Renal cell carcinoma, uterine and cutaneous leiomyomas are the hallmarks of HLRCC [1]. Neither kidney tumors nor uterine leiomoymas are likely to cause any symptoms during early stages of the disease, but cutaneous nodules can readily be observed. They may form on the patients' trunk, arms or legs, and rarely on their face. Cutaneous leiomyomas are firm, skin-colored, reddish or brown papules or nodules initially measuring a few millimeters in diameter. Over time, existing tumors grow to a size of up to 2 cm and new leiomyomas develop. If they are touched, patients may describe paresthesias, increased sensitivity or even painfulness. It has been estimated that about 75% of HLRCC patients develop cutaneous leiomyomas during their life, with the mean age at symptom onset being 25 years [2]. By contrast, nearly all female patients will develop uterine leiomyomas or, less frequently, leiomyosarcomas. Most women develop multiple large uterine leiomyomas that are often symptomatic. Affected females report pelvic pain, irregular menstruation and menorrhagia [3].

Approximately one in five patients is eventually diagnosed with papillary renal cell carcinoma [3]. Despite the aggressiveness of HLRCC-associated kidney tumors, clinical symptoms are not usually noted until advanced stages of the disease. Few individuals present with flank pain, hematuria and a palpable abdominal mass, a symptom triad sometimes described as characteristic of renal cell cancer. Those suffering from metastatic renal cell carcinoma may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight, and report discomfort related to the site of metastatic spread.

The diagnosis of HLRCC relies on the identification of the underlying mutation in the FH gene. Targeted genetic studies should be carried out in patients presenting with multiple leiomyomas or in those presenting with a single leiomyoma but who have a family history of HLRCC. Patients diagnosed with type 2 papillary renal cell cancer should queried as to their medical history: Kidney tumors are often diagnosed years after the detection of leiomyomas and a connection between both findings may easily be overlooked.

In order to recognize and identify leiomyoma or leiomyosarcoma, and papillary renal cell carcinoma, diagnostic imaging and histological examinations are required:

• Sonography and computed tomography may be employed to display renal and uterine neoplasms, but magnetic resonance imaging is recommended to detect kidney tumors in an early stage [4]. Contrary to other forms of hereditary renal cell carcinoma, HLRCC-associated kidney tumors are often confined to one kidney and appear as solitary lesions [5].
• Histological studies are particularly necessary to distinguish cutaneous leiomyomas from other, more common dermatological lesions, to identify uterine neoplasms and to define the subtype of renal cell carcinoma. HLRCC-associated tumors are typically composed of large tumor cells with big nuclei and prominent eosinophilic nucleoli surrounded by a clear halo [3]. While leiomyomas consist of interlacing bundles of smooth muscle cells, abundant eosinophilic cytoplasm and an overall papillary or tubulopapillary architecture are characteristic of type 2 papillary renal cell carcinoma [6].

Finally, the FH gene has to be sequenced to identify the causal mutation and to confirm the diagnosis. If genetic studies don't provide confirmatory results despite an ongoing suspicion of HLRCC, fumarate hydratase activity may be measured [2].

Causal therapies aiming at a compensation of the effects of fumarate hydratase deficiency are not yet available, but clinical trials on the efficacy of vandetanib, bevacizumab and erlotinib in HLRCC are currently underway. At present, though, HLRCC-related tumors are generally removed by means of surgery:

• Asymptomatic cutaneous leiomyomas require no treatment. Surgical excision may be performed to alleviate paresthesias and pain in case of symptomatic lesions. Cryoablation and similar measures may also be considered. Pharmacotherapy is a further possibility to reduce pain due to cutaneous leiomyomas.
• In order to treat uterine tumors, affected females usually undergo hysterectomy. Myomectomy may be chosen to preserve fertility, but women should be advised of the high risk of recurrence and of the possibility of malignant transformation. In preparation for surgery or in order to provide temporary relief from symptoms associated with uterine tumors, gonadotropin-releasing hormone analogues may be administered.
• A conservative approach to therapy is often recommended for patients with hereditary renal cell cancer, but it is not acceptable in case of HLRCC. HLRCC-associated renal cell carcinomas are known to grow aggressively and to metastasize early. They should be surgically removed as soon as possible. Nephron-sparing surgery or partial nephrectomy with wide surgical margins is recommended [3]. Lymphadenectomy should be performed for better tumor staging.

Cutaneous and uterine leiomyomas may cause esthetic and fertility concerns as well as pain, but they are not life-threatening. The probability of leiomyoma transforming into leiomyosarcoma is equally low. By contrast, renal involvement is a matter of major concern. While papillary renal cell carcinomas are usually characterized as slow-growing neoplasms unlikely to metastasize, HLRCC-associated kidney cancer often grows aggressively and may form metastases despite an apparently "safe" tumor size [4]. In fact, metastatic disease has been reported in teenagers [7] [8]. Metastatic renal cell carcinoma is the most common cause of death in HLRCC patients.

HLRCC is inherited in an autosomal dominant manner with a high penetrance. The disease has been related to mutations in the FH gene, which encodes for fumarate hydratase and is located on the long arm of chromosome 1 [1]. More than 100 different mutations have been described to date and they may occur along the whole FH gene. Data regarding possible genotype-phenotype correlations are not yet available. However, some authors distinguish between multiple cutaneous and uterine leiomyomatosis or Reed syndrome, and HLRCC. Both diseases, if they are to be considered distinct entities, predispose for the development of cutaneous and uterine leiomyomas, but renal cell cancer is only observed in HLRCC patients. Both are caused by mutations in the FH gene, and this fact may either suggest strong genotype-phenotype correlations or the presence of genetic modifiers that trigger the onset of renal cancer. To date, such modifiers could not yet be identified [9].

