Facial Infiltrating Lipomatosis (FIL), which is also called:
All of the above synonyms are being used for the same ultra-rare craniofacial overgrowth condition. FIL is a congenital (meaning born with), non hereditary, condition that causes overgrowth of one half of the face. The manifestation is very variable ranging from mild to severe. The overgrowth is typically present at birth.
FIL was first described in 1983 by Slavin and colleagues. About 59 reported cases have been found in literature. There are likely many undiagnosed, misdiagnosed and those who have not been published in medical literature. The condition seems to affect boths genders equally and is seen among different ethnicities.
FIL can be an isolated condition or as a component of other conditions like CLOVES syndrome which is also a part of the PIK3CA Related Overgrowth Spectrum (PROS). You can read more about PROS further down this page.
Signs & symptoms
The most common features, affecting only one side of the face, are:
Not all patients with FIL have all these symptoms.
A diagnosis of FIL can be based solely on clinical observations. Magnetic Resonance Imaging (MRI) provides the best delineation.
The cause of FIL is a mutation in the PIK3CA gene. The mutation is mosaic, meaning that it is not in every cell. There are several other rare overgrowth conditions caused by PIK3CA and they have been gathered under the umbrella term PIK3CA Related Overgrowth Spectrum (PROS). You can read more about the cause under "Genetics" on this page.
For FIL patients the PIK3CA mutation can be confirmed by doing a Next Generation DNA sequencing on affected tissue taken by puncture biopsy (or collected from surgery) or a mouth swab. The latter is a pain-free option we recommend. You will not find the mutation in a blood sample. Since the mutation is mosaic a negative result does not rule out a clinical diagnosis of FIL(/PROS).
There is currently no cure for FIL(/PROS) and treatment options are few. Options are surgical treatment with a very high risk of post-op regrowth (79% chance reported in article review) and/or drug treatment. Surgical removal of the fatty tissue is often subtotal due to it infiltrating important facial structures.
The current drug treatment options are targeted therapeutic drugs in the PI3K/AKT/mTOR signalling pathway. Below is a description of the drug options.
Rapamycin / Sirolimus
This drug is indicated for the prevention of organ transplant rejection and the treatment of a rare lung disease, but there has been off-label use of this drug for patients with overgrowth diseases for several years.
The conclusion from a recent study of Rapamycin in PROS patients:
“This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS.”
Miransertib / ARQ092
This drug is currently in clinical trial for the treatment of both PROS and Proteus Syndrome (another overgrowth condition caused by AKT1 mutation). Interim data from phase 1/2 of this trial showed a manageable safety profile and the majority of patients demonstrated no disease progression. This trial is still open for recruitment.
Alpha-specific PI3K (PIK3CA) inhibitor
Alpelisib / Piqray (previously BYL719)
Was FDA approved summer 2019 for the treatment of HR+/HER2- advanced breast cancer.
A (non clinical) study was published in Nature June 2018 about a cohort of 19 PROS patients who were given the drug and all patients demonstrated great improvements and minimal side effects by this treatment (long term side effects still unknown).
This drug is currently only available through compassionate use program/managed access program, for those who are eligable. A clinical trial for PROS patients is rumored to start soon (2020). A retrospective study of PROS patients who have received Alpelisib as part of a compassionate use program is estimated to start March 18th with completion date June 30th.
Above is a simplified illustration of the PI3K/AKT/mTOR signaling pathway. A crucial pathway for cell survival, angiogenesis (development of new blood vessels) and proliferation (reproduction).
Growth factor (i.e. insulin) activities PI3K, which will further activate AKT, which will in turn activate mTOR. mTOR influences diverse transcription factors that finally leads to the expression of the gene products (growth, angiogenesis, proliferation).
Included in the illustration are the above mentioned inhibitors and where they target in the pathway.
There are several single, dual and multi-target inhibitors for this pathway currently in development for the treatment of several different forms of cancer.
PIK3CA is an oncogene (a gene that has the potential to cause cancer) that plays an important role in tumor progression, but it does NOT seem that FIL patients are more prone to cancer. There is however a need for collection of data and research about the risk. In one article there were 4 out of 122 patients with the PROS condition CLOVES who had been diagnosed with Wilms’ tumor. On the basis of this article quarterly abdominal scans up till the age of 8 (when the risk reduces) has been recommended. No FIL patients have been reported to have had Wilms’ tumor.
The cause of FIL is a random, non-inherited mutation in the PIK3CA gene located on the long arm of chromosome 3. It occurs in the early stages of development. In one of the cells one of the four DNA nucleotides is changed, which is called a missense mutation. This change causes a different amino acid to be inserted into the protein. In FIL this amino acid change creates an overactivity, a gain of function. Cells derived from this mutated founding cell will also carry this mutation. This gives the person cells with two genotypes, cells with the mutation and cells without. It's called mosaicism. So not every cell is affected, but theoretically the cells with this mutation may influence non-mutated cells nearby.
Illustration of a gene without and one with a missense mutation.
Gain of function mutations in the PIK3CA gene can cause a wide range of rare malformation and overgrowth diseases. These diseases have been gathered under the collective term PIK3CA Related Overgrowth Spectrum (PROS). Some may have phenotypic features that clearly falls into one of the entities, but for others clinical delineation can be difficult as features can be overlapping.
This website is intended to connect families and people with the condition, share experiences, provide information and support. The website is not intended for medical diagnostic use or to replace medical consultation. No images on this website may be used or reproduced.
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