Outgrowths related to PIK3CA (PROS: PIK3CA -related Overgrowth Spectrum) - Gen PIK3CA.
The obrecrecimientos s related PIK3CA gene, have found somatic mutations in this gene have been renamed PROS (PIK3CA -related Spectrum Overgrowth). These alterations form a set that can affect various regions of the body and vary in the severity of their clinical presentations in patients affected, so that some seem to have a specific distribution in some tissues while others are more pleiotropic.
Initially, in 1997, a new alteration Overgrowth with a combination including macrocephaly, megalencephaly, congenital telangiectasia, cutis marmorata and anomalies of different feet alteration known as congenital cutis marmorata telangiectasia described. Megalencephaly syndromes (MEG), sporadic disturbances arise as overgrowth, and are associated as additional variables malformations, such as cortical dysplasia, development of vascular abnormalities, distal limb malformations and dysplasias variables connective tissue. After two syndromes megalencephaly (MEG) were recognized:
- Syndrome megalencephaly-malformation capillary (MCAP: megalencephaly-Capillary Malformation syndrome), formerly called macrocephaly-malformation capillary (MCM: Macrocephaly-Capillary Malformation) syndrome, characterized by CNS involvement, deregulation of growth nervous system body asymmetries (hemihiperplasias ), vascular abnormalities and distal extremities malformations (polydactyly and syndactyly). This syndrome is characterized by a basic set of brain disorders including megalencephaly, ventriculomegaly (which may progress to hydrocephalus), cerebellar tonsillar ectopia (which may progress to Chiari malformation) and cerebral cortical abnormalities, especially Polymicrogyria -PMG -. Some clinical signs are similar to those found in MPPH syndrome (see below). The MCAP syndrome can be distinguished from MHHP somatoform syndrome based on facts found at birth, such as, especially capillaries vascular malformations skin on the face, and cutis marmorata; syndactyly and postaxial Polydactyly, or polysyndactyly; the connective tissue dysplasia and focal segmental growth or body.
- Syndrome Megalencephaly-Polymicrogyria-polydactyly-Hydrocephalus (MPPH: megalencephaly-polymicrogyria-Polydactyly-Hidrocephalus syndrome), which is closely related to MCAP syndrome, but lacks vascular malformations and syndactyly syndrome found in MCAP.
These two changes have similar brain involvement with megalencephaly (or hemimegalencephaly), ventriculomegaly Polymicrogyria and cerebellar tonsillar ectopia progresses to Chiari anomaly. In almost all cases the MCAP / MPPH syndromes described postzygotic mutations in PIK3CA gene, and in some cases mutations have been detected in the AKT3 and PIK3R2 genes. More recently CCND2 gene mutations in patients with MPPH syndrome lacking mutations in the genes of the PI3K / AKT pathway is described.
Besides the MCAP and MPPH syndrome, they described postzygotic PIK3CA gene mutations in other overgrowth syndromes, such as:
- CLOVES syndrome (Congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal abnormalities). This syndrome differs from MCAP syndrome further deregulation of growth, lipomatous tissues showing complex congenital overgrowths typically appear as lipomatous masses in the trunk, together with a combination of vascular and lymphatic malformations. This syndrome is characterized by a congenital lipomatous overgrowth, vascular malformations, epidermal nevus, skeletal and spinal anomalies (scoliosis).
- Hemihyperplasia multiple lipomatosa (HHML: Multiple hemihyperplasia lipomatosis). This process was originally described as moderate abnormalities of asymmetry and overgrowth with multiple subcutaneous lipomas, and hemihyperplasia could be static or slightly progressive.
- Overgrowth fibroadipose FAO (Fibroadipose overgrowth). This syndrome shares some clinical CLOVES syndrome and molecular characteristics, and may affect the trunk or limbs. It is characterized by progressive segmental overgrowths in various body regions including internal organs, subcutaneous, muscular, and skeletal tissues fibroadipose. The principal manifestation of this process is a progressive fibro segmental visceral and subcutaneous tissue overgrowth, sometimes associated with muscle and skeletal overgrowth. They have been recently diagnosed patients with facial infiltrative lipomatosis characterized by overgrowth hemifacial soft tissue and skeletal, dental early development, macrodontia, hemimacroglosia and mucosal neuromas. There are also overlaps between HHML demonstrations, FAO and some cases of CLOVES syndrome syndromes.
