FaCD Online Syndrome Fact Sheet

Last updated: 31 May 2011

Name: Hereditary Leiomyomatosis and Renal Cell Cancer

Synonym: HLRCC, Reed syndrome, Hereditary Multiple Leiomyomata of Skin and Uterus

Mode of Inheritance: AD

Genes

FH, mapped to 1q42.1

Tumor features

collecting duct renal cell cancer
cutaneous leiomyoma
renal cell cancer, papillary type 2
uterine leiomyoma

Tumor features (possible)

(sub)cutaneous angioleiomyoma
breast cancer
gastrointestinal stromal tumor (GIST)
leiomyosarcoma
urinary bladder cancer
Wilms' tumor (nephroblastoma)

Comment

Familial multiple cutaneous leiomyomata have been reported[1].The skin lesions may develop as early as in puberty and appear to arise from the arrector pilorum muscle of the hairs (piloleiomyoma), for classification see Thyresson and Su[2]. In some families the cutaneous lesions are associated with uterine leiomyomata[2-4], a combination also reported in sporadic cases[5]. Renal cell cancer of various histology, predominantly the papillary type (type II), is a known complication (10-16%) of the syndrome[6-10,14]. Tubulo-papillary, tubular, mixed and solid tumors have also been observed. Merino et al suggested that the hallmark of renal tumors in this syndrome is the presence of a characteristic large nucleus with a very prominent inclusion like orangiophilic or eosinophilic nucleolus, surrounded by a clear halo.[14]. The renal tumors are considered to be more aggressive than in other hereditary renal cancer syndromes[13]. HLRCC may present with renal cell cancer in the absence of other features of the syndrome and/or a positive family history[17]. It has therefore been suggested to test the FH gene in every patient with type 2 papillary renal cell cancer diagnosed before the age of 40 years, or when the renal tumour harbours characteristic histologic features[17].

A few other tumor types have been suggested to be associated with HLRCC. Lehtonen studied Finnish families with the syndrome and found some evidence for the association of breast and bladder carcinoma[15]. The combination of familial multiple piloleiomyomas with a solitary angioleiomyoma has been reported once[11] and a case of GIST[12] and Wilms' tumor[16] has been reported as well.

References

[1] Kloepfer HW, Krafchuk J, Derbes V, Burks J. Hereditary multiple leiomyoma of the skin. Am J Hum Genet 1958; 10:48-52.
[2] Thyresson HN, Su WP. Familial cutaneous leiomyomatosis. J Am Acad Dermatol 1981; 4(4):430-434.
[3] Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol (Stockh) 1973; 53:409-416.
[4] Garcia Muret MP, Pujol RM, Alomar A, Calaf J, de Moragas JM. Familial leiomyomatosis cutis et uteri (Reed's syndrome). Arch Dermatol Res 1988; 280(Suppl):S29-32.
[5] Engelke H, Christophers E. Leiomyomatosis cutis et uteri. Acta Derm Venereol 1979; 59(suppl.85):51-54.
[6] 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, Aittomäki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA, . Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature genetics 2002; 30(4):406-10.
[7] Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clinical and experimental dermatology 2005; 30(1):75-8.
[8] Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. The British journal of dermatology 2005; 153(1):11-7.
[9] 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. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. American journal of human genetics 2003; 73(1):95-106.
[10] 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. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. Journal of medical genetics 2006; 43(1):18-27.
[11] Rikihisa W, Kiryu H, Furue M. Multiple piloleiomyomas associated with solitary angioleiomyoma. Eur J Dermatol 1999; 9(4):309-310.
[12] Lamba M, Verma S, Prokopetz R, Pierscianowski TA, Jabi M, Moyana T. Multiple cutaneous and uterine leiomyomas associated with gastric GIST. Journal of cutaneous medicine and surgery 2005; 9(6):332-5.
[13] Grubb RL, 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. Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. The Journal of urology 2007; 177(6):2074-9; discussion 2079-80.
[14] Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. The American journal of surgical pathology 2007; 31(10):1578-85.
[15] Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, Salovaara R, Herva R, Koivisto PA, Vierimaa O, Aittomäki K, Pukkala E, Launonen V, Aaltonen LA. Increased risk of cancer in patients with fumarate hydratase germline mutation. Journal of medical genetics 2006; 43(6):523-6.
[16] Badeloe S, van Spaendonck-Zwarts KY, van Steensel MA, van Marion AM, van Essen AJ, Jonkman MF, Steijlen PM, Poblete-Gutiérrez P, van Geel M, Frank J. Wilms tumour as a possible early manifestation of hereditary leiomyomatosis and renal cell cancer? Br J Dermatol. 2009 Mar;160(3):707-9.
[17] Gardie B, Remenieras A, Kattygnarath D, Bombled J, Lefèvre 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, Méjean A, Mortemousque I, Plessis G, Poppe B, Pruvost-Balland C, Rooker S, Roume J, Soufir N, Steinraths M, Tan MH, Théodore C, Thomas L, Vabres P, Van Glabeke E, Meric JB, Verkarre V, Lenoir G, Joulin V, Deveaux S, Cusin V, Feunteun J, Teh BT, Paillerets BB, Richard S; on behalf of the French National Cancer Institute "Inherited predisposition to kidney cancer" network. 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 Mar 12. [Epub ahead of print]