Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: FH (HGNC:3700)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 05/15/2023
• Curation Status: Released (1.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
FH	hereditary leiomyomatosis and renal cell cancer (0007888)	150800	Moderate Actionability

Actionability Assertion Rationale

• Most experts agreed with the assertion computed according to the rubric. There are small numbers of pediatric patients and limited data overall.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from HLRCC-associated renal cell cancer / Evaluation and surveillance by specialist to detect renal cell cancer and guide treatment	2	1C	2C	3	8CC

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of hereditary leiomyomatosis and renal cell cancer (HLRCC) is unknown. Over 300 families with HLRCC have been reported. HLRCC is likely to be under-recognized.

Clinical Features (Signs / symptoms)

HLRCC is a hereditary cancer syndrome characterized by a predisposition to cutaneous and uterine leiomyomas and an aggressive form of renal cell cancer (RCC) distinct to this syndrome classified as “HLRCC-associated RCC”. Benign cutaneous leiomyomas are common, present as multiple or single nodules that are skin colored to reddish brown, and are usually localized to the trunk and extremities but may also appear on the head and neck. They are usually sensitive to touch, heat, or cold temperature and may be painful. Uterine leiomyomas (fibroids) tend to be numerous and large and are associated with symptoms of pelvic pain and irregular or heavy menstrual bleeding. Cutaneous leiomyosarcoma and uterine leiomyosarcoma are rare. Renal tumors may present with lower back pain, hematuria, a palpable mass, or may be asymptomatic. These tumors are usually unilateral and solitary; with a spectrum of renal tumors including type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma. Pheochromocytoma and paraganglioma have also been described in a small number of families.

Natural History (Important subgroups & survival / recovery)

The majority of individuals with HLRCC present with a single or multiple cutaneous leiomyomas. Cutaneous leiomyomas usually present at a mean age of 30 years (range 10 to 77 years) and tend to increase in size and number with age, with 40% having five or fewer lesions. Uterine leiomyomas appear at a mean age of 30 years (range 18 to 63 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. Surgical intervention for uterine leiomyomata has been reported to occur at a median age of 35 years. The significant morbidity caused by the presence of these aggressive uterine leiomyomata has led to about 80% of individuals reporting a moderate to severe impact on quality of life. The renal carcinomas associated with HLRCC behave aggressively and have a poor prognosis compared with other forms of hereditary RCC. The median age of detection of RCC is 37-44 years. Between 1-7% of individuals with RCC are diagnosed before age 20 years. HLRCC-associated RCC (even small lesions < 3 cm) often rapidly progress to metastatic disease and death. Retrospective cohorts demonstrate that HLRCC-associated RCCs have worse outcomes than other conventional forms of RCC. In one study nine of 13 individuals with renal tumors died from metastatic disease within 5 years of diagnosis. In another study of 31 individuals with follow-up data available, 82% developed metastatic disease: 16 (47%) were metastatic at diagnosis and another 12 (35%) became metastatic within three years. In another study the mean survival following diagnosis of symptomatic RCC was 38 months.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 1000

One study estimated the FH carrier frequency in two population databases (1000 Genomes Project and ExAC). The frequency of known pathogenic/likely pathogenic FH variants was 1 in 1,344. When other likely pathogenic variants were included (loss of function, stop loss, start loss) the frequency increased to 1 in 901 to 1 in 1,252.

Tier 3

Unknown

Approximately 90% of probands with HLRCC have a detectable pathogenic variant on sequence analysis. Another ~10% have a pathogenic variant detectable by gene-targeted deletion/duplication analysis.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

5-39 %

A study using data from two population databases (1000 Genomes and ExAC) estimated the lifetime penetrance of HLRCC-associated RCC based on the frequency of pathogenic/likely pathogenic variants and estimates of the annual number of HLRCC/RCC cases. The estimated lifetime penetrance of RCC in FH pathogenic variant carriers ranged from 3.9% to 17.3%, depending on the database.

Tier 3

5-39 %

The risk of RCC in HLRCC is uncertain due to the considerable variation of RCC prevalence among published cohorts of families. Individuals with HLRCC have an estimated 15-30% lifetime risk of RCC. The risk for individuals with pathogenic variants in FH to develop renal cancer by age 20 years is estimated between 1-7%. A study of 151 family members from 44 families with genetically confirmed HLRCC identified renal tumors in 18% (27/151).

Tier 3

>= 40 %

A French National Cancer Institute study of 151 family members from 44 families with genetically confirmed HLRCC identified cutaneous leiomyomas in 68% (102/151) and uterine leiomyomas in 82% (76/93 females). A retrospective review of 48 individuals from 12 families, molecularly diagnosed with HLRCC reported the presence of cutaneous leiomyomas in 46% (22/48) and uterine leiomyomas in 62% (18/29 females).

