Hereditary leiomyomatosis and renal cell cancer syndrome

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Reed’s syndrome
Other namesFamilial leiomyomatosis cutis et uteri
Hereditary leiomyomatosis and renal cell carcinoma associated RCC -- high mag.jpg
Micrograph showing the characteristic hyalinized papillary cores found in some hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas. H&E stain.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or Reed's syndrome is rare autosomal dominant disorder associated with benign smooth muscle tumors and an increased risk of renal cell carcinoma. It is characterised by multiple cutaneous leiomyomas and, in women, uterine leiomyomas. It predisposes for renal cell cancer, an association denominated hereditary leiomyomatosis and renal cell cancer, [1] [2] and it is also associated with increased risk of uterine leiomyosarcoma. [3] The syndrome is caused by a mutation in the fumarate hydratase gene, which leads to an accumulation of fumarate. The inheritance pattern is autosomal dominant and screening can typically begin in childhood.

Contents

Signs and symptoms

Almost all women present with uterine fibroids, approximately 76% with dermal manifestations and 10–16% with renal tumors. [3]

The uterine fibroids tend to occur at younger age and larger and more numerous than in the general population. They may be distinguishable from sporadic fibroids by special histological features such as prominent nucleoli with perinucleolar halos. [4]

The skin presentation is of asymmetrical, reddish-brown nodules or papules with a firm consistency, predominantly located on the limbs (multiple cutaneous leiomyoma), although they may occur anywhere, including the face. The lesions, which are typically painful and most often present during the third decade of life, are piloleiomyomata—a benign smooth muscle tumour arising from the arrectores pilorum muscles of the skin. These tumours may also arise in the tunica dartos of the scrotum and the mammillary muscle of the nipple (genital leiomyoma), the smooth muscle of blood vessels (angioleiomyoma) and the lung (pulmonary lymphangioleiomyomatosis). [5] A pseudo-Darier sign may be present.

The renal cell carcinoma tends to be of the papillary (type 2) form and tends to occur more commonly in women than men with this syndrome. These cancers present earlier than is usual for renal cell carcinomas (typically in the twenties and thirties) and to be at relatively advanced stages at presentation. Tumours have rarely been reported in children. These tumours occur in ~20% of those with this mutation suggesting that other factors are involved in the pathogenesis.

These growths increase in size and number throughout the lifetime. [6] People with HLRCC have an approximately 15% chance of developing renal cell carcinoma in their lifetime. [7] This is most commonly type II papillary renal cell carcinoma, which is an aggressive form. [6]

Associated conditions

Other relatively rare conditions have been reported in association with this disease. It is not yet known if these associations are fortuitous or manifestations of the condition itself.

Cerebral cavernomas and massive, macronodular adrenocortical disease have also been reported in association with this syndrome. [8] [9] A case of cutis verticis gyrata, disseminated collagenoma and Charcot–Marie–Tooth disease in association with a mutation in the fumarate hydratase gene has also been reported. [10] Two cases of ovarian mucinous cystadenoma have also been reported with this mutation. [11]

Cause

HLRCC is an autosomal dominant condition caused by a mutation in the FH gene, which results in dysfunction of the citric acid cycle, leading to an accumulation of fumarate. [7] [12]

The fumarate hydratase gene is located on the long arm of chromosome 1 (1q42.3-43), spans 22 kilobases and has 10 exons; the first exon codes for a signal peptide.

