Genetics of von Hippel-Lindau disease

Genetic studies have identified the VHL gene located on the short arm of chromosome 3 (3p26-25). The VHL gene and its product (pVHL) function as a tumor suppressor gene through the regulation of hypoxia-inducible factor 1-alpha (HIF1α) and hypoxia-inducible factor 2-alpha (HIF2α). The VHL protein stabilizes HIF1α and HIF2α by forming a complex with elongin B and C in association with cullin-2. Together the pVHL/elongin BC/cullin-2 complex binds to HIF1α and HIF2α and aid in targeting the bound HIF molecule for ubiquitin-mediated proteosomal degradation. Under conditions of hypoxia, or when pVHL is dysfunctional because of mutation (pseudohypoxia), HIF is allowed to regulate several proteins involved in the pathways of angiogenesis and proliferation, including vascular endothelial growth factor, transforming growth factor alpha, and platelet-derived growth factor bets. Mutations in VHL lead to dysregulation and overaccumulation of HIF1α and HIF2α, causing activation of pathways for neovascularization and cellular proliferation in target tissues.

Inheritance of VHL is an autosomal dominant germline mutation resulting in a heterozygous, highly penetrant form of disease affecting 1 person in 36,000. The development of a second mutation causing deletion of the normal VHL allele leads to tumor formation in affected individuals. More than 300 different types of mutations have been described that involve the three exons of the VHL gene. Differences in the phenotype associated with VHL mutations have been identified and are thought to be related to the location and type of mutation. Clustering of certain tumor types from variations in phenotypic expression have been characterized broadly into four main groups ( Table 1 ). Type 1 describes VHL kindreds who do not develop pheochromocytomas. In type 2 families, pheochromocytomas are more common; this category may be subdivided further into three subtypes: 2a has low risk for renal cancer, 2b has a high risk for renal cancer, and 2c has pheochromocytoma only. It is unclear how these subtypes relate to forms of mutations in VHL and the resultant variety of seemingly dissimilar tumor types in an isolated number of organ systems.

Clinical features

All individuals who inherit VHL gene mutations express some form of the phenotype, although significant variation in the severity of disease can be seen even in families who share the same mutation. Earliest manifestations, particularly ocular and brain tumors, can be seen in children and infants. By age 25 years, most affected individuals have a detectable lesion. Multiorgan involvement often requires the attention and coordination of clinical care by a number of specialties.

Screening and follow-up regimens for patients who have VHL have been described. Ocular evaluation should be performed in neonates and followed annually. Neurologic, otologic, and endocrine evaluation of children should be initiated at age 8 years or earlier for any signs associated with central nervous system involvement or pheochromocytoma including tinnitus, vertigo, symptoms of loss of balance, palpitations, sweating, or frequent headaches. Abdominal imaging with ultrasound is recommended starting at age 8 years to evaluate the kidneys, adrenals, and pancreas. An MRI of the brain and spine is recommended at age 11 years. Routine CT scan imaging usually is initiated at about the age of 18 years and repeated as clinically indicated. When possible, efforts should be made to limit radiation exposure from frequent imaging studies.

Although ocular and central nervous system hemangiomas have been the most common finding and cause of morbidity for patients who have VHL, kidney cancer has been the leading cause of death. Renal lesions, found in 40% of patients who have VHL, typically are multifocal and bilateral with cystic and partly cystic lesions detected ( Fig. 1 ). Management strategies focus on preservation of renal function and limiting intervention until solid tumors reach 3 cm in diameter on imaging studies. Nephron-sparing surgery at the time of surgical intervention involves the removal of all appreciable lesions from the kidney with priority given to lesions containing solid components, although an attempt also should be made to remove more simple-appearing cystic lesions ( Fig. 2 ). Because patients are at lifetime risk for forming tumors, repeat procedures commonly are necessary and hold a greater likelihood of complications, although reasonable functional outcomes can be obtained. Minimally invasive approaches including laparoscopic and robotic partial nephrectomy for multiple tumors and percutaneous ablation procedures have been described with favorable results at experienced centers. Long-term outcomes with regard to efficacy and renal function have not been reported.

Axial abdominal CT in a patient who has VHL demonstrating the spectrum of multifocal, bilateral renal cysts and semicystic and solid renal tumors. Small cysts and enhancing neuroendocrine tumor are visible in the uncinate process of the pancreas ( circled ).

