Leiomyomatosis syndrome and hereditary kidney cancer is an autosomal dominant inheritance disorder characterized by skin leiomyomas, uterine leiomyomas, and poor prognosis type 2 papillary renal carcinoma. It is caused by germline mutations in FH, a gene that encodes for the protein fumarate hydratase, which participates in the Krebs cycle.
Although it is a rather rare disease, in 2016 Arenas et al. they make the first report of a Colombian family with this syndrome and it is not ruled out that there are other affected families, so improving knowledge about the disease in the country’s medical community is crucial. This review, based on an exhaustive search of literature, explains the pathophysiology and provides the main guidelines for the diagnosis and treatment of the syndrome.
Leiomyomatosis syndrome and hereditary kidney cancer (HLRCC) is a fairly rare disease of which there are no incidence and prevalence data at present. Since his first report in 1973 by Reed et al.1, a little more than 200 families in the world have been described in the world literature, being these in your majority from Norteamérica2,3, Uk, the Netherlands and Finlandia2.
This is an autosomal dominant inheritance pathology that can occur with 3 major clinical manifestations: skin leiomyomas, uterine leiomyomas, and type 2 papillary renal cancer, the latter with poor prognosis, early onset, and aggressive behaviour.4
In this article is a review of the most relevant aspects of this disease, purpose of the report by our group of research, as far as we know, the first colombian family with the syndrome HLRCC; in that he called attention to the presence along 4 generations of individuals affected by kidney cancer papillary type 2, who died for this cause to children5.
In this sense, a clinical and genetic characterization of 20 members of this family was performed, and in 6 of them – including testing, the only one affected by renal cancer at the moment-a mutation never described in the FH gene called c. 1349_1352delATGA was identified, which generates a truncation of the protein and is therefore considered pathogenic. Skin leiomyomas, which are the most common manifestation of the disease, were not found in any of the affected individuals.; but renal cysts, some rare tumors within the spectrum of HLRCC, and uterine leiomyomas in women were documented.5
Thus, the fundamental objective of this article is to contribute to the knowledge of the disease in our country, in an effort to improve the management of those suffering from this syndrome, which we believe may be being underdiagnosed
A narrative review was made. The literature search was conducted in the Pubmed, Science direct and Springer Link databases using keywords: HLRCC, fumarate hydratase, FH, diagnosis and treatment. The search boundaries were established between 1970 and 2016 and articles in languages other than English were excluded.
HLRCC syndrome is a predisposition to cancer disease, the clinical and molecular characterisation of which has occurred in a relatively recent period; it was only in 2001 that it was established with complete certainty that it was a disease with a dominant inheritance, in which some patients could develop, in addition to skin and uterine leiomyomas, a rare type of renal cancer, the papillary Type 26. In 2002, Tomlinson et al.7 they discover that it is produced by germline mutations in the FH gene (1q42.3-43), thus beginning to elucidate their pathophysiology.
Pathophysiology of leiomyomatosis syndrome and hereditary kidney cancer
In patients affected by the syndrome, it is believed that there is an almost complete loss of the activity of the fumarate hydratase, which results in an accumulation of fumarate intracelular9,13,14 which in turn generates 4 pathological effects main
Under stress conditions, it can be initiated by different cell damage (fig. 2), NRF2 dissociates from KEAP1 and escapes from the degradación19–22 then translocarse to the nucleus, where with the help of proteins musculo-aponeurotic fibrosarcoma (MAFK), is able to bind to the element ARE the promoter of their genes blanco19–23.
The importance of NRF2 in the pathophysiology of HLRCC is that it has been attributed both antitumoral and protumoral actions. The first have to do with which is able to induce pathways of cellular cytoprotection against the toxicity-derived reactive oxygen species (ROS), stress, electrophilic, radiation, drugs and toxinas15,21,22,24. On the other hand, the overexpression of NRF2 and some of its downstream genes may favor cell malignancy by increasing cellular survival routes 15,18,24-26, cellular growth 27,28, metastasis24, and chemoresistance.
More than 75% of those affected (carriers of FH mutation) may present them at an average age of 25 years. They are a series of papular or nodular lesions, of light brown or erythematous colour, which are distributed preferably on the back, trunk and extremities. Their diameter is approximately 0.4 and 2.5 mm, although they tend to increase their number and size with edad2,4.
In most cases, skin leiomyomas are asymptomatic; however,they are sometimes accompanied by pain or paraesthesia in the area where they are located.2,4 Histologically, they are recognized as smooth muscle cell clusters, with elongated oval nuclei