Hereditary kidney cancer syndromes

UpToDate: Hereditary kidney cancer syndromes


Hereditary kidney cancer syndromes were originally described based upon clinical observations that defined the disease phenotype. Family studies and advances in molecular genetics have provided important insights into the molecular pathways underlying the pathogenesis of these syndromes as well as new insights into sporadic renal cell carcinoma (RCC) [1,2]. Each of these syndromes has its own molecular alteration, and these are often reflected in distinctive histologic features and clinical course. Less than 5% of all RCC cases are thought to be due to a hereditary syndrome [3].

The inherited kidney cancer syndromes are summarized and reviewed here (table 1). Other topics provide more general discussions of RCC and its management.

Polycystic kidney disease

Autosomal dominant polycystic kidney disease is a common disorder, occurring in approximately 1 in every 400 to 1000 live births. It is estimated that less than one-half of these cases are diagnosed during an individual’s lifetime, since the disease is often clinically silent.

The incidence of renal cell carcinoma (RCC) in patients with polycystic kidney disease does not appear to be increased compared with the general population [4,5]. However, the tumors are more often bilateral at presentation (12 versus 1 to 4% in sporadic RCC in the general population), multicentric (28 versus 6%), and sarcomatoid in type (33 versus 1 to 5%).

Hereditary papillary renal carcinoma

Hereditary papillary renal carcinoma (HPRC) is a familial cancer syndrome in which affected individuals are at risk for the development of type 1 papillary renal cell carcinomas (RCCs) [6].

HPRC is a highly penetrant, autosomal dominant condition. Both early and late onset forms of HPRC have been described [7,8]. HPRC is manifested primarily by the development of papillary renal tumors, which are often multifocal and bilateral. On imaging studies, the lesions are relatively hypovascular and grow slowly [9].

Genetic linkage analyses found that the HPRC gene (the MET protooncogene) is located on the long arm of chromosome 7 [10]. This gene codes for a membrane-bound receptor for hepatocyte growth factor (HGF) and has an intracellular tyrosine kinase domain. Mutations in MET constitutively activate the tyrosine kinase domain of this protein in patients with HPRC [11].

Most patients have bilateral, multifocal tumors. As such, nephron-sparing procedures such as partial nephrectomy are preferred to maintain renal function while minimizing the risk of distant metastases [12]. Patients with tumors less than 3 cm generally are managed with observation.

In patients with distant metastases or unresectable disease, agents targeting the MET pathway are being developed. As an example, a phase II multicenter study of the dual MET/vascular endothelial growth factor receptor-2 inhibitor, foretinib demonstrated a response in 5 out of 10 patients with HPRC [13].

Germline MET mutation analysis is recommended for patients with HPRC. Techniques are being developed to detect carriers of germline mutations in family members of patients with HPRC [8,10].

Kidney cancer associated with germline mutations of the tricarboxylic acid cycle

Inherited mutations involving enzymes of the tricarboxylic acid (Krebs) cycle are associated with aggressive forms of renal cell carcinoma (RCC) that have a propensity to metastasize even at a small size (<1 cm). Therefore, early surgical intervention is warranted, even for very small tumors. To date, two enzyme mutations have been characterized: fumarate hydratase, which causes hereditary leiomyomatosis and RCC, and succinate dehydrogenase, which is associated with hereditary paraganglioma and pheochromocytoma, and rarely, RCC.

Hereditary leiomyomatosis and renal cell cancer syndrome

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a syndrome in which affected family members have cutaneous and uterine leiomyomas, and/or papillary type 2 renal cell carcinomas (RCCs). This syndrome is also called the multiple cutaneous and uterine leiomyomatosis syndrome (MCUL1) or Reed’s syndrome.

Family studies have linked HLRCC to abnormalities in the fumarate hydratase (FH) gene, which is located on the long arm of chromosome 1 [14]. FH is part of the mitochondrial Krebs or tricarboxylic acid cycle. The mechanism by which alterations in FH lead to HLRCC is not completely understood, although it may involve increased cellular dependence on glycolysis and pseudohypoxia [15]. One study showed that an antioxidant response element controlled gene, the aldo-keto reductase family 1 member B10 (AKR1B10), is upregulated in FH knockdown and FH null cell lines [16]. Other experiments have found that inactivating mutations of FH appear to result in the generation of reactive oxygen species and stabilization of hypoxia-inducing-factor (HIF)-1 alpha, which is necessary for the generation of pseudohypoxia [17].