Pathogenesis

While the pathogenetic mechanisms underlying the lesions remain unclear, it has been suggested that the accumulation of fumarate may lead to overexpression of the aldo-keto reductase enzyme, AKR1B10. [13] It has also been found that fumarate is present in the mitochondria and in the cytoplasm. The cytoplasmic form appears to have a role in the protection of DNA from molecular injury. [14] Fumarate has been shown to be a competitive inhibitor of prolyl hydroxylase. This inhibition leads to the stabilisation of a number of hypoxia-inducible factors which are thought to predispose to tumorigenesis. An alternative pathway for the metabolism of fumarate in the presence of these mutations has been described. [15] Other genes involved affected by this mutation are Keap1, Nrf2 and HMOX1. [16]

Diagnosis

The diagnosis is made either by testing of the fumarate hydratase activity in cultured skin fibroblasts or lymphoblastoid cells and demonstrating reduced activity (≤60%) or by molecular genetic testing. [3] Special histologic features of fibroids may allow an early diagnosis in absence of other symptoms. [4]

Histology

The skin lesions may be difficult to diagnose clinically but a punch biopsy will usually reveal a Grenz zone separating the tumour from the overlying skin. Histological examination shows dense dermal nodules composed of elongated cells with abundant eosinophilic cytoplasm arranged in fascicles (spindle cells). The nuclei are uniform, blunt-ended and cigar-shaped with only occasional mitoses. Special stains that may be of use in the diagnosis include Masson's trichrome, Van Gieson's stain and phosphotungstic acid–haematoxylin.

The renal cell carcinomas have prominent eosinophilic nucleoli surrounded by a clear halo.

Differential diagnosis

Differential diagnosis of this condition includes the Birt–Hogg–Dubé syndrome and tuberous sclerosis. As the skin lesions are typically painful, it is also often necessary to exclude other painful tumors of the skin (including blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumor and granular cell tumor; the mnemonic "BLEND-AN-EGG" may be helpful). Other skin lesions that may need to be considered include cylindroma, lipoma, poroma and trichoepithelioma; these tend to be painless and have other useful distinguishing features.

Treatment

Leiomyomas do not typically require treatment unless they cause pain. [6] The skin lesions may be difficult to treat as they tend to recur after excision or destructive treatment. Drugs which affect smooth muscle contraction, such as doxazosin, nitroglycerine, nifedipine and phenoxybenzamine, may provide pain relief.

Uterine fibroids can be treated with the same methods like sporadic uterine fibroids including antihormonal treatment, surgery or embolisation. Substantially elevated risk of progression to or independent development of uterine leiomyosarcoma has been reported which may influence treatment methods. [3]

The predisposition to renal cell cancer calls for screening and, if necessary, urological management.

Topical lidocaine patches have been reported to decrease in severity and frequency of pain cutaneous leiomyomas. [17]

Prognosis

A 2006 review stated that RS often leads renal cancer between ages 30–50. Renal cancer kills about 1 in 3 people, but 5-year survival rates improved between 1974–1976 and 1995–2000, from 52% to 64%. [18]

History

The syndrome was first described by Reed et al in 1973. [19] The link with the fumarate hydratase gene was uncovered in 2002. [20]

Epidemiology

HLRCC affects males and females equally. [6] Thus far, HLRCC has been found in 300 families worldwide. [12]

Notes

A database of the mutations of the fumarate hydratase gene is available. [21] Autosomal recessive mutations cause a serious neurological disease known as fumarase deficiency, which is associated with a variety of congenital lesions in the brain.

See also

Related Research Articles

<span class="mw-page-title-main">Renal cell carcinoma</span> Medical condition

Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, responsible for approximately 90–95% of cases. RCC occurrence shows a male predominance over women with a ratio of 1.5:1. RCC most commonly occurs between 6th and 7th decade of life.

<span class="mw-page-title-main">Leiomyoma</span> Medical condition

A leiomyoma, also known as a fibroid, is a benign smooth muscle tumor that very rarely becomes cancer (0.1%). They can occur in any organ, but the most common forms occur in the uterus, small bowel, and the esophagus. Polycythemia may occur due to increased erythropoietin production as part of a paraneoplastic syndrome.

<span class="mw-page-title-main">Benign tumor</span> Mass of cells which cannot spread throughout the body

A benign tumor is a mass of cells (tumor) that does not invade neighboring tissue or metastasize. Compared to malignant (cancerous) tumors, benign tumors generally have a slower growth rate. Benign tumors have relatively well differentiated cells. They are often surrounded by an outer surface or stay contained within the epithelium. Common examples of benign tumors include moles and uterine fibroids.