The overall incidence and prevalence of HLRCC, a disorder that affects both men and women equally, are unknown [2]. It may be assumed that the disease is underdiagnosed, a fact that may have distinct causes. On the one hand, uterine leiomyoma, the most common manifestation of HLRCC, has a high prevalence in the general population. On the other hand, years may pass between the diagnosis of uterine and kidney tumors. Thus, it wouldn't come as a surprise if no connection is established between a medical history of uterine leiomyomatosis and renal cell cancer.

Both cutaneous and uterine leiomyomas develop in early adulthood, possibly even in adolescence, and thus about a decade earlier than in sporadic disease. Renal tumors are diagnosed at a mean age of 40 years, i.e., HLRCC patients diagnosed with kidney cancer are significantly younger than the remainder of people suffering from renal cell cancer [10].

As has been indicated above, HLRCC is caused by mutations in the FH gene. This gene encodes for fumarate hydratase, an enzyme catalyzing the conversion of fumarate to malate. This reaction is part of the Krebs cycle. Interestingly, fumarate is able to inactivate prolyl hydroxylases, which are enzymes required for the hydroxylation of hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α, respectively). Under physiological, normoxic conditions, hydroxylated HIF1α and HIF2α are degraded via ubiquitin-mediated proteolysis. Consequently, FH mutations associated with fumarate hydratase deficiency lead to an accumulation of fumarate, an inhibition of prolyl hydroxylases, an inadequate hydroxylation and insufficient degradation of HIF1α and HIF2α [11].

HIF1α and HIF2α are transcription factors that regulate the expression of genes encoding for glucose transporter GLUT1 and vascular endothelial growth factor, among others. If the expression of these genes is increased, as is the case with high concentrations of HIF1α and HIF2α, glucose uptake and vascularization are enhanced. These are favorable conditions for tumor growth. What's more, increased glucose uptake by tumor cells provides valuable substrates for glycolysis and ATP production, and partially compensates for the interruption of the Krebs cycle caused by fumarate hydratase deficiency [11].

HLRCC is inherited in an autosomal dominant pattern with very high penetrance. Thus, the vast majority of patients has a family history of HLRCC [7] [12]. In this context, genealogical analyses may help to identify possible carriers [13]. These people may undergo genetic tests before the onset of any symptoms. The respective studies should be carried out in childhood. In case of positive results, carriers should be referred for annual abdominal magnetic resonance imaging. Screenings should start in the early second decade of life and continue until old age, because aggressive neoplasms have been detected in HLRCC patients aged 10 to 77 years [4] [5].

HLRCC is a hereditary cancer susceptibility syndrome that has first been defined by Launonen et al. in 2001 [5]. However, an association between cutaneous and uterine benign smooth muscle tumors had been established before: The disease has previously been called "multiple cutaneous and uterine leiomyomatosis" or "cutaneous leiomyomata with uterine leiomyomata" [14].

HLRCC patients are prone to develop cutaneous and uterine leiomyomas and possibly leiomyosarcomas as well as papillary renal cell carcinoma. The disease is caused by germline mutations in the FH gene, which encodes for an enzyme partaking in the tricarboxylic acid or Krebs cycle, but which is also implicated in the regulation of transcription factor levels. Carriers of the mutated allele are likely to develop multiple cutaneous leiomyomas in early adulthood and virtually all affected women are diagnosed with uterine leiomyomatosis during their third or fourth decade of life. Fortunately, life-threatening renal cell carcinoma has the lowest penetrance of all traits associated with HLRCC. It affects about 20% of HLRCC patients and is of the type 2 papillary subtype. It is characterized by aggressive growth and a high tendency to metastasize.

Surgery is the treatment of choice for uterine and renal tumors, and surgical interventions may also be required to remove single cutaneous leiomyomas. Otherwise, an ablative approach may be chosen to treat the latter. The overall prognosis of HLRCC patients is good if they don't develop renal cell carcinoma. HLRCC-associated kidney tumors are associated with a poor prognosis and is usually fatal within less than five years.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a cancer susceptibility syndrome caused by mutations in the FH gene, which is located on chromosome 1. The disease is inherited in an autosomal dominant manner, i.e., people will suffer from HLRCC if they inherit a mutated allele from either one of their parents. Renal cell carcinoma, uterine and cutaneous leiomyomas are the hallmarks of HLRCC:

• Affected individuals are likely to develop cutaneous leiomyomas during their third decade of life. These are benign tumors that may be of skin tones, pink or reddish color, that measure a few millimeters in size but may grow up to a size of 2 cm. Cutaneous leiomyomas may be painful and are most commonly found on the trunk, on arms or legs. If necessary, their surgical excision can be performed.
• In their third or fourth decade of life, women suffering from HLRCC tend to develop uterine leiomyomas, which are also benign tumors. However, they may reach a considerable size and cause pelvic pain and irregular menstruation. Women who want to preserve their fertility may opt for the surgical removal of uterine leiomyomas, but there are often multiple tumors and the risk of recurrence is high. Thus, the surgical removal of the entire uterus is usually done.
• About one in five HLRCC patients is eventually diagnosed with renal cancer. This diagnosis is made at a mean age of 40 years. Because HLRCC-associated kidney tumors tend to grow aggressively and to metastasize early, the require a proactive approach to therapy and early surgery.

People with a family history of HLRCC may get tested for mutations in the FH gene. If genetic analyses yield positive results, they are recommended to undergo annual screenings to detect uterine and renal tumors as early as possible.

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