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Home > Be Healthy > Health Library > Hereditary Leiomyomatosis and Renal Cell Cancer (PDQ®): Genetics - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is characterized by the presence of one or more of the following: cutaneous leiomyomas (or leiomyomata), uterine leiomyomas (fibroids) in females, and renal cell cancer (RCC). Germline pathogenic variants in the FHgene are responsible for the susceptibility to HLRCC. FH encodes fumarate hydratase, the enzyme that catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle (Krebs cycle).
Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis. In 1973, two kindreds were described in which multiple members over three generations exhibited cutaneous leiomyomas and uterine leiomyomas and/or leiomyosarcomas inherited in an autosomal dominant pattern. That report also described a woman aged 20 years with uterine leiomyosarcoma and metastatic RCC. Subsequently, the association of cutaneous and uterine leiomyomas became known as Reed syndrome. However, the clear association of cutaneous leiomyomas and RCC was not described until 2001, when a study reported two Finnish families in whom cutaneous and uterine leiomyomas and papillary type 2 RCC cosegregated  and the name hereditary leiomyomatosis and renal cell cancer (HLRCC) was introduced.
The FHgene consists of ten exons encompassing 22.15 kb of DNA. The gene is highly conserved across species. The human FH gene is located on chromosome 1q42.3-43.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome; inheritance of a single variant FHallele predisposes the individual to develop manifestations of the disease. Inherited biallelic pathogenic variants cause autosomal recessive fumarate hydratase deficiency (FHD), a disorder characterized by rapidly progressive neonatal neurologic impairment including hypotonia, seizures, and cerebral atrophy. (Refer to the Genetically Related Disorders section of this summary for more information.)
Renal tumors that develop in individuals who inherit a germline pathogenic variant in FH typically display a loss of heterozygosity because of a second somatic FHmutation. This finding suggests that loss of function of the fumarate hydratase protein is the basis for tumor formation in HLRCC and supports a tumor suppressor function for FH.[2,3]
Various pathogenic variants in FH have been identified in families with HLRCC. Most are missense pathogenic variants, but nonsense, frameshift, and splice-site variants have been described.[2,4,5,6] Recently, whole-gene or partial deletions have been identified.
The prevalence of HLRCC is unknown. Older estimates suggested a prevalence of 1 in 200,000 individuals. However, this may be more common than previously thought: an analysis of non–population based cohorts found an FHcarrier frequency of 1 in 1,000 individuals, suggesting a larger reservoir of asymptomatic cases.
Penetrance ofFHPathogenic Variants
On the basis of the observation that most patients with HLRCC have at least one of the three major clinical manifestations, the penetrance of HLRCC in carriers of pathogenic FH variants appears to be very high. However, the estimated cumulative lifetime incidence of renal cell cancer (RCC) varies widely, with most estimates ranging from 15% to 30% in families with germline FH pathogenic variants, depending on ascertainment method and the imaging modalities used.[3,4,5,10,11,12] Based on a much higher prevalence of FH variants, the lifetime risk of kidney cancer may be significantly lower than current estimates.
No genotype -phenotype correlations have been described. Thus, no correlation has been observed between specific FH variants and the occurrence of cutaneous lesions, uterine leiomyomas, or RCC in HLRCC.
Although smaller studies have suggested the presence of different variant spectra in FHD and HLRCC,[2,4] a study that included a larger cohort of patients indicated that the variant distribution is fairly similar in these two entities. The predisposition to HLRCC versus FHD likely results from a difference in gene dosage, rather than the location of the FH variant as originally suggested.
Using bidirectional DNA sequencing methodology, pathogenic variants in FH have been detected in more than 85% of individuals with HLRCC.[4,5,13]
Genetically Related Disorders
Fumarate hydratase deficiency (fumaric aciduria, FHD)
FHD, resulting from the inheritance of biallelic pathogenic variants in FH, is an autosomal recessive inborn error of metabolism characterized by rapidly progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy. Homozygous or compound heterozygous germline pathogenic variants in FH are found in individuals with FHD.[14,15] To date, RCC has not been reported in FHD-affected individuals, possibly because most individuals with FHD survive only a few months with very few surviving to early adulthood. However, a parent (heterozygous carrier) of an individual with FHD developed cutaneous leiomyomas similar to those observed in HLRCC.