<span class="mw-page-title-main">Birt–Hogg–Dubé syndrome</span> Rare autosomal dominant cancer syndrome

Birt–Hogg–Dubé syndrome (BHD), also Hornstein–Birt–Hogg–Dubé syndrome, Hornstein–Knickenberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons is a human, adult onset, autosomal dominant genetic disorder caused by the FLCN gene. It can cause susceptibility to kidney cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles, called fibrofolliculomas. The symptoms seen in each family are unique, and can include any combination of the three symptoms. Fibrofolliculomas are the most common manifestation, found on the face and upper trunk in over 80% of people with BHD over the age of 40. Pulmonary cysts are equally common (84%) and 24% of people with BHD eventually experience a collapsed lung. Kidney tumors, both cancerous and benign, occur in 14–34% of people with BHD; the associated kidney cancers are often rare hybrid tumors.

<span class="mw-page-title-main">Uterine fibroid</span> Medical condition with benign tumors of uterus

Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bladder, causing a frequent need to urinate. They may also cause pain during penetrative sex or lower back pain. A woman can have one uterine fibroid or many. Occasionally, fibroids may make it difficult to become pregnant, although this is uncommon.

<span class="mw-page-title-main">Cowden syndrome</span> Medical condition

Cowden syndrome is an autosomal dominant inherited condition characterized by benign overgrowths called hamartomas as well as an increased lifetime risk of breast, thyroid, uterine, and other cancers. It is often underdiagnosed due to variability in disease presentation, but 99% of patients report mucocutaneous symptoms by age 20–29. Despite some considering it a primarily dermatologic condition, Cowden's syndrome is a multi-system disorder that also includes neurodevelopmental disorders such as macrocephaly.

<span class="mw-page-title-main">Fumarase</span> Type of enzyme

Fumarase is an enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial isoenzyme is involved in the Krebs cycle and the cytosolic isoenzyme is involved in the metabolism of amino acids and fumarate. Subcellular localization is established by the presence of a signal sequence on the amino terminus in the mitochondrial form, while subcellular localization in the cytosolic form is established by the absence of the signal sequence found in the mitochondrial variety.

Fumarase deficiency is an exceedingly rare autosomal recessive metabolic disorder in the Krebs cycle, characterized by a deficiency of the enzyme fumarate hydratase, which causes a buildup of fumaric acid in the urine and a deficiency of malate. Only 13 cases were known worldwide in 1990, after which a cluster of 20 cases was documented in a community in Arizona, US that has practiced successive endogamy.

<span class="mw-page-title-main">Nevoid basal-cell carcinoma syndrome</span> Medical condition

Nevoid basal-cell carcinoma syndrome (NBCCS) is an inherited medical condition involving defects within multiple body systems such as the skin, nervous system, eyes, endocrine system, and bones. People with this syndrome are particularly prone to developing a common and usually non-life-threatening form of non-melanoma skin cancer. About 10% of people with the condition do not develop basal-cell carcinomas (BCCs).

<span class="mw-page-title-main">Endometrial intraepithelial neoplasia</span>

Endometrial intraepithelial neoplasia (EIN) is a premalignant lesion of the uterine lining that predisposes to endometrioid endometrial adenocarcinoma. It is composed of a collection of abnormal endometrial cells, arising from the glands that line the uterus, which have a tendency over time to progress to the most common form of uterine cancer—endometrial adenocarcinoma, endometrioid type.

<span class="mw-page-title-main">Muir–Torre syndrome</span> Medical condition

Muir–Torre syndrome is a rare hereditary, autosomal dominant cancer syndrome that is thought to be a subtype of HNPCC. Individuals are prone to develop cancers of the colon, genitourinary tract, and skin lesions, such as keratoacanthomas and sebaceous tumors. The genes affected are MLH1, MSH2, and more recently, MSH6, and are involved in DNA mismatch repair.