- Macrodactyly syndrome (Type I or lipofibromatoso Macrodactyly hamartoma of nerves), also known as lipomatosa macrodistofia. This process is characterized by enlargement of fibrofatty and bone tissue overgrowth, typically in the territory innervated by nerve with increased diameter and length of peripheral nerves. A subset of patients also have muscle hemihyperplasia macrodactilia. The original descriptions of syndromes macrodactilia, FAO and HHML overlapped and were difficult to distinguish from one another.
genetic alterations
These syndromes megalencephaly capillary malformation not inherited. In those affected, a mutation in the PIK3CA gene in a cell arises randomly during the early stages of development before birth. As the cells continue to divide, some cells have the mutation and not others, a condition known as mosaicism.
These processes are due to heterozygous mutations of PIK3CA postzygotic gene. This gene is part of the P13K / AKT / mTOR pathway, in which the products encoding 21 genes (PIK3R1, PIK3R2, PIK3CA, PTEN, PDK1, PDK2, KRAS, AKT1, AKT2, AKT3, rictor, MAPKAP1, mLST8 involved , mTOR, IRS1, GAB1, GAB2, THEM4, MAPK8I1, PTPN11, RAPTOR).
The PIK3CA gene (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), located on the long arm of chromosome 3 (3q26.3), encoding the p110 protein, a subunit of the enzyme phosphatidylinositol 3-kinase (PI3K ). The p110 catalytic subunit protein is because performing the action of PI3K, while the other subunit (encoded by a different gene), regulates the activity of the enzyme. Like other kinases, PI3K add a phosphate group to other proteins through phosphorylation. PI3K enzyme plays a role in chemical signaling within cells. PI3K signaling is important for many cellular activities, including cell growth and proliferation, cell migration, the coding of new proteins, the transport of substances within the cells, and cell survival. These functions are important for the development of tissues throughout the body, including the brain and blood vessels. It is believed that PI3K signaling may be involved in the regulation of various hormones and may play a role in the maturation of adipocytes.
Most PIK3CA gene mutations associated with MCAP substituted amino acids in the protein p110 resulting encoding a p110 subunit altered causing PI3K overactivation. The altered kinase signaling triggers a chemical unregulated in cells, allowing the cells to grow and divide continuously. Increased cell proliferation leads to overgrowth of the brain and other tissues and organs in people with MCAP. Despite the involvement of PIK3CA gene mutations in some cancers and excessive cell growth due to changes in this gene, individuals with MCAP not appear to have an elevated risk of developing cancer.
PIK3CA mutations in the gene found
Some mutations have been found in all related syndromes PIK3CA, and others only in some of them:
MCAP syndrome: E81K, R88Q, G364R, E365K, C378Y, E452K, E453K, E453del, E542K, E545K, E726K, G914R, Y1021C, T1025A, A1035V, H1047L, H1047R, M1043I, H1047Y, G1049S.
- CLOVES syndrome: C420R, E542K, E545K, H1047L, H1047R.
- Syndrome FAO / HHML: E542K, E545K, H1047L, H1047R.
- Macrodactyly: R115P, E542K, E545K, H1047L, H1047R
- Hemimegalencephaly: E542K, E545K.
- Muscular hemihyperplasia: E542K, E545K, H1047L, H1047R, L1067fs.
- Infiltrative lipomatosis facial: E452K, E453K, E453del, E542K, E545K, H1047L, H1047R.
- Epidermal Nevus: E542K, E545K.
- Seborrheic keratosis: E542K, E545K, H1047L, H1047R.
- Benign lichenoid keratosis: E542K, E545K.
Diagnostic criteria required for the diagnosis of PROS syndrome
- Presence of at least one somatic mutation. If you are not diagnosis should be considered only as presumptive PROS.
- Congenital onset or initial childhood.
- Overgrowth sporadic and mosaic.
- Some of the facts described below as associated or isolated criteria.
Criteria associated (two or more)
- Adipose, muscle, nerve, or skeletal overgrowth.