Biallelic somatic loss of FH has been identified in two early-onset sporadic uterine leiomyomas and a soft tissue sarcoma of the lower limb without other associated tumor characteristics of the heritable disease.[17,18] Few somatic FH mutations have been identified in sporadic forms of RCC.[17,19]
The mechanisms by which alterations in FH lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) are currently under investigation. Biallelic inactivation of FH has been shown to result in loss of oxidative phosphorylation and reliance on aerobic glycolysis to meet cellular energy requirements. Interruption of the Krebs cycle because of reduced or absent fumarate hydratase activity results in increased levels of intracellular fumarate. This increase inhibits the activity of hypoxia-inducible factor (HIF) prolyl hydroxylases, resulting in the accumulation of HIF-alpha.[1,2] Inactivating variants of FH also appear to result in the generation of reactive oxygen species, further contributing to the stabilization of HIF-alpha. Activation of the HIF pathway leads to a pseudohypoxic state and an upregulation of a transcriptional program contributing to aggressive tumor growth. In addition, accumulated fumarate can activate the antioxidant response pathway which enables cancer cells to survive in an environment of oxidative stress. Fumarate, an electrophile, is able to posttranslationally modify KEAP1 by succination on cysteine sulfhydryls, thereby releasing KEAP1 inhibition of NRF2. The resultant stabilization of NRF2 leads to transcriptional upregulation of antioxidant response element–controlled genes such as AKR1B10, possibly contributing to the neoplastic process.
The clinical characteristics of hereditary leiomyomatosis and renal cell cancer (HLRCC) include cutaneous leiomyomas, uterine leiomyomas (fibroids), and renal cell cancer (RCC). Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; an RCC that is typically solitary, or no renal tumors; and/or uterine leiomyomas. HLRCC is phenotypically variable; disease severity shows significant intrafamilial and interfamilial variation.[1,2,3]
Cutaneous leiomyomas present as firm papules or nodules that appear pink or reddish-brown. These lesions usually appear on the trunk and the extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 10–47 y) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature; they can also be painful. Pain is correlated with severity of cutaneous involvement. The presence of multiple cutaneous leiomyomas is associated with HLRCC until proven otherwise and should prompt a genetic workup. One series reported the presence of cutaneous leiomyomas in 22 of 48 patients (46%) with a pathogenic or likely pathogenic variant in FH. The same series demonstrated that 18 of 19 individuals (95%) with multiple leiomyomas had a pathogenic variant in FH. A solitary leiomyoma requires careful analysis of family history. (Refer to the Clinical diagnosis and Differential diagnosis sections of this summary for more information.)
The onset of uterine leiomyomas in women with HLRCC occurs at a younger age than in women in the general population. The age at diagnosis ranges from 18 to 63 years (mean age, 30 y). One series reported uterine leiomyomas in 18 of 29 women (62%) with a pathogenic or likely pathogenic variant in FH; the ages of the women ranged from 24 to 63 years. Uterine leiomyomas are usually large and numerous. Most women with HLRCC experience irregular or heavy menstruation and pelvic pain; thus, they require treatment for leiomyomas at a younger age than women in the general population. Women with HLRCC undergo hysterectomy or myomectomy for symptomatic uterine leiomyomas at a younger age (<30 y) than women in the general population (median age, 45 y).[3,5,6,7]
Renal Cell Cancers (RCCs)
The symptoms of RCC may include hematuria, lower back pain, and a palpable mass. However, a large number of individuals with RCC are asymptomatic. Furthermore, not all individuals with HLRCC present with or develop RCC. Most RCCs are unilateral and solitary; in a few individuals, they are multifocal. The exact incidence of RCC in affected individuals remains to be determined, and widely varying estimates have been provided by different groups (1%–60%).[1,3,8] The incidence appears to vary on the basis of where the study was performed, the referral patterns of individual groups, and the extent to which individuals were screened for RCC. In studies from the National Cancer Institute (NCI), RCC was identified in approximately 32% of families evaluated.[1,3] The median age at detection of RCC was 37 years, although some cases have been reported to occur as early as age 10 years. Another large series of 135 patients estimated that the lifetime risk was 20.8% by age 85 years. In contrast to other hereditary RCC syndromes, RCCs associated with HLRCC are aggressive,[12,13] with a Fuhrman nuclear grade of 3 or 4 in many cases and 9 of 13 individuals dying from metastatic disease within 5 years of diagnosis.Figure 1 depicts RCCs in a patient with HLRCC.