<span class="mw-page-title-main">Papillary hidradenoma</span> Medical condition

A papillary hidradenoma, also termed hidradenoma papilliferum or mammary-like gland adenoma of the vulva, is a rare, but nonetheless most common benign tumor that occurs in and between anal and genital regions of females. These hidradenomas are sharply circumscribed, nodular tumors that usually develop in women's anogenital area but uncommonly occur in other sites in women and men. Papillary hidradenomas that develop outside of the anogenital region are termed ecctopic papillary hidradenomas or ectopic hidradenoma papilliferums.

<span class="mw-page-title-main">CYLD (gene)</span> Protein-coding gene in the species Homo sapiens

The CYLD lysine 63 deubiquitinase gene, also termed the CYLD gene, CYLD is an evolutionary ancient gene found to be present as far back on the evolutionary scale as in sponges. In humans, this gene is located in band 12.1 on the long arm of chromosome 16 and is known to code multiple proteins through the process of alternative splicing.

Genital leiomyomas are leiomyomas that originate in the dartos muscles, or smooth muscles, of the genitalia, areola, and nipple. They are a subtype of cutaneous leiomyomas that affect smooth muscle found in the scrotum, labia, or nipple. They are benign tumors, but may cause pain and discomfort to patients. Genital leiomyoma can be symptomatic or asymptomatic and is dependent on the type of leiomyoma. In most cases, pain in the affected area or region is most common. For vaginal leiomyoma, vaginal bleeding and pain may occur. Uterine leiomyoma may exhibit pain in the area as well as painful bowel movement and/or sexual intercourse. Nipple pain, enlargement, and tenderness can be a symptom of nipple-areolar leiomyomas. Genital leiomyomas can be caused by multiple factors, one can be genetic mutations that affect hormones such as estrogen and progesterone. Moreover, risk factors to the development of genital leiomyomas include age, race, and gender. Ultrasound and imaging procedures are used to diagnose genital leiomyomas, while surgically removing the tumor is the most common treatment of these diseases. Case studies for nipple areolar, scrotal, and uterine leiomyoma were used, since there were not enough secondary resources to provide more evidence.

<span class="mw-page-title-main">MORT (long non-coding RNA)</span> Non-coding RNA in the species Homo sapiens

MORT is a long non-coding RNA (lncRNA) of the intergenic type (lincRNA) that is specific to humans and great apes. The MORT transcript is produced in all mortal cell types, but is lost in a large fraction of the most common human cancers and therefore might have a tumor suppressive function.

<span class="mw-page-title-main">Papillary renal cell carcinoma</span> Medical condition

Papillary renal cell carcinoma (PRCC) is a malignant, heterogeneous tumor originating from renal tubular epithelial cells of the kidney, which comprises approximately 10-15% of all kidney neoplasms. Based on its morphological features, PRCC can be classified into two main subtypes, which are type 1 (basophilic) and type 2 (eosinophilic).

<span class="mw-page-title-main">Oncometabolism</span>

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CYLD cutaneous syndrome (CCS) is the recently designated term for three rare inherited cutaneous adnexal tumor syndromes: multiple familial trichoepithelioma (MFT1), Brooke–Spiegler syndrome (BSS), and familial cylindromatosis (FC). Cutaneous adnexal tumors are a large group of skin tumors that consist of tissues that have differentiated towards one of the four primary adnexal structures found in normal skin: hair follicles, sebaceous sweat glands, apocrine sweat glands, and eccrine sweat glands. CCS tumors are hair follicle tumors.