HLRCC is transmitted in an autosomal dominant fashion, and the FH gene is thought to act as a tumor suppressor gene. Germline alterations that have been identified include missense, nonsense, insertion, deletion, and splice-site mutations [18].

The most striking clinical feature of the disease is the occurrence of severely symptomatic uterine fibroids among affected women, often requiring hysterectomy at a young age due to uterine bleeding or discomfort [19]. Transformation of leiomyomas to leiomyosarcomas has been reported in rare cases [20].

Cutaneous leiomyomas are common among individuals with HLRCC. These leiomyomas typically develop on the trunk and extremities and are quite apparent and symptomatic. In a few cases, patients may have only subtle skin findings [19,21].

Renal tumors occur in 20 to 30% of patients [14,21]. These renal carcinomas tend to be aggressive, with rapid nodal and distant dissemination even if the primary tumor is relatively small and contained. As an example, in one series, one-half of the patients had metastases present at diagnosis [22].

Patients with suspected HLRCC should undergo a thorough imaging evaluation and early intervention. Complete wide excision including lymph node dissection has been recommended in patients with localized or locally advanced disease. Close follow-up is required after initial treatment. Systemic therapy has not been shown to be effective for patients with metastatic disease [23].

A multidisciplinary approach, including gynecologists, dermatologists, and genetic counselors, is required for optimal patient management.

Succinate dehydrogenase mutation

This enzyme deficiency is associated with an autosomal dominant condition called hereditary paraganglioma and pheochromocytoma. The syndrome is characterized by paragangliomas involving the head and neck region, thorax, abdomen, pelvis, and/or urinary bladder. Paragangliomas typically develop in patients in their thirties. However, rarely an aggressive variant of renal cell carcinoma is also seen with this syndrome. Succinate dehydrogenase (SDH) is comprised of four subunits (SDHA, SDHB, SDHC, and SDHD), and each subunit has been associated with cases of RCC [24]. SDH-associated RCC presents at an early age [24], although the age at diagnosis ranges from 24 to 73 years [25,26]. The histologic type of kidney cancer varies, though in most cases, pathologic analysis showed either a clear cell or chromophobe type RCC [25,26].

Testing for SDH mutations is advised in patients with early-onset kidney cancer (ie, age <45 years), bilateral or multifocal tumors, and those with a family history of pheochromocytoma or paraganglioma and kidney cancer [24].

Birt-Hogg-Dubé syndrome

Birt-Hogg-Dubé (BHD) syndrome is an inherited syndrome in which affected individuals are at risk for the development of bilateral, multifocal kidney cancer, as well as various dermatologic and pulmonary lesions [27].

BHD syndrome is caused by mutations in the folliculin (FLCN) gene (also known as the BHD gene), which is localized to the short arm of chromosome 17 [28]. Mutations in the germline of affected individuals have been identified in 90% of affected families [29]. DNA sequencing of renal tumors from patients with germline FLCN mutations has identified somatic mutations in the wild-type copy of the gene, suggesting that FLCN is a loss-of-function, tumor suppressor gene [30].

The FLCN gene may be involved in energy, metabolism, and nutrient sensing through the mammalian target of rapamycin (mTOR) pathway. The folliculin-interacting protein, FNIP1, interacts with 5′ AMP-activated protein kinase (AMPK), a key molecule for energy sensing to negatively regulate mTOR activity [31].

The penetrance of renal cancer in patients with BHD is up to 30% [32,33]. In the largest series of 124 patients with BHD syndrome, the risk of renal tumors was 27% at a mean age of 50 years [32]. However, the incidence of renal tumors may vary in different families, and BHD may be underdiagnosed in patients with variable skin findings.

The histology of renal tumors in patients with BHD syndrome varies. Tumors containing a mixed pattern of chromophobe and oncocytic renal cancer are typical, but other histologies may be present [27,32].

Dermatologic manifestations of BHD syndrome include skin lesions called fibrofolliculomas, which are benign hamartomatous tumors of hair follicles [27]. These whitish papules are most common on the nose and cheeks and typically are first observed around age 20 years.