Tier 3

>= 40 %

In a study of 185 individuals in 69 families from four UK regional genetics clinics with a clinical and/or molecular diagnosis of HLRCC, cutaneous leiomyomata were confirmed in 48.6%, with an age-related prevalence to age 75 years of 78%. Uterine leiomyomata were confirmed in 31% of females, with an age-related prevalence of 42% by age 75 years. Renal tumors were confirmed in 12%. Age-related prevalence of renal cancer was 21% by age 75 years.

Tier 5

Unknown

The lifetime risks for pheochromocytoma and paraganglioma are unknown, as they have only been reported in a few individuals.

Tier 4

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on relative risk was not available.

Expressivity

Affected individuals may have single, multiple, or no cutaneous leiomyomas; a single or no renal tumors; and/or uterine fibroids. Disease severity shows significant intra- and interfamilial variation. A heterozygous parent may or may not have manifestations.

Tier 3

In an in-depth characterization of clinical and genetic features in 21 families with HLRCC, the phenotypes displayed a wide range of clinical presentations. Expression of cutaneous leiomyomas ranged from absent to mild to severe, and there was a spectrum of renal tumors.

Tier 3

The degree of clinical severity is not predictable. Recent studies have shown wider phenotypic variability in individuals with HLRCC than previously described.

Tier 4

Intervention Effectiveness

Patient Management

Initial screening for major clinical manifestations in individuals with HLRCC includes screening for renal, skin, and gynecological manifestations. Referral to a cancer genetics professional should be considered.

Tier 2

To establish the extent of disease and management needs in an individual diagnosed with HLRCC, the following evaluations are recommended:

• baseline blood pressure

• consultation with a clinical geneticist, cancer genetics program, and/or genetic counselor

• consider baseline MRI from skull base through pelvis and fractionated plasma metanephrines for genotypes associated with paraganglioma or persons with a personal/family history of paraganglioma

Tier 4

Because of the aggressive nature of renal cancers associated with HLRCC immediate surgical intervention is recommended. Management of a suspected renal cancer most often consists of partial nephrectomy. Total radical nephrectomy should be considered if there is doubt that a partial nephrectomy would be curative. A study that performed CT for adult at risk family members identified 19 individuals with renal lesions and genetically confirmed HLRCC, with only two individuals being asymptomatic for renal tumors at the time of screening. Of 19 individuals 13 (68%) presented with advanced disease (stage 3 or 4). Initial management included radical nephrectomy in 15 individuals and partial nephrectomy in three. At a median follow-up of 34 months (range 6 to 141 months) 10 of the 19 individuals with HLRCC (53%) had died of kidney cancer or had advanced disease and 9 (including all three individuals diagnosed at stage 1) were free of detectable disease at last follow-up.

Tier 2

Cutaneous leiomyomas should be examined by a dermatologist. Management for cutaneous leiomyomas includes surgical excision or other destructive methods (e.g., cryoablation) for isolated lesions, or pharmacologic management of multiple symptomatic lesions.

Tier 3

Uterine fibroids should be evaluated by a gynecologist. Since HLRCC-related fibroids can lead to loss of fertility, early referral to a fertility specialist may be useful to assist with family planning.

Tier 4

Surveillance

Kidney-specific screening recommendations for individuals with confirmed HLRCC who do not yet have a radiographic or pathologic diagnosis of RCC have been published.

• One guideline recommends abdominal MRI (preferred), or CT be performed annually starting at age 8-10 years.

• Another recommends annual renal MRI from the age of 8 years.

• A third guideline says renal MRI should be offered from 8-10 years but that surveillance before age 18 years should be made on an individual basis.

Renal ultrasound is not recommended due to the low sensitivity to detect small lesions unless ultrasound is the only available imaging modality. Individuals capable of childbearing who are planning conception should consider renal imaging prior to pregnancy.

Tier 2

Renal screening in relatives has shown benefit in detecting early-stage HLRCC-associated RCCs. In one study 81 individuals with HLRCC and no personal history of renal tumors underwent screening MRI, and three pre-symptomatic RCCs were detected (all stage 1). Considering both screen-detected and symptomatic RCC presentations in family members, mean survival of individuals diagnosed with stage 3 or 4 RCC was significantly shorter at 15.8 months (all 9/9 individuals deceased at 36 months) as compared with 80.7 months for individuals diagnosed with stage 1 or 2 RCC. Details on the three screen-detected RCCs:

• Detected at age 11 years. Treated with total nephrectomy. Alive after 101 months.

