PROS at a glance..
A syndrome family for malformation and overgrowth conditions caused by activating mutations in the same gene, PIK3CA.
Varying from an isolated skin lesion to severe overgrowth of the extremeties or brain. The mutation happens at random during early development, not every cell is affected and there is no known cases of inheritance. Only rarely is the mutation found in blood so testing should be done on affected tissue. There is no cure for PROS conditions, but advances made in targeted therapy is creating new hope for possible treatments.
About PIK3CA Related Overgrowth Spectrum (PROS)
Other variants of umbrella terms used for the same syndrome family
PIK3CA Associated Overgrowth Syndrome
PIK3CA-associated segmental overgrowth
Segmental PIK3CA Overgrowth syndromes
Segmental Overgrowth Disorders Due to PIK3CA
PIK3CA-associated somatic overgrowth disorders
PIK3CA Vascular Overgrowth Syndrom
Some of the currently identified conditions associated with PROS
The diagnostic umbrella term PROS for the wide range of overgrowth conditions caused by activating mutations in PIK3CA was designated by a workshop group at the National Institutes of Health (NIH) in 2013.
The mutation causes a change in one of the four DNA nitrogenous bases (A, T, C, G). This is called a missense mutation, basicly a copying error. Due to the change a different amino acid is inserted into the protein and in PROS conditions this creates an overactivity, a "gain of function".
All cells derived from the mutated founding cell will carry the mutation. This gives the person cells with two different genotypes, cells with the mutation and cells without. This is called genetic mosaicism. Meaning not every cell is affected, but theoretically cells with the mutation could influence nearby non-mutated cells. Timing of the mutation, specific location on the gene (mutation variant) and cell type may play a part in how much is affected and the severity.
The affected tissues can include all or some of the types of tissue found in the body. Due to this very wide spectrum of disorders, ranging from an isolated skin lesion to severe overgrowth of the extremities or brain with refractory epilepsy, some may have phenotypical features that clearly falls into one of the entities on the spectrum (entities that were named before the genetic cause was known), for others a clinical delineation can be difficult as features often can be overlapping. Some are now receiving a diagnosis of PROS instead of a single entity on the spectrum. PROS is then sometimes referred to as PIK3CA Related Overgrowth Syndrome. There are both upsides and downsides with receiving only this broader diagnosis.
PIK3CA is an oncogene, which is a gene that has the potential to
transform a cell into a tumour cell, and PIK3CA plays an important
role in tumor progression. There is a published article where 4 out
of 122 patients diagnosed with CLOVES syndrome developed
Wilms Tumor (also known as nephroblastoma, a rare kidney cancer,
all developed by age 2). There is a need for further risk assessment
for the other diagnosis on the spectrum, but on the basis of this article
quarterly abdominal scans up till the age of 8 (when the risk reduces) has been recommended.
You would usually not find the mutation in a blood sample and due to the mosaic nature genetic testing must be preformed correctly. The mutation can be confirmed by doing a Next Generation DNA sequencing (NGS), as standard sequencing is ineffective at detecting changes that only affects a small percentage of cells. Testing should be done on affected tissue taken by puncture biopsy (or collected from surgery). For patients with face/head involvement a non-invasive buccal swab, also called a cheek-swab have shown a high diagnostic sensitivity similar to detection rate in tissue biopsi. Other testing options for patients with face/head involvement are testing on shed teeth or gingival (gum) biopsy. The latter option can be done as a "brush biopsy" which is non-invasive. Since the mutation is mosaic a negative result does not necessarily rule out a clinical diagnosis on the PIK3CA Related Overgrowth Spectrum.
The significance of a confirmed mutation is espicially due of the rising
potential of pharmacological intervention.
I.e. targeted therapy/precision medicine and present and upcoming clinical trials where you’ll need a documented mutation in order to be considered for treatment.
Management will vary greatly depending on what's affected, but there is currently no cure for PROS conditions and treatment options are few. For surgical interventions there can often be seen recurrence of the overgrowth.
The advances made in targeted therapy is creating new hope for potential treatment.
One of the most promising drug treatments currently is the PIK3CA inhibitor
Alpelisib which have shown remarkable results in a (non clinical) study.
“During 6 months of treatment, all patients showed substantial clinical
improvement”. One of the authors of the article, Dr.Canaud, held a speech
about the results at the ESHG 2019. You can watch it here (from 57:00).
A clinical trial is rumored to start within 2020 (COVID-19 delays may occur).
The current drug treatment options are targeted therapeutic drugs in the
PI3K/AKT/mTOR signalling pathway. There are also several single, dual
and multi-target inhibitors for this pathway currently in development for
the treatment of several different forms of cancer.
Below is a description of the drug options currently available upon eligibility.
*Off-label means the use of a drug for a condition other than for that which it has been officially approved for.
Conditions on the PIK3CA Related Overgrowth Spectrum
Most of these conditions were defiened as single diagnostic entities before the genetic cause was known. Many patients may experience overlaps of features from the conditions on the spectrum. Following is a brief description of the currently identifyed conditions associated with the PIK3CA-Related Overgrowth Spectrum.
A neurological condition where one-half of the brain is abnormally larger than the other. The structure of the brain on the affected side may be markedly abnormal or show only subtle changes.
Isolated Lymphatic Malformation is characterized by fluid filled masses that often occur in the head and neck region.
Key features are capillary, lymphatic and venous malformations as well as bone and soft-tissue hypertrophy.
Megalencephaly-capillary malformation syndrome´s primary features are large brain (megalencephaly) and abnormalities of small blood vessels in the skin called capillaries (capillary malformations). Some also have segmental overgrowth.
Isolated overgrowth and malformation of a digit, whether of the hand or foot.
Overgrowth on one side of the body and may also be referred to as muscular hemihypertrophy
Skin lesions - Epidermal Nevus,benign lichenoid keratosis, or seborrheic keratosis
Abnormal overgrowth of cells in the skin.
Key features are capillary malformation of the lower lip, lymphatic malformation mainly on the face and neck, asymmetry, and partial/generalized overgrowth
CLOVES is an acronym for Congenital Lipomatous Overgrowth, Vascular malformation, Epidermal nevi, Skeletal/Spinal/scoliosis. Some of the most consistent features are Fatty Truncal Mass, vascular anomalies, skin lesions and abnormal extremities.
Fibro-Adipose Vascular Anomaly is characterized by tough, fibrous, fatty tissue infiltrating a muscle in one or more limbs. FAVA can also cause venous and/or lymphatic abnormalities.
Fibroadipose hyperplasia (FH) or Overgrowth (FAO)
Characterized by progressive patchy fatty, fibrous and/or blood vessel overgrowth of a limb or part of the body.
Facial Infiltrating Lipomatosis - A craniofacial overgrowth condition affecting one half of the face/skull. It affects both soft and hard tissues (facial skeleton including teeth).
HemiHyperplasia-Multiple Lipomatosis is a condition with key features being asymmetric nonprogressive overgrowth, multiple lipomas, and superficial vascular malformations
Articles about PIK3CA Related Overgrowth Spectrum - PROS
PROS Related Websites
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