Operative images of multiple renal cysts and tumors before ( left ) and after ( right ) excision with nephron-sparing techniques to treat all visible sites of disease.

Pheochromocytomas are detected in type 2 forms of the disease and can pose a significant threat to patients if unrecognized, particularly during surgery for hemangioblastomas where there is risk of severe bleeding. Functional adrenal studies should be performed annually in all patients who have VHL, and it is recommended that meta-iodobenzylguanidine studies be performed in patients who have positive functional studies because of the possibility of extra-adrenal paragangliomas: these tumors may be multiple and reside in atypical sites including the paravesicle space ( Fig. 3 ). Surgical excision using open or laparoscopic techniques typically is performed with perioperative adrenergic blockade. Pheochromocytomas involving the adrenal gland may be resected safely using partial adrenalectomy approaches to spare a portion of the normal adrenal tissue and prevent the need for lifelong replacement steroid therapy.

Axial pelvic MRI of a female patient who has VHL demonstrating extra-adrenal right perivesical pheochromocytoma ( arrow ) at the bladder neck adjacent to the ureter.

Genetics of hereditary papillary renal carcinoma

Type 1 HPRC has been linked to an activating mutation in the c-Met oncogene on chromosome 7 (7q31). Tumors from patients who have heritable and sporadic forms of type 1 papillary renal tumors have demonstrated this defect in c-Met, which causes aberrant activity of the intracellular tyrosine kinase domain of the membrane-bound c-Met receptor, producing the cascade of activation of the hepatocyte growth factor/c-Met pathway. Germline defects in c-Met have been identified in affected individuals; these defects may be passed on in an autosomal dominant pattern with variable penetrance, requiring trisomy of chromosome 7 with duplication of the mutated parental allele.

Clinical features

HPRC was described initially in 1994 with further features of the disease discovered through screening and clinical studies of affected kindreds. Patients inheriting the mutation show a variable degree of penetrance exhibited by the formation of renal tumors that often are multifocal and bilateral. As far as has been determined, the formation of papillary renal tumors is the only phenotype associated with the mutation. Median age of survival for affected members of these families was 52 years. Tumors often were discovered incidentally by radiographic screening.

Management of patients who have HPRC includes genetic counseling and screening within families because of the often insidious nature of these occult tumors. Preferred treatment is surgical excision with nephron-sparing approaches when possible, recognizing that these tumors often are multifocal. There are data suggesting that expectant management for HPRC tumors, allowing growth up to 3 cm in diameter before resection, does not jeopardize long-term survival or risk of metastases.

Genetics of Birt-Hogg-Dubé syndrome

Linkage studies have identified and localized the BHD gene to chromosome 17 (17p12q11) with inheritance demonstrating an autosomal dominant pattern. The BHD gene codes for the folliculin protein which becomes abnormally truncated and accumulates in certain tissues of patients who have BHD gene mutations. Folliculin has been proposed to take part in regulation of the mammalian target of rapamycin pathway through recently described folliculin-interacting protein and 5′-AMP–activated protein kinase. BHD normally is found in a variety of organs including brain, parotid gland, lung, pancreas, breast, prostate, kidney, and skin. Absence of BHD mRNA in renal tumors from patients who have the syndrome supports its role as a tumor suppressor gene.

Clinical features

Before the identification of the gene, diagnosis of BHD was made on clinical findings alone. The classic triad of skin fibrofolliculomas, pulmonary cysts, and renal tumors, as characterized in original screening studies of multigenerational families, defined the phenotype. Zbar and colleagues reported on 223 screened members of 33 families with the disease, identifying 98 affected individuals with clinical findings and 13 haplotype carriers. Of the 111 persons who had genetic mutations in BHD , 14% had renal tumors, compared with 2% of the nonaffected family members. Spontaneous pneumothoraces, seen predominantly in younger family members (< 40 years), were encountered in 23% of individuals who had BHD and in 1% of nonaffected family members. Only a subset of patients were evaluated with high-resolution lung CT scans, which identified lung cysts in 83% of family members who had BHD and in 10% of nonaffected relatives. Importantly, colonic polyps, which had been reported as part of the syndrome, were evaluated and found to have a statistically similar prevalence among family members with and without BHD. A more recent study in 50 new syndromic families demonstrated cutaneous manifestations in 90% of the family members who had BHD and renal tumors in 34% of affected relatives.