References

  1. ↑ Tolvanen, J.; Uimari, O.; Ryynanen, M.; Aaltonen, L. A.; Vahteristo, P. (2012). "Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening". Human Reproduction. 27 (6): 1865–9. doi: 10.1093/humrep/des105 . PMID   22473397.
  2. ↑ Toro, J.; Nickerson, M.; Wei, M.; Warren, M.; Glenn, G.; Turner, M.; Stewart, L.; Duray, P.; Tourre, O.; Sharma, N.; Choyke, P.; Stratton, P.; Merino, M.; Walther, M. M.; Linehan, W. M.; Schmidt, L. S.; Zbar, B. (2003). "Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America". The American Journal of Human Genetics. 73 (1): 95–106. doi:10.1086/376435. PMC   1180594 . PMID   12772087.
  3. 1 2 3 4 Pithukpakorn, M.; Toro, J. R. (2010) [2006]. Pagon, R. A.; Adam, M. P.; Bird, T. D.; Dolan, C. R.; Fong, C. T.; Stephens, K. (eds.). "Hereditary Leiomyomatosis and Renal Cell Cancer". GeneReviews. PMID   20301430.
  4. 1 2 Garg, K.; Tickoo, S. K.; Soslow, R. A.; Reuter, V. E. (2011). "Morphologic Features of Uterine Leiomyomas Associated with Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome". The American Journal of Surgical Pathology. 35 (8): 1235–1237. doi:10.1097/PAS.0b013e318223ca01. PMID   21753700. S2CID   1342593.
  5. ↑ Kogan, E. A.; Mikhaĭlov, O. I.; Sekamova, S. M.; Kornev, B. M.; Osipova, I. N.; Osipenko, V. I.; Romanova, E. A.; Mukhin, N. A. (2001). "Combination of pulmonary lymphangioleiomyomatosis with skin leiomyomatosis and uterine leiomyoma". Arkhiv Patologii. 63 (6): 39–44. PMID   11810925.
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  8. ↑ Campione, E.; Terrinoni, A.; Orlandi, A.; Codispoti, A.; Melino, G.; Bianchi, L.; Mazzotta, A.; Garaci, F. G.; Ludovici, A.; Chimenti, S. (2007). "Cerebral Cavernomas in a Family with Multiple Cutaneous and Uterine Leiomyomas Associated with a New Mutation in the Fumarate Hydratase Gene". Journal of Investigative Dermatology. 127 (9): 2271–2273. doi: 10.1038/sj.jid.5700851 . PMID   17476294.
  9. ↑ Matyakhina, L.; Freedman, R. J.; Bourdeau, I.; Wei, M. H.; Stergiopoulos, S. G.; Chidakel, A.; Walther, M.; Abu-Asab, M.; Tsokos, M.; Keil, M.; Toro, J.; Linehan, W. M.; Stratakis, C. A. (2005). "Hereditary Leiomyomatosis Associated with Bilateral, Massive, Macronodular Adrenocortical Disease and Atypical Cushing Syndrome: A Clinical and Molecular Genetic Investigation". Journal of Clinical Endocrinology & Metabolism. 90 (6): 3773–3779. doi: 10.1210/jc.2004-2377 . PMID   15741255.
  10. ↑ Marque, M.; Gardie, B.; Bressac De Paillerets, B.; Rustin, P.; Guillot, B.; Richard, S.; Bessis, D. (2010). "Novel FH mutation in a patient with cutaneous leiomyomatosis associated with cutis verticis gyrata, eruptive collagenoma and Charcot-Marie-Tooth disease". British Journal of Dermatology. 163 (6): 1337–1339. doi:10.1111/j.1365-2133.2010.09912.x. PMID   20560959. S2CID   32673334.
  11. ↑ Ylisaukko-Oja, S. K.; Cybulski, C.; Lehtonen, R.; Kiuru, M.; Matyjasik, J.; Szymañska, A.; Szymañska-Pasternak, J.; Dyrskjot, L.; Butzow, R.; Orntoft, T. F.; Launonen, V.; Lubiñski, J.; Aaltonen, L. A. (2006). "Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma". European Journal of Human Genetics. 14 (7): 880–883. doi: 10.1038/sj.ejhg.5201630 . PMID   16639410.
