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Disease Profile

PIK3CA-related overgrowth spectrum

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

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ICD-10

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Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

PIK3CA-associated segmental overgrowth

Summary

PIK3CA-related overgrowth spectrum (PROS) is a group of rare disorders that cause overgrowth of parts of the body, due to mutations in the PIK3CA gene. Specific disorders in this spectrum include:[1][2][3][4]

Signs and symptoms of PROS depend on the specific disorder present. Depending on the disorder, they can include having a larger-than-normal brain (megalencephaly), low muscle tone (hypotonia), seizures, intellectual disability, changes in the blood vessels (vascular system), and overgrowth of one area of the body (focal overgrowth) or of multiple areas of the body (segmental overgrowth), with normal growth elsewhere.[1]

PROS is usually caused by somatic mutations in the PIK3CA gene. These changes typically are only present in some cells or some areas of the body (called mosaicism), and are not known to be inherited. Rarely, PROS is caused by a de novo germline mutation, which is present in all cells of the body. The diagnosis of a PROS disorder can be confirmed with genetic testing of the PIK3CA gene. Treatment for a PROS disorder may involve surgical interventions, special education, and speech and physical therapies.[1]

Symptoms

The signs and symptoms of PIK3CA-related overgrowth spectrum (PROS) vary depending on the particular disorder each person has. for example:

CLOVES syndrome
is associated with fatty (lipomatous) growths that typically affect the trunk; blood vessel differences (vascular malformations); patches or growths on the skin (epidermal nevi); and differences in the bones (skeletal system). Skeletal abnormalities can include a curve in the spine (scoliosis) and having very large fingers or toes (macrodactyly). Fibroadipose hyperplasia typically has signs and symptoms that are very similar to those of CLOVES syndrome.[1]

Megalencephaly-capillary malformation syndrome (MCAP syndrome) is associated with having a very large brain (megalencephaly) or having one half of the brain larger than expected (hemimegalencephaly). It also causes differences in the smallest blood vessels, called the capillaries. Megalencephaly can cause symptoms including low muscle tone (hypotonia), seizures, and intellectual disability. Other features of MCAP syndrome may include having fingers or toes that are fused together (syndactyly), having extra fingers or toes (polydactyly), and being very flexible (joint hypermobility). Some people with MCAP syndrome may have heart anomalies.[1]

Hemihyperplasia‐multiple lipomatosis syndrome (HHML syndrome) is associated with non-progressive, asymmetrical, moderate overgrowth usually affecting the limbs. It is also associated with slow-growing, painless, subcutaneous lipomatous masses (made up of fat cells) distributed throughout the body. Vascular malformations may also be present.[5]

Facial infiltrating lipomatosis (FIL) causes overgrowth and enlargement of one side of the face. It can also cause mucosal neuromas (masses that grow from a nerve), hemimacroglossia (enlargement of half of the tongue), bone enlargement, and premature dental eruption.[4]

Because PROS causes cells of the body to grow and divide more quickly, there is an increased risk of cancer in people with some forms of PROS.[6] PIK3CA mutations are frequently found in the tumors of people without PROS in many cancers including colon, breast, brain, liver, stomach, and lung.[1]

Cause

PIK3CA-related overgrowth spectrum (PROS) is caused by changes in the PIK3CA gene. When a genetic change causes a syndrome, it is also known as a mutation or pathogenic variant. The PIK3CA gene provides instructions to the body to make a protein that helps control the signaling of other proteins. This protein therefore helps many processes occur at the correct times including cell growth and division, cell movement, and cell survival. When there is a change in the PIK3CA gene, the body does not receive instructions to make the signaling protein correctly. This causes mistakes in cell growth and division and how long a cell survives. If cells are dividing too quickly or if they survive longer than they should, overgrowth of that part of the body can occur. This causes the signs and symptoms associated with PROS.[7]

