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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Genetics

The Biology and Genetics of Hemifacial Hyperplasia

At a Glance

Hemifacial hyperplasia (HFH) is caused by a random, non-inherited genetic mutation in the PIK3CA gene that occurs after conception. This mutation acts as a cellular growth switch stuck in the "on" position, causing benign facial tissue overgrowth. It is part of the PROS spectrum and is not cancer.

To understand Hemifacial Hyperplasia (HFH), it is helpful to look at the “instruction manual” for the body—our DNA. In most people, every cell in the body has the same set of instructions. In HFH, however, the instructions have a small, localized change that acts as a “growth switch” stuck in the “on” position [1][2].

Somatic Mosaicism: The “Localized Typo”

The biological cause of HFH is a process called somatic mosaicism [3][4]. Imagine a book where a typo occurs in only one specific chapter after the book has already been started.

  • Somatic means the change happened in a body cell after conception, rather than being present in the egg or sperm [3][1].
  • Mosaicism refers to the fact that the body is a “mosaic” of two types of cells: normal cells and cells with the genetic change [3][5].

Because this change happens randomly during early development, HFH is not inherited from parents and cannot be passed down to your children [5][6]. The “typo” is only present in the tissues on the affected side of the face [1][7].

The “Growth Switch”: PIK3CA and the mTOR Pathway

The most common “typo” found in HFH occurs in a gene called PIK3CA [1][4]. This gene provides instructions for a protein that belongs to a communication line inside cells called the PI3K/AKT/mTOR pathway [4][8].

In a typical cell, this pathway acts like a switch: it turns “on” when the body needs more tissue and “off” when growth should stop. In HFH, a mutation in the PIK3CA gene keeps this switch permanently “on” in the affected facial tissues [2][9]. This tells the cells to keep dividing and growing, even when they should be resting [2][10].

What is PROS?

Doctors now use the term PIK3CA-Related Overgrowth Spectrum (PROS) to describe a group of conditions caused by these specific PIK3CA mutations [11][5]. HFH (and its subtype, CIL-F) are considered part of this spectrum [1][12]. While each condition in the PROS family looks different depending on where the mutation occurred, they all share the same underlying biological “stuck switch” [13][14].

Why This is Not Cancer

Hearing the words “mutation” and “growth pathway” can be frightening, as these terms are often associated with cancer. However, the overgrowth in HFH is benign (non-cancerous) [2][15].

Feature PROS / Hemifacial Hyperplasia Malignant Cancer
Growth Type Organized overgrowth of normal-looking tissue [2] Disorganized, invasive growth of abnormal cells [16]
Genetics Usually a single, mosaic PIK3CA mutation [3] Often involves many “layers” of mutations and loss of control genes [16][17]
Spreading Stays localized to the affected area (e.g., one side of the face) [1] Can spread to distant parts of the body (metastasis)

In PROS, the cells are simply doing “too much of a normal thing” (growing) because of a single instruction error, rather than becoming the aggressive, destructive cells seen in cancer [2][10].

Common questions in this guide

Is hemifacial hyperplasia inherited?
No, hemifacial hyperplasia is not inherited from your parents and cannot be passed down to your children. It is caused by a random genetic change that occurs during early development, known as somatic mosaicism.
Does having a PIK3CA mutation mean I have cancer?
No, the overgrowth associated with hemifacial hyperplasia is entirely benign. While the PIK3CA gene mutation acts as a growth switch stuck in the "on" position, it causes an organized overgrowth of normal-looking tissue, not aggressive or disorganized cancer cells.
What is the PIK3CA-Related Overgrowth Spectrum (PROS)?
PROS stands for PIK3CA-Related Overgrowth Spectrum. It is a group of conditions, including hemifacial hyperplasia, that are all caused by mutations in the PIK3CA gene. These conditions share the same biological 'stuck switch' that causes localized tissue overgrowth.
How do doctors test for the gene mutation in hemifacial hyperplasia?
Because the mutation is only present in the affected tissues on one side of the face, standard blood tests will not show the genetic change. Your doctor will likely need a tissue sample from the specific area of overgrowth to identify the PIK3CA mutation.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.If this genetic change isn't in my blood, how do we perform the right test to confirm it's in the affected tissue?
  2. 2.What specific PIK3CA mutation was found in my (or my child's) tissue sample?
  3. 3.Are there any secondary genetic markers you look for to ensure the overgrowth remains benign?
  4. 4.How does knowing the specific pathway mutation (PI3K/AKT/mTOR) help in planning future care or potential drug therapies?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (17)
  1. 1

    Congenital infiltrating lipomatosis of the face with lingual mucosal neuromas associated with a PIK3CA mutation.