Approximately 80% of patients with BHD have multiple pulmonary cysts that can be identified by computed tomography (CT) of the lungs [27]. Spontaneous pneumothorax may be seen in up to one-fourth of patients [34-36].

The kidney cancers observed in patients with BHD syndrome tend to be bilateral or multifocal in more than one-half of cases and are usually slow growing. Thus, the recommended management approach includes observation of tumors less than 3 cm; when surgery is recommended, all visible tumors should be removed [37]. As with hereditary papillary renal carcinoma, nephron-sparing surgery is preferred to radical nephrectomy [27,38]. Follow-up in patients undergoing nephron-sparing surgery is important given the high risk of disease recurrence in the ipsilateral kidney.

An animal model of BHD has been developed to provide a model for the evaluation of therapeutic approaches to this syndrome [39]. In this model, treatment with the mTOR inhibitor, rapamycin led to tumor shrinkage.

Tuberous sclerosis complex

Tuberous sclerosis complex (TSC, also called tuberous sclerosis) is a hereditary condition that is due to mutations in one of two interacting tumor-suppressor gene products, hamartin (TSC1) or tuberin (TSC2). The clinical manifestations include bilateral, multifocal renal lesions, which typically are angiomyolipomas.

The predominant management issue for patients with TSC is the risk of growth and bleeding from the renal angiomyolipoma. These issues are discussed separately.

Less than 5% of patients with TSC develop renal cell carcinoma (RCC) [40]. In one series, the TSC-associated RCC tumors occurred at a younger age than sporadic tumors and occurred primarily in women [41]. Most tumors displayed clear cell histology. Four of the six patients died of metastatic disease.

Von Hippel-Lindau disease and other clear cell hereditary syndromes

Von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors, including clear cell carcinoma of the kidney. The pathogenesis of VHL syndrome and the management of patients with VHL are discussed separately. Familial non-VHL clear cell renal cell carcinoma (RCC) may also be associated with chromosome 3 translocations [42]. Recently, a novel germline mutation in BAP1 gene was found to predispose to familial clear cell RCC [43].


Recognition of the clinical features that are associated with hereditary renal cell carcinoma (RCC) is the most important step in establishing the diagnosis. These initial clinical findings and the patient’s family history continue to be an effective means for identifying affected individuals and family members.

The identification of genetic risk factors in a patient or family member may be an indication for a treatment strategy that can minimize or prevent disease-related morbidity. However, one has to be careful about the potential misuse of this genetic information, the potential for causing anxiety, and the social, ethical, and potentially legal considerations involving family disclosure.

The consequences associated with genetic screening may not be fully understood. Thus, such discussions should involve a trained genetic counselor who can review any issues with patients prior to proceeding with genetic testing.

Clinical and molecular characteristics of the most common hereditary kidney cancer syndromes

Syndrome Gene/protein Chromosomal locus Potential pathway Clinical features
Hereditary papillary renal cancer c-MET 7q31 HGFR Papillary type I renal cell carcinoma
Hereditary leiomyomatosis renal cell carcinoma Fumarate hydratase 1q42 Krebs cycle/HIF1 Papillary type II renal cell carcinoma/skin carcinoma, and uterine leiomyoma
Birt-Hogg-Dube Folliculin 17p11 mTOR Chromophobe, oncocytic, hybrid, and clear cell renal cell carcinoma, fibrofolliculoma, pulmonary cysts, pneumothorax
Hereditary paraganglioma and pheochromocytoma Succinate dehydrogenase 5p15 Krebs cycle/hypoxia Clear cell, chromophobe renal cell carcinoma, pheochromocytoma, paragangliomas
Tuberous sclerosis complex (TSC) TSC1TSC2 9q3416p13 mTOR Clear cell renal cell carcinoma, angiomyolipoma
von Hippel-Lindau (VHL) VHL gene 3p25 HIF-1 Clear cell renal cell carcinoma, hemangioblastomas, retinal angiomas, pheochromocytomas, endolymphatic sac tumors of the middle ear

HGFR: hepatocyte growth factor receptor (also known as c-MET); HIF-1: hypoxia-inducible factor 1; mTOR: mammalian target of rapamycin.


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