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Hereditary multiple cutaneous leiomyomatosis

Written2008-10Sadhanna Badeloe, Jorge Frank
Maastricht University Center for Molecular Dermatology (MUCMD), Department of Dermatology, University Hospital Maastricht, P. Debyelaan 25, Postbus 5800, 6202 AZ Maastricht, The Netherlands

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Other namesMultiple cutaneous and uterine leiomyomatosis (MCUL)
Hereditary leiomyomatosis and renal cell cancer (HLRCC)
Atlas_Id 10127
Genes implicated inFH  
Note Multiple cutaneous leiomyomatosis (MCUL) is characterized by multiple leiomyomas of the skin and uterus. When associated with renal cell cancer, this syndrome is referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC).
Inheritance Autosomal dominant with incomplete penetrance and variable expressivity.


Phenotype and clinics Hereditary multiple cutaneous leiomyomatosis is a tumor predisposition syndrome characterized by multiple cutaneous and uterine leiomyomas and an increased risk of developing renal cancer.
The penetrance of leiomyoma of the skin is very high. They tend to develop in the second to fourth decade of life as multiple grouped skin colored to brown-red papules. These benign skin lesions are typically painful in response to touch or cold. Leiomyomas gradually increase in size and number and the extent of skin lesions is variable, even within one family. Some patients suffer from extensive disease, with multiple leiomyomas covering large areas of the body, whereas others only have a few inconspicuous papules. Interestingly, multiple cutaneous leiomyomas do not exclusively manifest in a diffuse and symmetric fashion. Rather frequently, a segmental manifestation pattern of these tumors can be observed, most likely reflecting mosaicism.
Uterine leiomyomas occur in more than 90% of females with MCUL/HLRCC. These patients may have a medical history of menorrhagia and pelvic pressure or pain, frequently requiring a hysterectomy before the age of 30 years.
  Figure 1. Segementally distributed cutaneous leiomyomas on the left shoulder and chest. Figure 2. Diffuse and symmetrically distributed cutaneous leiomyomas on the back.
Neoplastic risk A small percentage (1 -17%) of families with MCUL also cluster renal cell cancer. The age of onset varies from 16 to 90 years. Type II papillary RCC is the predominant type of kidney malignancy in HLRCC. These tumors tend to be very aggressive. Metastases are seen in more than 50% of affected individuals, even in those with relatively small primary tumors. Furthermore, sporadic cases of collecting duct carcinoma, oncocytoma, clear cell carcinoma, and Wilms tumor have been described.
A minority of female patients with MCUL/HLRCC are apparently predisposed to the development of highly aggressive uterine leiomyosarcoma.
A broad range of other benign and malignant tumors has also been observed in MCUL/HLRCC families. These mostly anecdotal reports include breast, prostate, and bladder cancer, testis leydig cell tumors, ovarian and kidney cysts, cerebral cavernomas, and adrenal gland adenomas. However, the majority of the aforementioned tumors encountered in these families most probably are not directly associated with either MCUL or HLRCC.
Treatment While solitary cutaneous leiomyomas can be easily treated by surgical excision, multiple leiomyomas covering large surfaces of the body are difficult to manage. Several different treatment modalities have been described for symptomatic pain relief or tumor destruction in cutaneous leiomyomatosis, including pharmacological agents such as nifedipine, gabapentin, doxazosin, phenoxybenzamine, hyoscine, hydrobromide, and nitroglycerine or invasive therapeutic strategies comprising extensive surgical excision, CO2 laser ablation and cryotherapy, all with variable success.
For symptomatic uterine leiomyomas different surgical approaches can be considered, including myomectomy, hysterectomy or abdominal uterus extirpation. Prior to recommending a specific therapy the patient's individual concerns should always be respected though, in particular the specific symptoms and their effect on quality of life and the possible request to preserve fecundancy.
Prognosis Genetic counseling of patients and their relatives should be self-evident. Once the diagnosis of hereditary multiple cutaneous leiomyomatosis is made, affected individuals must be considered at risk for the occurrence of other tumors. Referral of all female patients to a gynecologist for annual evaluation is warranted.
There are no specific screening guidelines for HLRCC, most likely due to the rareness of the disease. We suggest that annual abdominal computational tomography could serve as screening procedure for both the detection of kidney tumors and uterine changes. Magnetic resonance imaging and ultrasound could serve as alternative techniques if contrast-enhanced computational tomography cannot be performed.

