All of the above are names being used for the same ultra-rare craniofacial overgrowth syndrome. One differential diagnosis is Congenital Hemifacial Hyperplasia (previously called Hemifacial Hypertrophy), but for this diagnosis the facial asymmetry remains consistent without progressive growth and the infiltrative lipocytes (fat cells).
Facial Infiltrating Lipomatosis, or FIL, is a congenital (meaning born with), non hereditary, disorder that causes overgrowth of one half of the face. The manifestation is variable ranging from mild to severe. The overgrowth is typically present at birth.
The condition was first described in 1983 by Slavin and colleagues. About 59 reported cases of FIL have been found in literature. Though ultra-rare (by definition less than 1 in 50 000) the prevalence of FIL is likely underestimated as there are multible terminologies for the condition, many undiagnosed, misdiagnosed and those who have not been published in medical literature. The condition seems to affect both genders equally and is seen among different ethnicities.
FIL can be an isolated condition or associated with other conditions like Hemimegalencephaly and CLOVES syndrome which are also a part of the PIK3CA Related Overgrowth Spectrum (PROS). You can read more about PROS further down this page.
A diagnosis of FIL can be based solely on clinical observations. Magnetic Resonance Imaging (MRI) provides the best delineation.
FIL is a diagnosis on a spectrum and to precisely differ between the variations can sometimes be difficult. Some doctors may not want to make a clinical delineation between the different entities on the spectrum and instead diagnose patients with the umbrella terms like Segmental Overgrowth Syndrome or PROS Syndrome. Each of the conditions on the spectrum brings with them a set of very different issues. Being affected in ones feet or spine is quite different from being affected in ones face. And due to the rarity of these conditions connecting with others with the same condition is important. Most doctors you meet will never have heard of these conditions before let alone treated it. WonderFIL smiles aimes to bridge the gap and can lead you towards experienced doctors.
If you do not have any experienced doctors near you, Boston Children’s Hospitals Vascular Anomalies Center does case reviews each week in conference meetings. They review medical history, look at photographs, radiographic images and pathology slides sent in by referring physicians or families from across the United States and around the globe. Based on this information, the team provides diagnoses and treatment recommendations, and answers specific questions posed to them by physicians and families, without the patient having to travel to Boston. Find out more about getting a free case review here.
The most common features, affecting only one side of the face, are:
Please note that not all patients with FIL have all these symptoms.
Mutations in the PIK3CA gene have been found to be the cause of Facial Infiltrating Lipomatosis. A non-hereditary spontaneous mutation arising in a cell during early stages of development. 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 buccal swab (cheek-swab). The latter is a pain-free option we recommend if you have no previous collected tissuesample. 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.
There is currently no cure for FIL(/PROS) and treatment options are few. Options are surgical with a very high risk of recurrence after surgery (79% chance reported in article review) and/or drug therapy. Surgical removal of the fatty tissue is often difficult due to it infiltrating important facial structures.
The current drug treatment options are targeted therapeutic drugs in the PI3K/AKT/mTOR signalling 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. The advances made in precision medicine is creating new hope for potential treatment. Below is a description of the drug options currently available upon eligibility.
Alpha-specific PI3K (PIK3CA) inhibitor
Generic name: Alpelisib Brand Name: Piqray (previously BYL719)
Alpelisib was FDA approved the summer of 2019 for the treatment of
HR+/HER2- advanced breast cancer. A (non clinical) study was published in the
science journal Nature in 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 started June 6th with completion date August 14th.
Generic name: Miransertib Name: ARQ 092
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. A preprint of an article (not undergone peer review)
published May 29th 2020 on the use of this drug in two children (one wit FIL)
can be found here.
Generic name: Sirolimus Brand Name: Rapamune
A drug 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.”
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.
The cause of Facial Infiltrating Lipomatosis 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. Why this mutation spontaneously occurs is not known. In one of the cells one of the four DNA nucleotides is changed, which is called a missense mutation, a copying error. 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.For people with FIL the cells that carry the mutation are restricted to one half of the face and/or skull. Timing of when the mutation occurred, how much is affected and severity varies greatly and is highly individual.
Below is an illustration of a gene without and one with a missense mutation. The nucleotide Adenine, which should be base paired with Thymine, is changed into Guanine (which should be paired with Cytosine). RNA bases are in groups of three and this is how amino acids are coded for. In the example below it reads the amino acid H (for Histidine), but in the one with the mutation it is A (for Arginine).
If we call DNA the recipe, then RNA is what brings the recipe to life.
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 4 out of 122 patients with the PROS condition CLOVES had been diagnosed with Wilms’ tumor (also known as nephroblastoma - a rare kidney cancer). 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.
PIK3CA Related Overgrowth Spectrum - PROS
Gain of function mutations in the PIK3CA gene can cause a wide range of rare malformation and overgrowth disorders. These conditions have been gathered under the collective umbrella 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 leaves some to only receive a diagosis of PROS, sometimes called PIK3CA Related Overgrowth Syndrome.
The mutation is only rarely detected in a bloodtest. Testing should be done on tissuesamples of the overgrowth area.
This website is intended to connect families and people with Facial Infiltrating Lipomatosis (FIL), share experiences, provide information and support.
It 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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