- Capillary, venous, or lymphatic arteriovenous: vascular malformations.
- Presence of epidermal nevus.
criteria isolated
- Large isolated lymphatic malformations.
- Macrodactyly isolated or overgrowth of feet or hands, limb overgrowth (synonyms: lipomatosa macrodistrofia, fibrolipoma macrodactilia, gigantism).
- Adipose stem overgrowth.
- Hemimegalencephaly (bilateral) / dysplastic / focal cortical dysplasia Megalencephaly.
- Presence of epidermal nevus.
- Seborrheic keratosis.
- Benign lichenoid keratosis.
differential diagnosis
Several syndromes to be differentiated from PROS syndrome because they share some clinical manifestations that overlap, such as the hemihiperplasias, overgrowths, vascular and skin abnormalities, tumor development, and scoliosis, among others.
These syndromes include:
- Proteus syndrome (PS: Proteus syndrome) - AKT1.
- PTEN tumor syndrome harmatoma (PHTS: PTEN hamartoma tumor syndrome) - Gene PTEN.
- Segmetario Cowden syndrome type II - Genes PTEN, KLLN, SDHB and SDHD.
- Neurofribromatosis type 1 - Gen NF1.
- Epidermal Nevus Syndrome - Gen FGFR3.
Tumor processes related to PIK3CA
- Squamous cell carcinoma, head and neck (squamous cell Head and neck carcinoma -HNSCC-)
The squamous cell carcinoma is a cancer that originates from squamous cells, which are located in the outer layer of the skin and mucous membranes. HNSCC is classified based on their location, can develop in the oral cavity, oropharynx, nasal cavity and paranasal sinuses, nasopharynx, larynx or hypopharynx. Depending on the location, the cancer may lead to the formation of ulcers in the mouth and throat, bleeding, sore mouth, congested sinuses, sore throat, ear pain, pain on swallowing or difficulty swallowing , hoarseness, shortness of breath and swelling of the lymph nodes. HNSCC may spread to other parts of the body such as the lymph nodes or lungs, which can be fatal.
PIK3CA mutations involved gene in squamous cell carcinoma resulting in the coding of a p110 subunit altered causing PI3K overactivation. The altered kinase signaling triggers a chemical unregulated in cells, allowing the cells to grow and divide continuously.
- other cancers
Mutations in PIK3CA gene are involved in many cancers, including ovarian cancer (30%), brain (27%), stomach (25%), breast (8%) and lung (4% ). These mutations are also involved in colorectal cancer. Mutations associated to cancer change specific amino acids in the protein p110. Two common mutations occur in the same region and the amino acid change glutamate at position 542 or position 545 the p110 protein, the amino acid lysine (Glu545Lys Glu542Lys and, respectively). Two other common mutations occur in other region, wherein the amino acid histidine is substituted for the amino acid arginine or leucine at position 1047 p110 (His1047Arg and His1047Leu respectively). PIK3CA gene mutations associated with cancer result encoding p110 subunit a and disrupts PI3K signal. An increase in PI3K signaling resulting in abnormal proliferation of cells, which causes the development of cancer.
PIK3CA gene mutations involved in the development of cancer are somatic, meaning they are acquired during a person 's life and are present only in tumor cells.
Tests in IVAMI: in IVAMI perform the detection of mutations in the PIK3CA gene or of other genes P13K / AKT / mTOR pathway such as AKT, PIK3R2 genes, by complete PCR amplification of the gene exons and subsequent sequencing.
Samples recommended: Genetically be a mosaicism, only some cells of the body, and even the affected area show mutations. Therefore, peripheral blood cells most likely not have, so that these samples are not recommended. They should be studied biopsy samples of affected tissues, possibly not including paraffin for higher performance in procedures. However, keep in mind that the usefulness of the samples depends on the percentage of affected cells containing, and under the best circumstances, only positive results are obtained in a limited percentage of cases. In some locations where the sample is not accessible without using invasive procedures, such as in cases of macrocephaly, results have been obtained using samples of saliva, especially when there is an overgrowth of the salivary glands. Recently they have obtained good results with samples of teeth, including deciduous teeth.