Figure 1. Hereditary leiomyomatosis and renal cell cancer–associated renal tumors are commonly unilateral and solitary; in a few individuals, they are multifocal. Red arrow indicates a retroperitoneal lymph node. White arrow indicates a left renal mass.
It is unclear whether women with HLRCC have a higher risk of developing uterine leiomyosarcomas than women of similar age in the general population. In the original description of HLRCC, it was reported that 2 of 11 women with uterine leiomyomas also had a uterine leiomyosarcoma, a cancer that may be clinically aggressive if not detected and treated at an early stage. To date, germline pathogenic variants in FH have been reported in six women with uterine leiomyosarcoma.[14,15] It seems that most FH pathogenic variant–positive families are not highly predisposed to uterine cancer, but a few individuals and families appear to be at high risk. In North American studies, no uterine leiomyosarcomas in HLRCC individuals or families have been reported. Therefore, the risk of uterine leiomyosarcoma in women with HLRCC is uncertain. This is a question in urgent need of a definitive answer.
Four FH-positive individuals with breast cancer, one case of bladder cancer, and one case of bilateral macronodular adrenocortical disease with Cushing syndrome have been reported. A series from the NCI found that 20 of 255 patients (7.8%) with HLRCC had adrenal nodules, some of which did not appear to be adenomas based on imaging characteristics. Because many of these lesions were fluorodeoxyglucose avid, resections were performed and all showed evidence of both micronodular and macronodular adrenal hyperplasia, suggesting that adrenal nodules could be an additional manifestation of HLRCC. It remains to be determined whether these manifestations are truly part of the HLRCC phenotype.[6,14,17] Similarly, pheochromocytomas in the adrenal glands have been described.[8,18] However, one of the largest cohorts from the United Kingdom did not report any pheochromocytomas; therefore, surveillance is not recommended until further evidence shows that they may be part of the HLRCC phenotype.
Cutaneous leiomyomas are believed to arise from the arrectores pilorum muscles attached to the hair follicles. Histologically, these are dermal tumors that spare the epidermis. Morphologically, these tumors have interlacing smooth muscle fibers interspersed with collagen fibers.
A review of the National Cancer Institute's experience with hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated uterine leiomyomas reported that most of these cases were well-circumscribed fascicular tumors with occasional cases showing increased cellularity and atypia. The hallmark feature of these cases was similar to those observed in HLRCC kidney cancer: the presence of orangeophilic, prominent nucleoli that are surrounded by a perinuclear halo. While some cases had atypical features, no cases had tumor necrosis or atypical mitosis suggestive of malignancy or leiomyosarcoma.
The renal cell cancers (RCCs) associated with HLRCC have unique histologic features, including the presence of cells with abundant amphophilic cytoplasm and large nuclei with large inclusion-like eosinophilic nucleoli. These cytologic features were attributed to type 2 papillary tumors in the original description. However, early studies reported that HLRCC is associated with a spectrum of renal tumors ranging from type 2 papillary to tubulopapillary to collecting duct carcinoma.[4,5] RCC associated with HLRCC may constitute a new renal pathologic entity or a unique HLRCC type. Two studies reported the morphologic spectrum of RCC in HLRCC syndrome after histologic examinations of 40 RCCs from 38 patients with germline FHpathogenic variants and HLRCC family histories.[5,6] A number of histologic patterns were seen, including cystic, tubulopapillary, tubulo-solid, and often mixed patterns.[5,6]
Diagnosis and Testing
Genetic testing for the FHgene is clinically available and performed by Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. FH currently is the only gene known to be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). Most patients with HLRCC have a germline pathogenic variant in FH.