• Detected at age 30 years. Treated with partial nephrectomy. Alive after 42 months.

• Detected at age 43 years. Treated with partial nephrectomy. Alive after 18 months.

Tier 2

Annual full skin exams by a pediatrician are recommended from the time of diagnosis, with referral to dermatology as needed to assess for the presence of leiomyomas and to be evaluated for changes suggestive of leiomyosarcoma.

Tier 2

Annual gynecologic examination is also recommended from the age of 20 years (or earlier with symptoms) to assess for uterine fibroids and for any changes such as significant growth that could be suggestive of leiomyosarcoma, with the addition of ultrasound as necessary.

Tier 2

Circumstances to Avoid

CT of the abdomen can be used for surgical planning but should be limited, if possible, for surveillance due to lifetime radiation exposure for hereditary syndromic individuals.

Tier 2

Nature of Intervention

Nature of Intervention

Individuals with HLRCC should undergo regular lifelong surveillance for renal lesions with a low threshold for early surgical intervention. Imaging modalities used for surveillance should try to minimize exposure to radiation. Hysterectomies due to uterine leiomyomas result in lost ability to bear children. Clinicians must balance the likely benefits and drawbacks of screening procedures with a paucity of evidence regarding the efficacy of screening.

Context: Adult Pediatric

Chance to Escape Clinical Detection

The family history of some individuals with HLRCC may appear to be negative because of limited family history information, failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Context: Adult Pediatric

Tier 3

Individuals may have atypical features (e.g., skin lesions), leading clinicians to not consider HLRCC for the diagnosis.

Context: Adult Pediatric

Tier 4

In one study of 37 families with genetically confirmed HLRCC, 24 (71%) of proband’s relatives with skin leiomyomas had not previously presented for medical attention. In most cases, individuals had noticed the lesions but had not sought medical advice because the lesions were long-standing and only mildly symptomatic. No individual who had presented with skin leiomyomas had been offered screening for uterine fibroids. Most individuals with severely symptomatic uterine fibroids had presented for treatment, but the syndrome had not been recognized because of little clinical awareness of the condition.

Context: Adult Pediatric

Tier 5

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			FH			150800	0007888

References List

Alam NA, Barclay E, Rowan AJ, Tyrer JP, Calonje E, Manek S, Kelsell D, Leigh I, Olpin S, Tomlinson IP. (2005) Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Archives of dermatology. 141(2):199-206.

Forde C, Lim DHK, Alwan Y, Burghel G, Butland L, Cleaver R, Dixit A, Evans DG, Hanson H, Lalloo F, Oliveira P, Vialard L, Wallis Y, Maher ER, Woodward ER. (2020) Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals. European urology oncology. 3(2588-9311):764-772.

Hereditary Leiomyomatosis and Renal Cell Cancer (PDQ(R)): Health Professional Version.. PDQ Cancer Information Summaries. Bethesda (MD) (2002) URL: https://www.ncbi.nlm.nih.gov/pubmed/33724749

HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER; HLRCC. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 150800, (2015) World Wide Web URL: http://omim.org/

Hereditary leiomyomatosis and renal cell cancer. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=523

Kamihara J, Schultz KA, Rana HQ.. FH Tumor Predisposition Syndrome.. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al., editors. GeneReviews((R)). Seattle (WA) (1993) URL: https://www.ncbi.nlm.nih.gov/pubmed/20301430

Ljungberg, B., Albiges, L., Bedke, J., Bex, A., Capitanio, U., Giles, R.H., Hora, M., Klatte, T., Marconi, L, Powles, T., Volpe, A.. EAU Guidelines on Renal Cell Carconima. European Association of Urology (2023) URL: https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelines-on-Renal-Cell-Carcinoma-2023.pdf

Malik K, Patel P, Chen J, Khachemoune A. (2015) Leiomyoma cutis: a focused review on presentation, management, and association with malignancy. American journal of clinical dermatology. 16(1179-1888):35-46.

Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM. (2014) Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Familial cancer. 13(1573-7292):637-44.

Motzer Rea. Motzer Rea. NCCN Clinical Practice Guidelines in Oncology, Kidney Cancer, Version 4.2023. NCCN Guidelines (2020) URL: https://www.nccn.org/guidelines/guidelines-process/transparency-process-and-recommendations/GetFileFromFileManagerGuid?FileManagerGuidId=3ff2cc19-675a-4927-8554-a9cdebde1147

Schultz KAP, Rednam SP, Kamihara J, Doros L, Achatz MI, Wasserman JD, Diller LR, Brugieres L, Druker H, Schneider KA, McGee RB, Foulkes WD. (2017) PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clinical cancer research : an official journal of the American Association for Cancer Research. 23(12):e76-e82.