Nomenclature

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.[1] 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 [2] and the name hereditary leiomyomatosis and renal cell cancer (HLRCC) was introduced.

References

1. Reed WB, Walker R, Horowitz R: Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol 53 (5): 409-16, 1973. [PubMed: 4127477]
2. Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001. [PMC free article: PMC30663] [PubMed: 11248088]

FH Gene

The FH gene 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. An individual can be predisposed to HLRCC disease manifestations when he/she inherits a heterozygous pathogenic variant in the FH gene.[1] Various FH pathogenic variants have been identified in families with HLRCC. Most are missense variants. However, nonsense variants, frameshift variants, splice-site variants, and whole-gene/partial deletions have also been identified and described.[2-6]

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 FH variant. 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.[2,7]

Inherited biallelic pathogenic variants in the FH gene (homozygous or compound heterozygous) can cause autosomal recessive fumarate hydratase deficiency (FHD) (also abbreviated as FMRD), a disorder characterized by rapid, progressive neonatal neurological impairment that includes hypotonia, seizures, and cerebral atrophy. For more information, see the Genetically Related Disorders section.

Prevalence

Prevalence estimates for HLRCC are evolving. Older estimates suggested a prevalence of 1 in 200,000 individuals.[8] However, an analysis of nonpopulation-based cohorts found an FH carrier frequency of 1 in 1,000 individuals, suggesting a larger number of asymptomatic cases than previously thought.[9] A clinical database analysis of over 120,000 records from individuals undergoing hereditary cancer genetic testing estimated a carrier frequency of 1 in 2,668 (0.04%). These estimates reflect the high rate of FH pathogenic variants that were detected incidentally in individuals undergoing cancer genetic testing for other indications. This finding suggests that HLRCC may be one of the most common hereditary cancer syndromes.[10]

Penetrance of FH Pathogenic 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.[3,4,7,11-13] A 2020 study showed that FH pathogenic variants have been detected at a higher rate than previously thought, indicating that lifetime risk of kidney cancer in individuals with HLRCC may be significantly lower than current estimates suggest.[9]

A study that analyzed patients undergoing cancer genetic testing suggested that RCC may be more common in males with HLRCC than in females with HLRCC.[10] Several studies have also reported an enrichment of FH germline pathogenic variants in individuals with RCC and African ancestry.[10,14]

Genotype-Phenotype Correlations

Correlations between specific FH variants and the occurrence of cutaneous/uterine leiomyomas, RCC, or other primary features of HLRCC have not been reported.[4]

However, certain FH variants (primarily missense variants) seem to be associated with an increased risk for paraganglioma (PGL)/pheochromocytoma (PHEO) in the absence of other HLRCC features.[15] Three recurrent variants with increased PGL/PHEO risk have been reported in the literature: (1) p.Thr234Ala, (2) p.Ala273Thr, and (3) p.Ala194Thr. Conversely, FH variants associated with autosomal dominant HLRCC and autosomal recessive FHD do not seem to correlate with increased PGL/PHEO risk. Although PGL/PHEO surveillance is not included in HLRCC guidelines, the authors suggest that surveillance similar to that which is recommended for SDHx carriers may be warranted. For more information, see the Surveillance section.

Sequence Analysis

Using bidirectional DNA sequencing methodology, pathogenic variants in FH have been detected in more than 85% of individuals with HLRCC.[3,4,16]