Because the genetic analysis of HLRCC is complex, any interpretation of a variant of unknown significance result needs to be performed with consultation by clinical cancer geneticists, ideally in a center that has significant experience with this disease.
There is no current consensus on the diagnostic criteria for HLRCC.
Some experts suggest that a clinical dermatologic diagnosis of HLRCC requires one of the following:
More recent comprehensive criteria for diagnosis have been suggested and are often used by experts in the field. Suggested criteria include dermatologic manifestations as above or a combination of two of the following manifestations:
Collecting duct RCC before age 40 years has been suggested as an additional criterion. Patients with seemingly sporadic tumors who have a negative family history and a single, histologically confirmed cutaneous leiomyoma may test positive for the presence of a germline FH pathogenic variant. Although the percentage of germline pathogenic variants in these patient populations is unknown, many centers may refer patients with a single cutaneous leiomyoma for genetic counseling and testing, regardless of family history.
Cutaneous leiomyomas are rare. The detection of multiple lesions is specific to HLRCC. Because leiomyomas are clinically similar to various cutaneous lesions, histologic diagnosis is required to objectively prove the nature of the lesion.
Uterine leiomyoma is the most common benign pelvic tumor in women in the general population. Most uterine leiomyomas are sporadic and nonsyndromic.
Diagnostic clues of HLRCC may rely on the presence of several phenotypic features in different organs (cutaneous, uterine, and renal). One or more of these characteristic features may be present in the patient or in one or more of their affected biologic relatives.
Although familial RCCs are associated with rather specific renal pathology, the rarity of these syndromes results in few pathologists gaining sufficient experience to recognize their histologic features.
The differential diagnoses may include other rare familial RCC syndromes with specific renal pathology, including:
Genetic testing is used clinically for diagnostic confirmation of at-risk individuals. It is recommended that both pretest and posttest genetic counseling be offered to persons contemplating germline pathogenic variant testing. Laboratories offering genetic testing for use in clinical decision making must be certified under CLIA laws.
Genetic testing for a germline FH pathogenic variant is indicated in all individuals known to have or who are suspected of having HLRCC, regardless of family history. This includes individuals with cutaneous leiomyomas, as described in the Clinical diagnosis section of this summary, or individuals who have renal tumors with histologic characteristics consistent with HLRCC.[13,14,15] (Refer to the Histopathology section of this summary for more information.)
Risk to family members
HLRCC is inherited in an autosomal dominant manner. If a parent of a proband is clinically affected or has a disease-causing variant, the siblings of the proband have a 50% chance of inheriting the pathogenic variant. Each child of an individual with HLRCC has a 50% chance of inheriting the pathogenic variant. The degree of clinical severity is not predictable. Prenatal genetic testing may be available in laboratories offering custom prenatal testing for families in which a pathogenic variant has been identified in an affected family member.
Parents of a proband
Although some individuals diagnosed with HLRCC have an affected parent, the family history may appear to be negative because of limited family history, failure to recognize the disorder in family members, early death of the affected parent before the onset of syndrome-related symptoms, or late onset of the disease in the affected parent.
Siblings of a proband
Testing of at-risk family members
Use of genetic testing for early identification of at-risk family members improves diagnostic certainty. It reduces the number of unnecessary costly and stressful screening procedures in at-risk members who have not inherited their family's disease-causing variant.[12,18,19]
Early recognition of clinical manifestations may allow timely intervention, which could, in theory, improve outcome. Therefore, clinical surveillance of asymptomatic at-risk relatives for early RCC detection is reasonable, but additional objective data regarding the impact of screening on syndrome-related mortality are needed.
Related genetic counseling issues
Predicting the phenotype in individuals who have inherited a pathogenic variant
It is not possible to predict whether HLRCC-related symptoms will occur or, if they do, what the age at onset, type, severity, or clinical characteristics will be in individuals who have a pathogenic variant. In an in-depth characterization of clinical and genetic features analyzed within 21 new families, the phenotypes displayed a wide range of clinical presentations and no apparent genotype -phenotype correlations were found.
