for those with hereditary risk requires regular coordination. Surveillance and prevention recommendations should be reviewed annually by genetics professionals to verify that they are still current and evidence based.

    Known carriers may have concerns and dilemmas about reproduction and the possibility of passing a mutation to offspring. These individuals often require ongoing psychosocial support to manage the consequences of their genetic predisposition. Oncology nurses can offer support to these individuals and their families and refer them to resources (see Figure 1).


    Management of individuals with hereditary renal syndromes requires accurate assessment of patients’ personal and family history, referral for genetic evaluation and testing, and implementation of complex surveillance plans to ultimately decrease the morbidity and mortality associated with these syndromes. Oncology nurses play an integral role in supporting these patients and families as they manage the complexities of their diagnoses and ongoing care.

    About the Author(s)

    Melissa Paquin, BS, MS, is a doctoral candidate and Tracy Fasolino, PhD, FNP-BC, ACHPN, is an associate professor, both in the School of Nursing at Clemson University in South Carolina. The authors take full responsibility for this content and did not receive honoraria or disclose any relevant financial relationships. Paquin can be reached at, with copy to



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