Genetically Related Disorders

References

1. Alam NA, Rowan AJ, Wortham NC, et al.: Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 12 (11): 1241-52, 2003. [PubMed: 12761039]
2. Tomlinson IP, Alam NA, Rowan AJ, et al.: Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30 (4): 406-10, 2002. [PubMed: 11865300]
3. Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PMC free article: PMC1180594] [PubMed: 12772087]
4. Wei MH, Toure O, Glenn GM, et al.: Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43 (1): 18-27, 2006. [PMC free article: PMC2564499] [PubMed: 15937070]
5. Bayley JP, Launonen V, Tomlinson IP: The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med Genet 9: 20, 2008. [PMC free article: PMC2322961] [PubMed: 18366737]
6. Vocke CD, Ricketts CJ, Merino MJ, et al.: Comprehensive genomic and phenotypic characterization of germline FH deletion in hereditary leiomyomatosis and renal cell carcinoma. Genes Chromosomes Cancer 56 (6): 484-492, 2017. [PMC free article: PMC6637959] [PubMed: 28196407]
7. Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001. [PMC free article: PMC30663] [PubMed: 11248088]
8. Forde C, Lim DHK, Alwan Y, et al.: Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals. Eur Urol Oncol 3 (6): 764-772, 2020. [PubMed: 31831373]
9. Shuch B, Li S, Risch H, et al.: Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer. Cancer 126 (16): 3657-3666, 2020. [PMC free article: PMC10316675] [PubMed: 32413184]
10. Lu E, Hatchell KE, Nielsen SM, et al.: Fumarate hydratase variant prevalence and manifestations among individuals receiving germline testing. Cancer 128 (4): 675-684, 2022. [PMC free article: PMC9170268] [PubMed: 34724198]
11. Alam NA, Olpin S, Leigh IM: Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol 153 (1): 11-7, 2005. [PubMed: 16029320]
12. Pfaffenroth EC, Linehan WM: Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. Expert Opin Biol Ther 8 (6): 779-90, 2008. [PMC free article: PMC2768039] [PubMed: 18476789]
13. Grubb RL, Franks ME, Toro J, et al.: Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol 177 (6): 2074-9; discussion 2079-80, 2007. [PubMed: 17509289]
14. Abou Alaiwi S, Nassar AH, Adib E, et al.: Trans-ethnic variation in germline variants of patients with renal cell carcinoma. Cell Rep 34 (13): 108926, 2021. [PubMed: 33789101]
15. Zavoshi S, Lu E, Boutros PC, et al.: Fumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma. Urology 176: 106-114, 2023. [PubMed: 36773955]
16. Alam NA, Barclay E, Rowan AJ, et al.: Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol 141 (2): 199-206, 2005. [PubMed: 15724016]
17. Coughlin EM, Christensen E, Kunz PL, et al.: Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab 63 (4): 254-62, 1998. [PubMed: 9635293]
18. Bourgeron T, Chretien D, Poggi-Bach J, et al.: Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J Clin Invest 93 (6): 2514-8, 1994. [PMC free article: PMC294471] [PubMed: 8200987]
19. Badeloe S, Frank J: Clinical and molecular genetic aspects of hereditary multiple cutaneous leiomyomatosis. Eur J Dermatol 19 (6): 545-51, 2009 Nov-Dec. [PubMed: 19939761]
20. Kamihara J, Horton C, Tian Y, et al.: Different Fumarate Hydratase Gene Variants Are Associated With Distinct Cancer Phenotypes. JCO Precis Oncol 5: 1568-1578, 2021. [PubMed: 34994643]
21. Kiuru M, Lehtonen R, Arola J, et al.: Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res 62 (16): 4554-7, 2002. [PubMed: 12183404]
22. Lehtonen R, Kiuru M, Vanharanta S, et al.: Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol 164 (1): 17-22, 2004. [PMC free article: PMC1602244] [PubMed: 14695314]
23. Linehan WM, Spellman PT, Ricketts CJ, et al.: Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med 374 (2): 135-45, 2016. [PMC free article: PMC4775252] [PubMed: 26536169]

References

1. Isaacs JS, Jung YJ, Mole DR, et al.: HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8 (2): 143-53, 2005. [PubMed: 16098467]
2. Pollard PJ, Brière JJ, Alam NA, et al.: Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14 (15): 2231-9, 2005. [PubMed: 15987702]
3. Sudarshan S, Sourbier C, Kong HS, et al.: Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol 29 (15): 4080-90, 2009. [PMC free article: PMC2715796] [PubMed: 19470762]
4. Pollard P, Wortham N, Barclay E, et al.: Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J Pathol 205 (1): 41-9, 2005. [PubMed: 15586379]
5. Alderson NL, Wang Y, Blatnik M, et al.: S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate. Arch Biochem Biophys 450 (1): 1-8, 2006. [PubMed: 16624247]
6. Ooi A, Wong JC, Petillo D, et al.: An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20 (4): 511-23, 2011. [PubMed: 22014576]

Cutaneous Leiomyomas

Cutaneous leiomyomas present as firm papules or nodules that appear pink or reddish-brown. These lesions usually appear on the trunk, on the extremities, and occasionally on the face. These lesions occur at a mean age of 25 years (age range, 10–47 y) and often 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.[3] The presence of multiple cutaneous leiomyomas is often indicative of HLRCC, and therefore, warrants 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.[4] The same series demonstrated that 18 of 19 individuals (95%) with multiple leiomyomas had a pathogenic variant in FH.[4] Therefore, the presence of a solitary leiomyoma requires careful analysis of an individual's family history. For more information, see the Clinical diagnosis and Differential diagnosis sections.

Uterine Leiomyomas

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.[4] 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).[3,5-7]

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,[9] although some cases have been reported to occur as early as age 10 years.[10] Another large series of 135 patients estimated that the lifetime risk was 20.8% by age 85 years.[11] 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.[3] 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.

Uterine Leiomyosarcomas

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.[2] 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.[3] Therefore, the risk of uterine leiomyosarcoma in women with HLRCC is uncertain. This is a question in urgent need of a definitive answer.