When neither parent of a proband with an autosomal dominant condition has the disease-causing variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, nonmedical explanations include the possibility of alternate paternity or undisclosed adoption. Genetic testing of at-risk family members is appropriate in order to identify the need for continued lifelong clinical surveillance. Interpretation of the pathogenic variant test result is most accurate when a disease-causing variant has been identified in an affected family member. Those who have a disease-causing variant are recommended to undergo lifelong periodic surveillance. Meanwhile, family members and offspring who have not inherited the pathogenic variant are thought to have RCC risks similar to those in the general population; no special management of these individuals is recommended.
Early detection of at-risk individuals affects medical management
Screening for early disease manifestations in HLRCC is an important aspect of clinical care of affected individuals. Although there are no prospective studies comparing specific renal cancer screening practices, the aggressive nature of HLRCC-associated RCC  justifies efforts directed at the early identification of cancer. When tumors are small and localized, partial nephrectomy may be a feasible option; however, the infiltrative nature of these tumors has led some groups to suggest a wide margin must be taken to achieve complete resection.
Uterine fibroids often cause significant symptoms related to bleeding and the presence of a large mass, but small fibroids may be asymptomatic. As HLRCC fibroids can lead to hysterectomies and loss of the ability to bear children in affected young women, the goal of screening in women interested in preserving fertility is to limit some of these irreversible complications. Although there are no specific management recommendations related to HLRCC-associated fibroids, various management strategies have proven effective in the treatment of sporadic fibroids. These strategies include use of hormonal therapies, pain medications, percutaneous and endovascular procedures, and surgical options. Early referral to a fertility specialist may be useful to assist with family planning.
It has been suggested that individuals with a suspected or confirmed diagnosis of HLRCC, individuals with heterozygous pathogenic variants in FH regardless of clinical manifestations, and at-risk family members who have not undergone genetic testing undertake the following regular surveillance, performed by physicians familiar with the clinical manifestations of HLRCC.
Any suspicious renal lesion (indeterminate, questionable, or complex cysts) at a previous examination should be closely followed with periodic imaging, preferably using the same modality to allow for comparisons. The use of renal ultrasound examination may be helpful in the characterization of cystic lesions identified on cross-sectional imaging. It should be cautioned that ultrasound examination alone is never sufficient. Renal tumors should be evaluated by a clinician familiar with HLRCC-related renal cancer.[9,23]
Because of the aggressive growth of these tumors, patients warrant regular surveillance with a low threshold for early surgical intervention for solid renal lesions. This strategy differs from that described for several other hereditary RCC syndromes, in which the tumor behavior is more indolent, and for which observation may be a viable option.[9,23,24]
Level of evidence (skin surveillance): 5
Level of evidence (uterine surveillance): 4
Level of evidence (renal surveillance): 4
Treatment of Manifestations
Cutaneous leiomyomas are most appropriately examined by a dermatologist. Generally, asymptomatic cutaneous leiomyomas require no treatment. Treatment of symptomatic cutaneous leiomyomas may be difficult if a patient has diffuse disease in a wide distribution. Surgical excision may be performed for a solitary painful lesion. Lesions can be treated by cryoablation and/or lasers. Several medications, including calcium channel blockers, alpha blockers, nitroglycerin, antidepressants, and antiepileptic drugs, reportedly reduce leiomyoma-related pain. A small, randomized clinical trial (09-C-0072 [NCT00971620]) showed that intralesional injection of botulinum toxin A (Botox) may improve quality of life.
Level of evidence: 5
Uterine leiomyomas are best evaluated by a gynecologist. HLRCC-associated leiomyomas are treated in the same manner as sporadic leiomyomas. However, because of the multiplicity, size, and potential rapid growth observed in HLRCC-related uterine leiomyomas, most women may require medical and/or surgical intervention earlier and more often than would be expected in the general population. Medical therapy (currently including gonadotropin-releasing hormone agonists, anti-hormonal medications, and pain relievers) may be used to initially treat uterine leiomyomas, both to decrease their size in preparation for surgical removal and to provide temporary relief from leiomyoma-related pain. When women desire fertility preservation, myomectomy can be used to remove leiomyomas and simultaneously preserve the uterus. Hysterectomy should be performed only when necessary.[5,6]
Level of evidence: 4
Efforts aimed at early detection of HLRCC-related RCC are prudent, given its biological aggressiveness. However, studies do not currently show that early detection is clearly associated with improved survival. Surgical excision of these malignancies at the first sign of disease is recommended, unlike management of other hereditary cancer syndromes. The propensity for lymph node involvement, even with small renal tumors, may necessitate a lymph node dissection for more appropriate staging. Radical nephrectomy or partial nephrectomy with wide margins should be considered in individuals with detectable renal masses, including small, subcentimetric tumors.[9,23,24]
Therapies under investigation
It has been suggested that hypoxia-inducible factor (HIF1)-alpha overexpression is involved in HLRCC tumorigenesis.[27,28] Therefore, potential targeted therapies for HLRCC-associated tumors may include HIF1-alpha targeting agents, when such agents become clinically available.