Renal tumors found in BHD are not as uniform as those encountered in other HRC syndromes. Tumor histologies include chromophobe tumors, oncocytoma, clear cellcarcinoma, and hybrid oncocytic tumors composed of elements of oncocytoma and chromophobe tumors. The approximate distribution of these cancers was evaluated in 130 tumors from 30 confirmed cases: 50% were hybrid oncocytoma/chromophobe tumors, 34% were chromophobe tumors, 9% were conventional clear cellcarcinoma, 5% were oncocytoma, and 2 5 were papillary tumors. Discordant histology was identified in 80% of patients, with a majority occurring as multifocal and/or bilateral tumors. Mean age at diagnosis in this cohort was 51 years.

Although clinical series suggest that most renal tumors may occur in older patients, significant tumors have been reported in younger patients. A locally invasive oncocytic tumor has been described in a 35-year-old man who developed subsequent pulmonary metastases of similar histology, and clear cell carcinoma has been resected from a patient at age 20 years. Leter and colleagues described a 39-year-old patient who had BHD and a renal tumor of mixed histology, including clear cell components, which developed distant progression resulting in death. These examples emphasize the heterogeneity of renal tumors encountered in BHD that may belie the indolent characteristics often attributed to the oncocytomas and chromophobe renal cancers associated with the disease. Untreated local tumor growth, even for more benign histologies, can result in progression to renal insufficiency and failure. For these reasons, tumors in patients who have BHD should be evaluated closely with nephron-sparing approaches initiated when possible. Intermediate data suggest that, as in patients who have VHL and HPRC, these tumors may be observed safely up to a size of 3 cm before intervention.

Genetics of hereditary leiomyomatosis renal cell carcinoma

Genetic alteration in HLRCC has been mapped to a region on chromosome 1 (1q42.3-43) containing 10 exons encoding for FH. Germline mutations in the gene may be inherited in an autosomal dominant fashion. Phenotypic expression shows high penetrance for cutaneous leiomyomas and uterine fibromas, leading many early investigators to refer to the syndrome as “multiple cutaneous and uterine leiomyomatosis” or “multiple leiomyomatosis.” The occurrence of renal tumors among patients who have the syndrome has been estimated at 2% to 21%, a prevalence low enough to prompt some researchers to continue to differentiate between multiple leiomyomatosis and HLRCC although they represent the same disease. In the syndrome of HLRCC, loss of heterozygosity reveals the tumor suppressor function of the gene, demonstrating impaired enzymatic function of FH with resultant effects in Krebs cycle catabolism. Biallelic loss of FH in several models indicate that aberrant signaling may be mediated through HIF-dependent pathways, suggesting that mechanisms of pseudohypoxia may play a role in tumorigenesis in a similar fashion to VHL. Reports of clear cell histology with FH mutation in a patient who had HLRCC may support a common mechanism of tumorigenesis through HIF activation.

Clinical features

Clinical features of this disease are notable for uterine leiomyomas (fibroids) of significant severity for which, in a recently described series in the United States, as many as 89% of affected women underwent hysterectomy, 44% of them before the age of 30 years. Isolated cases of uterine leiomyosarcomas have been reported. (Ylisaukko 2006) Most patients who have the syndrome harbor some form of cutaneous leiomyoma, although these lesions may be subtle and difficult to identify. These features of cutaneous lesions and a striking familial history for highly symptomatic uterine fibroids are helpful for clinical screening of patients before considering genetic testing that may be impractical or unreliable.

Patients who have renal tumors may exhibit an aggressive, rapidly progressive disease with evidence of advanced stages of metastases despite small primary tumor size. The National Cancer Institute reported a series of 19 surgically managed patients who had HLRCC renal tumors; the median age was 39 years. Four of seven patients who had T1 tumors (≤ 7.0 cm) had regional lymph node involvement at the time of initial surgery, and 9 of 19 (49%) had evidence of metastases at the time of initial diagnosis. Based on these observations, careful evaluation and regular follow-up, including annual abdominal imaging studies, is required for patients who have HLRCC. Suspicious renal lesions may appear partly cystic and need more frequent imaging evaluation. Interval growth or change in character may require intervention. The role of nephron-sparing surgery has been questioned in this setting, emphasizing that any surgical approach must be undertaken with care. Preoperative positron emission tomography scans may prove beneficial when lymph node or nonlocalized disease is suspected.