Hereditary leiomyomatosis and renal cell cancer syndrome

Almost all women present with uterine fibroids, approximately 76% with dermal manifestations and 10–16% with renal tumors. 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 tend 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. 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. Two cases of ovarian mucinous cystadenoma have also been reported with this mutation. ==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. 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. 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. 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. Other genes involved affected by this mutation are Keap1, Nrf2 and HMOX1. ==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. Special histologic features of fibroids may allow an early diagnosis in absence of other symptoms. 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. 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 as sporadic uterine fibroids including anti-hormonal treatment, surgery, or embolisation. Substantially elevated risk of progression to or independent development of uterine leiomyosarcoma has been reported which may influence treatment methods. == Prognosis ==

A 2006 review stated that Reed's Syndrome often is the leading cause of 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%. ==History==

The syndrome was first described by Reed et al in 1973. The link with the fumarate hydratase gene was uncovered in 2002. == Epidemiology ==

HLRCC affects males and females equally. ==Notes==