Loss of oxidative phosphorylation resulting from biallelic inactivation of FH renders HLRCC tumors almost entirely reliant on aerobic glycolysis for meeting cellular adenosine triphosphate and other bioenergetics requirements. Consequently, targeting aerobic glycolysis is being explored as a therapeutic strategy.[29,30] A phase II study (10-C-0114 [NCT01130519]) examining the combination of bevacizumab and erlotinib for the treatment of advanced HLRCC is ongoing and is based partly on the premise that this combination might inhibit effective glucose delivery to tumor cells.
Other investigations  evaluating the known consequences of FH inactivation in HLRCC kidney cancer have confirmed very high expression of NAD(P)H dehydrogenase quinine 1 (NQO1) in HLRCC kidney tumors, compared with that seen in two other types of hereditary RCC, including clear cell RCC from von Hippel-Lindau disease and type 1 papillary RCC from HPRC. The activation of an oxidative stress response pathway mediated by NRF2, a transcription factor that regulates the transcription of NQO1, could explain NQO1 overexpression in these tumors. Vandetanib, an oral VEGFR2 and EGFR inhibitor with additional activity against Abl-1 kinase, has potent activity against FH-deficient cells in vitro and induces regression of HLRCC-derived xenografts in mice. The activity of vandetanib in this model is mediated, at least in part, by its ability to disrupt the NRF2-mediated cytoprotective oxidative stress response pathway in an Abl-dependent fashion. Furthermore, metformin, an activator of 5'–AMP activated protein kinase (AMPK), was synergistic with vandetanib both in vitro and in mouse xenografts derived from FH-deficient human renal cancer. These data provided the basis for a clinical trial (NCT02495103) to evaluate the efficacy of this combination in HLRCC patients with advanced kidney cancer.
General information about clinical trials is also available from the NCI website.
Prognosis is quite good for cutaneous and uterine manifestations of hereditary leiomyomatosis and renal cell cancer (HLRCC). Local management of cutaneous manifestations, when required, and hysterectomy, where indicated, address these sites fairly effectively and with minimal long-term consequences. The incidence of uterine leiomyosarcomas is likely quite low and is unlikely to substantively affect median survival at a cohort level. Renal cell cancer (RCC) in the context of HLRCC is a considerably more ominous manifestation, and the HLRCC patients who develop RCC [1,2,3,4,5] are at high risk of developing metastatic disease. Metastatic RCC associated with HLRCC is characterized by an aggressive clinical course. There are no sufficiently large patient cohorts or databases that provide a precise estimate of survival in this population; however, retrospective cohorts demonstrate that these cancers have worse outcomes than other conventional forms of RCC.
There are two major unmet needs, other than the availability of effective medical therapy for metastatic disease, in the management of patients with hereditary leiomyomatosis and renal cell cancer (HLRCC). The first is the ability to predict who will develop renal cell cancer to allow detection earlier and with a higher degree of precision. The development of diagnostic blood-based tests or imaging tools that permit cost-effective surveillance of the kidneys of patients with HLRCC would have a major positive effect on the outcomes of these individuals. The second major unmet need is for a more accurate determination of the genotype -phenotype correlations for various genetic lesions found in the FHgene. New polymorphisms in the FH gene are frequently of uncertain significance, and considerable effort needs to be expended to determine their clinical significance. Devising in silico prediction tools and linking these to robust patient databases and registries will expand our understanding of specific FH gene variants.
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