Genes involved and Proteins

Gene NameFH (fumarate hydratase).
Location 1q43
Description The FH gene spans 22 kb and consists of 10 exons.
Note FH is an enzyme of the Krebs cycle, which catalyzes the conversion of fumarate to malate.
Note To date, approximately 75 different mutations distributed throughout the FH gene have been reported in hereditary multiple cutaneous leiomyomatosis. These sequence deviations include missense, nonsense, frameshift, and splice-site mutations as well as whole gene and exonic deletions and, together, demonstrate the molecular heterogeneity associated with disorder caused by FH mutations.


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PMID 11807464
Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome.
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Arch Dermatol. 2005 Feb;141(2):199-206.
PMID 15724016
Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43.
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Am J Hum Genet. 2001 May;68(5):1264-9. Epub 2001 Mar 14.
PMID 11283798
Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer.
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J Mol Diagn. 2005 Oct;7(4):437-43.
PMID 16237213
Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.
Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, Potts ED, Crone M, Wilkinson S, Camacho-Martinez F, Jablonska S, Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S, Tomlinson IP.
Hum Mol Genet. 2003 Jun 1;12(11):1241-52.
PMID 12761039
Hereditary multiple cutaneous leiomyoma resulting from novel mutations in the fumarate hydratase gene.
Badeloe S, Bladergroen RS, Jonkman MF, Burrows NP, Steijlen PM, Poblete-Gutierrez P, van Steensel MA, van Geel M, Frank J.
J Dermatol Sci. 2008 Aug;51(2):139-43. Epub 2008 Jun 2.
PMID 18514489
From gene to disease; cutaneous leiomyomatosis.
Badeloe S, van Geel M, van Steensel MA, Steijlen PM, Poblete-Gutierrez P, Frank JA.
Ned Tijdschr Geneeskd. 2007 Feb 3;151(5):300-4.
PMID 17326474
Successful treatment of pain in two patients with cutaneous leiomyomata with the oral alpha-1 adrenoceptor antagonist, doxazosin.
Batchelor RJ, Lyon CC, Highet AS.
Br J Dermatol. 2004 Apr;150(4):775-6.
PMID 15099382
The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency.
Bayley JP, Launonen V, Tomlinson IP.
BMC Med Genet. 2008 Mar 25;9:20.
PMID 18366737
Cerebral cavernomas in a family with multiple cutaneous and uterine leiomyomas associated with a new mutation in the fumarate hydratase gene.
Campione E, Terrinoni A, Orlandi A, Codispoti A, Melino G, Bianchi L, Mazzotta A, Garaci FG, Ludovici A, Chimenti S.
J Invest Dermatol. 2007 Sep;127(9):2271-3. Epub 2007 May 3.
PMID 17476294
Familial leiomyomatosis cutis et uteri.
Cassetty CT.
Dermatol Online J. 2004 Nov 30;10(3):5.
PMID 15748575
Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer.
Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA.
Clin Exp Dermatol. 2005 Jan;30(1):75-8.
PMID 15663510
Treatment of multiple cutaneous leiomyomas with CO2 laser ablation.
Christenson LJ, Smith K, Arpey CJ.
Dermatol Surg. 2000 Apr;26(4):319-22.
PMID 10759817
Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene.
Chuang GS, Martinez-Mir A, Engler DE, Gmyrek RF, Zlotogorski A, Christiano AM.
Clin Exp Dermatol. 2006 Jan;31(1):118-21.
PMID 16309500
Familial multiple cutaneous leiomyomas.
