Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: Hereditary Leiomyomatosis and Renal Cell Cancer
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of HLRCC is unknown. Over 300 families with HLRCC have been reported.
Clinical Features
(Signs / symptoms)
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by a predisposition to cutaneous and uterine leiomyomas and, in some families, to renal cell cancer. Benign cutaneous leiomyomas are common, present as multiple or single nodules that are skin colored to light brown, and are usually localized to the trunk and extremities but may also appear on the face. They are usually sensitive to touch and/or cold temperature and may be painful. Uterine Leiomyomas (fibroids) are associated with symptoms of pelvic pain and irregular or heavy menstrual bleeding. Renal tumors may present with back pain, hematuria, or may be asymptomatic. These tumors are usually unilateral and solitary; most are type 2 with a characteristic papillary architecture but other tumor types are also found.
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Natural History
(Important subgroups & survival / recovery)
The majority of individuals with HLRCC (76%) present with a single or multiple cutaneous leiomyomas. Cutaneous leiomyomas usually present at an average age of 25 (range 10 to 47 years), and tend to increase in size and number with age. Uterine leiomyomas have been reported in 77% of women with HLRCC and appear at an average age of 30 (range 18 to 52 years) with symptoms preceding discovery. Fibroids tend to be numerous and large with earlier onset, and may require intervention (hysterectomy or myomectomy) at a younger age than fibroids seen in the general population. The renal carcinomas associated with HLRCC behave aggressively and have a poor prognosis compared with other forms of hereditary RCC. Only a small proportion of individuals with HLRCC develop renal cell cancer (RCC) at a median age of detection of 44 years. In contrast to other hereditary renal cancer syndromes, renal cancers associated with HLRCC are more aggressive, often rapidly progressing to metastatic disease and death. In one study about 10-16% of those with HLRCC who presented with multiple cutaneous leiomyomas had renal tumors and nine of these 13 individuals died from metastatic disease within 5 years of diagnosis.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and management needs in an individual diagnosed with HLRCC, the following evaluations are recommended: detailed dermatologic examination for evaluation of extent of disease and lesions suspicious for cutaneous leiomyosarcoma to include biopsy for histologic confirmation; baseline pelvic examination, pelvic MRI and/or transvaginal pelvic ultrasound to screen for uterine fibroids; baseline renal ultrasound and MRI to screen for renal tumors (or abdominal CT scan with contrast if MRI contraindicated); consultation with a medical geneticist and/or genetic counselor. (Tier 4)
Because of the aggressive nature of renal cancers associated with HLRCC excision of these malignancies requires earlier and more extensive surgery than other hereditary renal cancers. Total nephrectomy should be strongly considered in individuals with a detectable renal mass. (Tier 4)
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There is no consensus on clinical surveillance; provisional recommendations state that individuals with a clinical diagnosis of HLRCC and those with heterozygous pathogenic FH variants and no clinical manifestations should undergo:
- full skin examination annually to every 2 years;
- annual gynecologic consultation;
- and yearly examination with abdominal MRI for those with normal baseline or followup abdominal MRI (or abdominal CT scan with contrast if MRI contraindicated).
Suspicious lesions detected at a previous examination should be followed with a CT scan with and without contrast (with or without the addition of renal ultrasound or PET-CT). (Tier 4)
Annual pelvic examination of patients 21 years of age or older is recommended for all women, based on expert opinion. (Tier 5)
Family Management
It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. (Tier 4)
Clinical surveillance of asymptomatic at-risk relatives for early detection may allow timely intervention and improve outcomes. At-risk family members who have not undergone molecular genetic testing should undergo the same surveillance recommended for those with a clinical diagnosis of HLRCC or those with pathogenic variants and no clinical manifestations. (Tier 4)
Circumstances to Avoid
No circumstances-to-avoid recommendations have been provided.
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
HLRCC is inherited in an autosomal dominant manner. Some have HLRCC as the result of de novo gene mutation.
Prevalence of Genetic Mutations
Genetic prevalence is unknown. FH is the only gene known to be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC), and 70% to 90% of individuals with clinically diagnosed HLRCC have identifiable sequence variants in FH. Deletions and duplications also account for an additional small proportion. (Tier 4)
Relative Risk
(Include any high risk racial or ethnic subgroups)
Based on the outcomes of cutaneous leiomyomas, uterine leiomyomas, or renal tumor, penetrance of HLRCC is considered to be very high. (Tier 4)
A French National Cancer Institute study of 44 families with genetically-confirmed HLRCC identified cutaneous leiomyomas in 68% of 151 affected members; uterine leiomyomas in 82% of 93 female affected members; and renal tumors in 18% of 151 affected members. (Tier 3)
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Renal cancer has low penetrance in HLRCC syndrome, with an estimated incidence from 2%-6% to 15%, and possibly as high as 32% of germline mutation affected families, depending upon selection bias and imaging utilized. (Tier 5)
Information on relative risk was not available.
Affected individuals may have multiple cutaneous leiomyomas, a single skin leiomyoma, or no cutaneous lesion; a single renal tumor or no renal tumors; and/or uterine fibroids. Disease severity shows significant intra- and interfamilial variation. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Surveillance is noninvasive. Abdominal CT scan may involve exposure to contrast material.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
In one study, 71% of 24 nonprobands (relatives) with skin leiomyomas had not previously presented for medical attention. No patient who had presented with skin leiomyomas had been offered screening for uterine fibroids. Fibroids were rarely recognized as cases of HLRCC. (Tier 5)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Renal cancer / Surveillance
Advanced uterine pathology / Annual GYN exam
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. M Pithukpakorn, JR Toro. Hereditary leiomyomatosis and renal cell cancer. 2006 Jul 31 [Updated 2015 Aug 06]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from:
2. Hereditary leiomyomatosis and renal cell cancer. Orphanet encyclopedia,
3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Hereditary leiomyomatosis and renal cell cancer; hlrcc. MIM: 150800: 2015 Dec 23. World Wide Web URL:
4. The american college of obstetricians and gynecologists. committee opinion number 534. committee on gynecologic practice. well-woman visit.. Obstet gynecol. 2012. reaffirmed 2014;120:421-4.. (2014) Website:
5. Gardie B, Remenieras A, Kattygnarath D, Bombled J, Lefevre S, Perrier-Trudova V, Rustin P, Barrois M, Slama A, Avril MF, Bessis D, Caron O, Caux F, Collignon P, Coupier I, Cremin C, Dollfus H, Dugast C, Escudier B, Faivre L, Field M, Gilbert-Dussardier B, Janin N, Leport Y, Leroux D, Lipsker D, Malthieu F, McGilliwray B, Maugard C, Mejean A, Mortemousque I, Plessis G, Poppe B, Pruvost-Balland C, Rooker S, Roume J, Soufir N, Steinraths M, Tan MH, Theodore C, Thomas L, Vabres P, Van Glabeke E, Meric JB, Verkarre V, Lenoir G, Joulin V, Deveaux S, Cusin V, Feunteun J, Teh BT, Bressac-de Paillerets B, Richard S. Novel fh mutations in families with hereditary leiomyomatosis and renal cell cancer (hlrcc) and patients with isolated type 2 papillary renal cell carcinoma. J Med Genet. (2011) 48(4):226-34.
6. Pfaffenroth EC, Linehan WM. Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. Expert Opin Biol Ther. (2008) 8(6):779-90.
7. Alam NA, Barclay E, Rowan AJ, Tyrer JP, Calonje E, Manek S, Kelsell D, Leigh I, Olpin S, Tomlinson IP. Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol. (2005) 141(2):199-206.
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