Other Manifestations

Four FH-positive cases 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. Resections were performed on many of these lesions since they were fluorodeoxyglucose avid. All of the lesions showed evidence of both micronodular and macronodular adrenal hyperplasia, suggesting that adrenal nodules could be an additional manifestation of HLRCC.[16] It remains to be determined if these manifestations are truly part of the HLRCC phenotype.[6,14,17] Similarly, pheochromocytomas (PHEOS) have been reported in the adrenal glands of individuals with HLRCC.[8,18] However, one of the largest cohorts from the United Kingdom did not report PHEOs in individuals with HLRCC. Therefore, surveillance of PHEOs is not recommended unless further evidence shows that this tumor is part of the HLRCC phenotype.[11]

References

1. Wei MH, Toure O, Glenn GM, et al.: Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43 (1): 18-27, 2006. [PMC free article: PMC2564499] [PubMed: 15937070]
2. Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001. [PMC free article: PMC30663] [PubMed: 11248088]
3. Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PMC free article: PMC1180594] [PubMed: 12772087]
4. Bhola PT, Gilpin C, Smith A, et al.: A retrospective review of 48 individuals, including 12 families, molecularly diagnosed with hereditary leiomyomatosis and renal cell cancer (HLRCC). Fam Cancer 17 (4): 615-620, 2018. [PubMed: 29423582]
5. Farquhar CM, Steiner CA: Hysterectomy rates in the United States 1990-1997. Obstet Gynecol 99 (2): 229-34, 2002. [PubMed: 11814502]
6. Alam NA, Barclay E, Rowan AJ, et al.: Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol 141 (2): 199-206, 2005. [PubMed: 15724016]
7. Stewart L, Glenn GM, Stratton P, et al.: Association of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer. Arch Dermatol 144 (12): 1584-92, 2008. [PMC free article: PMC2937541] [PubMed: 19075141]
8. Muller M, Ferlicot S, Guillaud-Bataille M, et al.: Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. Clin Genet 92 (6): 606-615, 2017. [PubMed: 28300276]
9. Shuch B, Vourganti S, Ricketts CJ, et al.: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32 (5): 431-7, 2014. [PMC free article: PMC3912328] [PubMed: 24378414]
10. Wong MH, Tan CS, Lee SC, et al.: Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC). Fam Cancer 13 (2): 281-9, 2014. [PubMed: 24526232]
11. Forde C, Lim DHK, Alwan Y, et al.: Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals. Eur Urol Oncol 3 (6): 764-772, 2020. [PubMed: 31831373]
12. Grubb RL, Franks ME, Toro J, et al.: Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol 177 (6): 2074-9; discussion 2079-80, 2007. [PubMed: 17509289]
13. Linehan WM, Bratslavsky G, Pinto PA, et al.: Molecular diagnosis and therapy of kidney cancer. Annu Rev Med 61: 329-43, 2010. [PMC free article: PMC2921612] [PubMed: 20059341]
14. Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, et al.: Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet 43 (6): 523-6, 2006. [PMC free article: PMC2564537] [PubMed: 16155190]
15. Ylisaukko-oja SK, Kiuru M, Lehtonen HJ, et al.: Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer 119 (2): 283-7, 2006. [PubMed: 16477632]
16. Shuch B, Ricketts CJ, Vocke CD, et al.: Adrenal nodular hyperplasia in hereditary leiomyomatosis and renal cell cancer. J Urol 189 (2): 430-5, 2013. [PMC free article: PMC4435969] [PubMed: 22982371]
17. Matyakhina L, Freedman RJ, Bourdeau I, et al.: Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical cushing syndrome: a clinical and molecular genetic investigation. J Clin Endocrinol Metab 90 (6): 3773-9, 2005. [PubMed: 15741255]
18. Clark GR, Sciacovelli M, Gaude E, et al.: Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab 99 (10): E2046-50, 2014. [PubMed: 25004247]

Cutaneous Leiomyomas

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.[1]

Uterine Leiomyomas

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.[2]

RCC

The renal cell cancers (RCCs) associated with HLRCC have unique histological 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.[3] 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 histological examinations of 40 RCCs from 38 patients with germline FH pathogenic variants and HLRCC family histories.[5,6] A number of histological patterns were seen, including cystic, tubulopapillary, tubulo-solid, and often mixed patterns.[5,6]

References

1. Fearfield LA, Smith JR, Bunker CB, et al.: Association of multiple familial cutaneous leiomyoma with a uterine symplastic leiomyoma. Clin Exp Dermatol 25 (1): 44-7, 2000. [PubMed: 10671972]
2. Sanz-Ortega J, Vocke C, Stratton P, et al.: Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol 37 (1): 74-80, 2013. [PMC free article: PMC3524342] [PubMed: 23211287]
3. Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001. [PMC free article: PMC30663] [PubMed: 11248088]
4. Wei MH, Toure O, Glenn GM, et al.: Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43 (1): 18-27, 2006. [PMC free article: PMC2564499] [PubMed: 15937070]
5. Merino MJ, Torres-Cabala C, Pinto P, et al.: The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol 31 (10): 1578-85, 2007. [PubMed: 17895761]
6. Merino MJ, Torres-Cabala CA, Zbar B, et al.: Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC): Clinical histopathological and molecular features of the first American families described. [Abstract] Mod Pathol 16 (Suppl): A-739, 162A, 2003.