Fernandez-Pugnaire MA, Delgado-Florencio V.
Dermatology. 1995;191(4):295-8.
PMID 8573925
Familial leiomyomatosis cutis et uteri (Reed's syndrome).
Garcia Muret MP, Pujol RM, Alomar A, Calaf J, de Moragas JM.
Arch Dermatol Res. 1988;280 Suppl:S29-32.
PMID 3408259
Familial leiomyomatosis: a review and discussion of pathogenesis.
Garman ME, Blumberg MA, Ernst R, Raimer SS.
Dermatology. 2003;207(2):210-3.
PMID 12920381
Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer.
Grubb RL 3rd, Franks ME, Toro J, Middelton L, Choyke L, Fowler S, Torres-Cabala C, Glenn GM, Choyke P, Merino MJ, Zbar B, Pinto PA, Srinivasan R, Coleman JA, Linehan WM.
J Urol. 2007 Jun;177(6):2074-9; discussion 2079-80.
PMID 17509289
Dohi Memorial Lecture. New aspects of cutaneous mosaicism.
Happle R.
J Dermatol. 2002 Nov;29(11):681-92.
PMID 12484429
Evidence for a founder effect of the germline fumarate hydratase gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer (HLRCC).
Heinritz W, Paasch U, Sticherling M, Wittekind C, Simon JC, Froster UG, Renner R.
Ann Hum Genet. 2008 Jan;72(Pt 1):35-40. Epub 2006 Oct 1.
PMID 17908262
Genetic heterogeneity among uterine leiomyomata: insights into malignant progression.
Hodge JC, Morton CC.
Hum Mol Genet. 2007 Apr 15;16 Spec No 1:R7-13. (Review)
PMID 17613550
Genodermatoses with malignant potential.
Holman JD, Dyer JA.
Curr Opin Pediatr. 2007 Aug;19(4):446-54.
PMID 17630610
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Holst VA, Junkins-Hopkins JM, Elenitsas R.
J Am Acad Dermatol. 2002 Apr;46(4):477-90; quiz, 491-4. (Review)
PMID 11907496
Multiple cutaneous and uterine leiomyomatosis (Reed's syndrome).
Kim G.
Dermatol Online J. 2005 Dec 30;11(4):21.
PMID 16403393
Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.
Kiuru M, Launonen V, Hietala M, Aittomaki K, Vierimaa O, Salovaara R, Arola J, Pukkala E, Sistonen P, Herva R, Aaltonen LA.
Am J Pathol. 2001 Sep;159(3):825-9.
PMID 11549574
Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families.
Kiuru M, Lehtonen R, Arola J, Salovaara R, Jarvinen H, Aittomaki K, Sjoberg J, Visakorpi T, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, Karhu A, Aaltonen LA.
Cancer Res. 2002 Aug 15;62(16):4554-7.
PMID 12183404
Type 2 segmental cutaneous leiomyomatosis.
Konig A, Happle R.
Acta Derm Venereol. 2001 Oct-Nov;81(5):383.
PMID 11800159
Type 1 segmental cutaneous leiomyomatosis.
Lang K, Reifenberger J, Ruzicka T, Megahed M.
Clin Exp Dermatol. 2002 Nov;27(8):649-50.
PMID 12472537
Inherited susceptibility to uterine leiomyomas and renal cell cancer.
Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3387-92. Epub 2001 Feb 27.
PMID 11248088
Conventional renal cancer in a patient with fumarate hydratase mutation.
Lehtonen HJ, Blanco I, Piulats JM, Herva R, Launonen V, Aaltonen LA.
Hum Pathol. 2007 May;38(5):793-6. Epub 2007 Jan 31.
PMID 17270241
Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors.
Lehtonen R, Kiuru M, Vanharanta S, Sjoberg J, Aaltonen LM, Aittomaki K, Arola J, Butzow R, Eng C, Husgafvel-Pursiainen K, Isola J, Jarvinen H, Koivisto P, Mecklin JP, Peltomaki P, Salovaara R, Wasenius VM, Karhu A, Launonen V, Nupponen NN, Aaltonen LA.
Am J Pathol. 2004 Jan;164(1):17-22.
PMID 14695314
Genetic basis of cancer of the kidney: disease-specific approaches to therapy.
