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There are less than 200 cases of hereditary leiomyomatosis and renal cell cancer (HLRCC) in the world.

Mutation of gene FH shortens the protein to 59 amino acids, passing from 510 to 451 amino acids. Photo: Bioinformatics and Systems Biology Professor Andrés Pinzón and students Andrea Cardona and Daniel Osorio)

One of the most frequent manifestations is the appearance of red or light brown skin lesions known as cutaneous leiomyomas.

The case arrived at the UNal Institute of Genetics.

There could be underdiagnosis of this type of cancer in Colombia among other reasons because skin leiomyomas may be confused with other types of conditions.

At the end of 2013, a 38 year man arrived at the Universidad Nacional de Colombia (UNal) Genetics Institute (IGUN, for its Spanish acronym) with a strange renal tumor pathology report: Papillary type 2. 

The fact that called the attention of IGUN geneticists, besides the renal tumor, was a family background which included data of eight family members which had passed away at relatively young ages (between 40 and 50 years of age) across three generations for the same type of cancer. 

With the information obtained they began a research project which ended in discovering a genetic mutation of the FH gene (responsible for the HLRCC syndrome) which had never been reported in Colombia. 

All genes code for proteins. The FH gene produces fumarate hydratase which participates in the Krebs cycle reaction in cell energy production. The mutation shortens the length of the protein causing a great impact on the normal function of the cell. 

“In this cycle fumarate turns into malate but when this reaction does not occur it accumulates in the cell and we believe this could cause cancer,” said UNal Human Genetics master’s student Carolina Arenas. 

Hereditary cancer 

The HLRCC syndrome has three main manifestations. The first and most frequent (75% of the cases and patients above 25 years of age) consists in the appearance of red or light brown skin lesions known as cutaneous leiomyomas. Occasionally they produce pain or a feeling of numbness. The second is the appearance of myomas in the uterus, irregular menstrual bleeding and pelvic pain. Given the seriousness of the symptoms women with HLRCC could require a hysterectomy or a surgical removal of the uterus, even before 30 years of age. The third manifestation is papillary type 2 cancer, a very aggressive tumor which only manifests itself between 10% and 16% of the patients and metastasizes in “young” stages of the tumor and for which most treatments are inefficient. 

In the case of the aforementioned patient the physical examination evidenced skin lesions. However the geneticists opted for a molecular confirmation of the diseases and sent blood samples to an American laboratory for gene sequencing. 

The laboratory confirmed the mutation and established that the protein had shortened from 510 amino acids to 451. The discovery also confirmed that the genetic alteration was indeed the causing agent of the HLRCC syndrome in this family. 

Once the report was confirmed the scientists contacted the other members of the family. They assessed a total of 19 “threatened” individuals between the ages of 12 and 66. After the analysis they discovered five people with the genetic mutation, three men and two women; none with skin lesions.

Arenas says this these results are in no way a death sentence as this is a disease which early detection and appropriate follow-up could have a great difference in treatment and prognosis. 

Possible subdiagnosis 

After the tests the researchers met with the family and carried out a genetic consultancy, both for those which were negative (without risk) as for those with positive results. 

The purpose was to explain the disease and provide advice and follow-up to the bearers of the mutation which included a dermatology assessment and an annual renal MRI to determine if lesions appear at any time. 

The study of this family, the first ever reported in Colombia with the HLRCC syndrome has scientists considering if this type of cancer has been underdiagnosed as skin leiomyomas are “very unspecific” and could be confused with other types of disorders. 

On the other hand as myomas are very normal in women (7 out of every 10 women) they can become unnoted if not linked to a hereditary disease. 

Furthermore as type 2 papillary cancer is infrequent in mutation bearers it is usually unnoticed. Also one of the lethal features of these tumors is that they generally do not produce symptoms and diagnosis is usually incidental. 

According to the experts, although the HLRCC syndrome is a very rare disease they do not dismiss that other families in Colombia could have this pathology so it is crucial to create awareness to the existence of this type of disorder among medical personnel (dermatologists, gynecologists, urologists and oncologists). 

Read the article in its entirety in Spanish at UN Periódico