Diagnosis and Testing

Genetic testing for the FH gene 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.

Surveillance

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.

• Skin. There are some published recommendations to perform skin exams on a regular basis, but there is no consensus regarding frequency of skin exams, and recommendations have not been prospectively validated.
• Uterine. For women with an intact uterus, annual gynecologic consultation is recommended, accompanied by periodic imaging. Imaging may include magnetic resonance imaging (MRI) of the pelvis or ultrasound to assess the severity of uterine leiomyomas and to search for changes suggestive of developing leiomyosarcoma.[6,7,16,22]
• Paraganglioma (PGL)/Pheochromocytoma (PHEO). Although PGL/PHEO surveillance is not included in suggested HLRCC guidelines, one study suggested that surveillance similar to that which is recommended for SDHx carriers could be considered for individuals with unique FH variants associated with increased PGL/PHEO risk (i.e., p.Thr234Ala, p.Ala273Thr, and p.Ala194Thr).[23] This surveillance regimen includes annual biochemical screening (urine or plasma metanephrines), careful physical exam with a focus on the neck and abdominal areas, and whole-body cross-sectional imaging.
• Renal. In view of the aggressive nature of this disease, annual imaging with either computed tomography (CT) scan with contrast or MRI with gadolinium is warranted even if the initial (baseline) evaluation reveals normal kidneys. Special attention to imaging is warranted in this population because subtle findings, such as a complex cyst, may sometimes represent an aggressive malignancy. The age to initiate renal screening is uncertain, however, because HLRCC has been described in children as young as 10 years. The HLRCC Family Alliance recommends annual imaging beginning at age 8 years in children at risk of HLRCC and those with HLRCC.[1] MRI has the advantage of sparing the patient radiation exposure and for this reason it may be preferred over CT for lifetime surveillance of HLRCC patients.
  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.[10,24]
  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.[10,24,25]

Level of evidence (skin surveillance): 5

Level of evidence (uterine surveillance): 4

Level of evidence (renal surveillance): 4

Treatment of Manifestations

References

1. HLRCC Family Alliance: The HLRCC Handbook. Version 2.0. Boston, MA: HLRCC Family Alliance, 2013. Available online. Last accessed November 6, 2024.
2. Schmidt LS, Linehan WM: Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis 7: 253-60, 2014. [PMC free article: PMC4074185] [PubMed: 25018647]
3. Smit DL, Mensenkamp AR, Badeloe S, et al.: Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet 79 (1): 49-59, 2011. [PubMed: 20618355]
4. Menko FH, Maher ER, Schmidt LS, et al.: Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer 13 (4): 637-44, 2014. [PMC free article: PMC4574691] [PubMed: 25012257]
5. Lehtonen HJ: Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam Cancer 10 (2): 397-411, 2011. [PubMed: 21404119]
6. Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PMC free article: PMC1180594] [PubMed: 12772087]
7. Stewart L, Glenn GM, Stratton P, et al.: Association of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer. Arch Dermatol 144 (12): 1584-92, 2008. [PMC free article: PMC2937541] [PubMed: 19075141]
8. Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [PubMed: 8308957]
9. Pavlovich CP, Walther MM, Eyler RA, et al.: Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26 (12): 1542-52, 2002. [PubMed: 12459621]
10. Linehan WM, Bratslavsky G, Pinto PA, et al.: Molecular diagnosis and therapy of kidney cancer. Annu Rev Med 61: 329-43, 2010. [PMC free article: PMC2921612] [PubMed: 20059341]
11. Schmidt LS, Linehan WM: Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 12 (10): 558-69, 2015. [PMC free article: PMC5119524] [PubMed: 26334087]
12. Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PubMed: 22134580]
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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of hereditary leiomyomatosis and renal cell cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The lead reviewers for Hereditary Leiomyomatosis and Renal Cell Cancer are:

• Alexandra Perez Lebensohn, MS, CGC (National Cancer Institute)
• Brian Matthew Shuch, MD (UCLA Health)
• Ramaprasad Srinivasan, MD, PhD (National Cancer Institute)

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PDQ® Cancer Genetics Editorial Board. PDQ Hereditary Leiomyomatosis and Renal Cell Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/publications/pdq/information-summaries/genetics/hlrcc-syndrome-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 33724749]

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