  12. 1 2 Reference, Genetics Home. "HLRCC". Genetics Home Reference. Retrieved 8 April 2019.
  13. ↑ Ooi, A.; Wong, J. C.; Petillo, D.; Roossien, D.; Perrier-Trudova, V.; Whitten, D.; Min, B. W. H.; Tan, M. H.; Zhang, Z.; Yang, X. J.; Zhou, M.; Gardie, B.; Molinié, V.; Richard, S. P.; Tan, P. H.; Teh, B. T.; Furge, K. A. (2011). "An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma". Cancer Cell. 20 (4): 511–523. doi: 10.1016/j.ccr.2011.08.024 . PMID   22014576.
  14. ↑ Yogev, Ohad; Yogev, Orli; Singer, E.; Shaulian, E.; Goldberg, M.; Fox, T. D.; Pines, O. (2010). Elledge, Steve (ed.). "Fumarase: A Mitochondrial Metabolic Enzyme and a Cytosolic/Nuclear Component of the DNA Damage Response". PLOS Biology. 8 (3): e1000328. doi: 10.1371/journal.pbio.1000328 . PMC   2834712 . PMID   20231875.
  15. ↑ Frezza, C.; Zheng, L.; Folger, O.; Rajagopalan, K. N.; MacKenzie, E. D.; Jerby, L.; Micaroni, M.; Chaneton, B.; Adam, J.; Hedley, A.; Kalna, G.; Tomlinson, I. P. M.; Pollard, P. J.; Watson, D. G.; Deberardinis, R. J.; Shlomi, T.; Ruppin, E.; Gottlieb, E. (2011). "Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase". Nature. 477 (7363): 225–228. Bibcode:2011Natur.477..225F. doi:10.1038/nature10363. PMID   21849978. S2CID   4397075.
  16. ↑ Kinch, L.; Grishin, N. V.; Brugarolas, J. (2011). "Succination of Keap1 and Activation of Nrf2-Dependent Antioxidant Pathways in FH-Deficient Papillary Renal Cell Carcinoma Type 2". Cancer Cell. 20 (4): 418–420. doi:10.1016/j.ccr.2011.10.005. PMC   3226726 . PMID   22014567.
  17. ↑ Hsu, Tina (2017). "Treatment of cutaneous leiomyomas with 5% lidocaine patches in a patient with hereditary leiomyomatosis and renal cell cancer (Reed syndrome)". JAAD Case Reports. 3 (5): 406–407. doi:10.1016/j.jdcr.2017.06.007. PMC   5581856 . PMID   28884140.
  18. ↑ Laber, Damian A. (2006). "Risk factors, classification, and staging of renal cell cancer". Medical Oncology. 23 (4): 443–454. doi:10.1385/MO:23:4:443. ISSN   1357-0560. PMID   17303902. S2CID   40025455.
  19. ↑ Reed, W. B.; Walker, R.; Horowitz, R. (1973). "Cutaneous leiomyomata with uterine leiomyomata". Acta Dermato-Venereologica. 53 (5): 409–416. doi: 10.2340/0001555553409416 . PMID   4127477. S2CID   34376892.
  20. ↑ Tomlinson, I. P. M.; Alam, N. A.; Rowan, A. J.; Barclay, E.; Jaeger, E. E. M.; Kelsell, D.; Leigh, I.; Gorman, P.; Lamlum, H.; Rahman, S.; Roylance, R. R.; Olpin, S.; Bevan, S.; Barker, K.; Hearle, N.; Houlston, R. S.; Kiuru, M.; Lehtonen, R.; Karhu, A.; Vilkki, S.; Laiho, P. I.; Eklund, C.; Vierimaa, O.; Aittomäki, K.; Hietala, M.; Sistonen, P.; Paetau, A.; Salovaara, R.; Herva, R.; Launonen, V. (2002). "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer". Nature Genetics. 30 (4): 406–410. doi:10.1038/ng849. PMID   11865300. S2CID   9756355.
  21. ↑ Bayley, J. P.; Launonen, V.; Tomlinson, I. P. (2008). "The FH mutation database: An online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency". BMC Medical Genetics. 9: 20. doi: 10.1186/1471-2350-9-20 . PMC   2322961 . PMID   18366737.
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