Diagnosis

A diagnosis of PIK3CA-related overgrowth spectrum (PROS) is often suspected based on characteristic signs and symptoms of the syndromes. For example, megalencephaly-capillary malformation syndrome (MCAP syndrome) can be diagnosed based on findings of megalencephaly and characteristic malformations of the smallest blood vessels (capillaries). CLOVES syndrome can be similarly diagnosed by observing signs and symptoms such as overgrowth, capillary malformations, skin findings, and skeletal abnormalities.[1][8]

A diagnosis of PROS can be confirmed with genetic testing of the PIK3CA gene. However, some people with these syndromes may have normal (negative) genetic testing. This is because the genetic changes (mutations or pathogenic variants) are only in some cells of the body. Therefore, multiple samples of different tissues may need to be tested for the PIK3CA genetic changes. In some cases, even if multiple tissues are tested, the diagnosis is not able to be confirmed with genetic testing.[1]

Treatment

Unfortunately, there is no cure for PIK3CA-related overgrowth spectrum (PROS). However, there are treatment options that can help manage symptoms of the syndromes. People with overgrowth may be treated with surgery to remove growths that are impacting movement. Surgery may also be necessary if there is too much pressure on the brain or to treat skeletal symptoms such as scoliosis. Medications may be used to treat seizures (epilepsy).[1] Researchers are investigating other potential medications that may be used to treat PROS.[9][10] 

People with PROS may be followed by a multi-disciplinary team that may include a neurologist, cardiologist, nephrologist (doctor that helps manage kidney problems), and an orthopedist. Other treatment options may include speech therapy, physical therapy, and special education in school.[1]

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    In-Depth Information

    • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
    • PubMed is a searchable database of medical literature and lists journal articles that discuss PIK3CA-related overgrowth spectrum. Click on the link to view a sample search on this topic.
    • The University of Cambridge has a resource about segmental overgrowth and opportunities to enroll in a database for future research opportunities.

      References

      1. Mirzaa G, Conway R,Graham JM, and Dobyns WB.. PIK3CA-Related Segmental Overgrowth. GeneReviews. August 15 2013; https://www.ncbi.nlm.nih.gov/books/NBK153722/.
      2. PIK3CA gene. Genetics Home Reference (GHR). August, 2016; https://ghr.nlm.nih.gov/gene/PIK3CA#conditions.
      3. Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, et al. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clin Genet. January, 2017; 91(1):14-21. https://www.ncbi.nlm.nih.gov/pubmed/27426476.
      4. Couto JA, Konczyk DJ, Vivero MP, et al. Somatic PIK3CA Mutations are Present in Multiple Tissues of Facial Infiltrating Lipomatosis. Pediatr Res. November, 2017; 82(5):850-854. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645230/.
      5. Hemihyperplasia-multiple lipomatosis syndrome. Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=276280. Accessed 7/10/2018.
      6. Gripp KW, Baker L, Kandula V, Conard K, Scavina M, Napoli JA, Griffin GC, Thacker M, Knox RG, Clark GR, Parker VE, Semple R, Mirzaa G, and Keppler-Noreuil KM. Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation. American Journal of Medical Genetics. October 2016; 170(10):2559-2569. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514817/.
      7. PIK3CA gene. Genetics Home Reference. August 2016; https://ghr.nlm.nih.gov/gene/PIK3CA.
      8. Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Dobyns W, and Biesecker LG. PIK3CA-Related Overgrowth Spectrum (PROS): Diagnostic and Testing Eligibility Criteria, Differential Diagnosis, and Evaluation. American Journal of Medical Genetics. February 2015; 167(2):287-295. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480633/.
      9. Suzuki Y, Enokido Y, Yamada K, Inaba M, Kuwata K, Hanada N, Morishita T, Mizuno S, and Wakamatsu N. The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS). Oncotarget. July 11, 2017; 8(28):45470-45483. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542201/.
      10. Keppler-Noreuil KM, Parker VER, Darling TN, and Martinez-Agosto JA. Somatic Overgrowth Disorders of the PI3K/mTOR Pathway & Therapeutic Strategies. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. December 2016; 172(4):402-421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592089/.

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