Linehan WM, Vasselli J, Srinivasan R, Walther MM, Merino M, Choyke P, Vocke C, Schmidt L, Isaacs JS, Glenn G, Toro J, Zbar B, Bottaro D, Neckers L.
Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6282S-9S. (Review)
PMID 15448018
A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein.
Lorenzato A, Olivero M, Perro M, Briere JJ, Rustin P, Di Renzo MF.
Int J Cancer. 2008 Feb 15;122(4):947-51.
PMID 17960613
Novel mutation in a fumalate hydratase gene of a Japanese patient with multiple cutaneous and uterine leiomyomatosis.
Makino T, Nagasaki A, Furuichi M, Matsui K, Watanabe H, Sawamura D, Shimizu H, Shimizu T.
J Dermatol Sci. 2007 Nov;48(2):151-3. Epub 2007 Sep 4.
PMID 17768033
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Merino MJ, Torres-Cabala C, Pinto P, Linehan WM.
Am J Surg Pathol. 2007 Oct;31(10):1578-85.
PMID 17895761
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Pfaffenroth EC, Linehan WM.
Expert Opin Biol Ther. 2008 Jun;8(6):779-90. (Review)
PMID 18476789
Familial occurrence of a type 2 segmental manifestation of cutaneous leiomyomatosis.
Renner R, Sticherling M.
J Dtsch Dermatol Ges. 2005 Sep;3(9):695-9.
PMID 16173977
Type 2 segmental manifestation of cutaneous leiomyomatosis in four unrelated women with additional uterine leiomyomas (Reed's Syndrome).
Ritzmann S, Hanneken S, Neumann NJ, Ruzicka T, Kruse R.
Dermatology. 2006;212(1):84-7.
PMID 16319483
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Rothman A, Glenn G, Choyke L, Srinivasan R, Linehan WM, Cowen EW.
J Am Acad Dermatol. 2006 Oct;55(4):683-6.
PMID 17010749
Familial cutaneous leiomyomatosis.
Thyresson HN, Su WP.
J Am Acad Dermatol. 1981 Apr;4(4):430-4.
PMID 7229147
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA; Multiple Leiomyoma Consortium.
Nat Genet. 2002 Apr;30(4):406-10. Epub 2002 Feb 25.
PMID 11865300
Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B.
Am J Hum Genet. 2003 Jul;73(1):95-106. Epub 2003 May 22.
PMID 12772087
Cutaneous leiomyomatosis with type 2 segmental involvement.
Tsoitis G, Kanitakis J, Papadimitriou C, Hatzibougias Y, Asvesti K, Happle R.
J Dermatol. 2001 May;28(5):251-5.
PMID 11436362
The syndrome of hereditary leiomyomatosis and renal cell cancer (HLRCC): The clinical features of an individual with a fumarate hydratase gene mutation.
Varol A, Stapleton K, Roscioli T.
Australas J Dermatol. 2006 Nov;47(4):274-6.
PMID 17034471
Familial leiomyomata.
Vellanki LS, Camisa C, Steck WD.
Cutis. 1996 Jul;58(1):80-2. (Review)
PMID 8823555
Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.
Wei MH, Toure O, Glenn GM, Pithukpakorn M, Neckers L, Stolle C, Choyke P, Grubb R, Middelton L, Turner ML, Walther MM, Merino MJ, Zbar B, Linehan WM, Toro JR.
J Med Genet. 2006 Jan;43(1):18-27. Epub 2005 Jun 3.
PMID 15937070


This paper should be referenced as such :
Badeloe, S ; Frank, J
Hereditary multiple cutaneous leiomyomatosis
Atlas Genet Cytogenet Oncol Haematol. 2009;13(10):772-775.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes FH FH

External links

OrphanetHereditary leiomyomatosis and renal cell cancer
Other databaseleiomyomatosis and renal cell cancer /diseases/10096/hereditary-leiomyomatosis-and-renal-cell-cancer (GARD)
Other databaseThe FH Mutation Database
Genes implicated inFH   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

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