    Briand C, Galmiche-Rolland L, Vabres P, et al.

    Pediatric dermatology 2020; (37(6)):1128-1130 doi:10.1111/pde.14302.

    PMID: 32770747
  2. 2

    Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

    Venot Q, Blanc T, Rabia SH, et al.

    Nature 2018; (558(7711)):540-546 doi:10.1038/s41586-018-0217-9.

    PMID: 29899452
  3. 3

    Molecular diagnosis of somatic overgrowth conditions: A single-center experience.

    Lalonde E, Ebrahimzadeh J, Rafferty K, et al.

    Molecular genetics & genomic medicine 2019; (7(3)):e536 doi:10.1002/mgg3.536.

    PMID: 30761771
  4. 4

    Unique Case of Congenital Lipomatous Overgrowth With Vascular Malformations, Epidermal Nevi, and Skeletal/Spinal Anomalies Syndrome in a Pediatric Patient.

    Quinn KE, Infante J, Thorson W, Thorson CM

    Cureus 2020; (12(9)):e10737 doi:10.7759/cureus.10737.

    PMID: 33145141
  5. 5

    CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS).

    Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, et al.

    Clinical genetics 2017; (91(1)):14-21 doi:10.1111/cge.12832.

    PMID: 27426476
  6. 6

    Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of "PIK3CA-Related Overgrowth Spectrum".

    Di Donato N, Rump A, Mirzaa GM, et al.

    Human mutation 2016; (37(3)):242-5 doi:10.1002/humu.22933.

    PMID: 26593112
  7. 7

    PIK3CA-related overgrowth with an uncommon phenotype: case report.

    Rotunno R, Diociaiuti A, Pisaneschi E, et al.

    Italian journal of pediatrics 2022; (48(1)):71 doi:10.1186/s13052-022-01268-9.

    PMID: 35551640
  8. 8

    Overgrowth Syndromes Caused by Somatic Variants in the Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Pathway.

    Akgumus G, Chang F, Li MM

    The Journal of molecular diagnostics : JMD 2017; (19(4)):487-497 doi:10.1016/j.jmoldx.2017.04.001.

    PMID: 28502730
  9. 9

    Somatic frameshift mutation in PIK3CA causes CLOVES syndrome by provoking PI3K/AKT/mTOR pathway.

    Yan W, Zhang B, Wang H, et al.

    Hereditas 2021; (158(1)):18 doi:10.1186/s41065-021-00184-y.

    PMID: 34074347
  10. 10

    PI3K/mTOR inhibition promotes the regression of experimental vascular malformations driven by PIK3CA-activating mutations.

    di Blasio L, Puliafito A, Gagliardi PA, et al.

    Cell death & disease 2018; (9(2)):45 doi:10.1038/s41419-017-0064-x.

    PMID: 29352118
  11. 11

    Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth.

    Griff JR, Duffy KA, Kalish JM

    Frontiers in pediatrics 2020; (8()):613260 doi:10.3389/fped.2020.613260.

    PMID: 33392121
  12. 12

    Papillary Intralymphatic Angioendothelioma in a Child With PIK3CA-Related Overgrowth Spectrum: Implication of PI3K Pathway in the Vascular Tumorigenesis.

    Debelenko L, Mansukhani MM, Remotti F

    Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 2023; (26(2)):166-171 doi:10.1177/10935266231152370.

    PMID: 36775953
  13. 13

    Phenotypic heterogeneity in PIK3CA-related overgrowth spectrum.

    Vahidnezhad H, Youssefian L, Baghdadi T, et al.

    The British journal of dermatology 2016; (175(4)):810-4 doi:10.1111/bjd.14618.

    PMID: 27037860
  14. 14

    PIK3CA vascular overgrowth syndromes: an update.

    Hughes M, Hao M, Luu M

    Current opinion in pediatrics 2020; (32(4)):539-546 doi:10.1097/MOP.0000000000000923.

    PMID: 32692051
  15. 15

    Constitutively active PIK3CA mutations are expressed by lymphatic and vascular endothelial cells in capillary lymphatic venous malformation.

    Le Cras TD, Goines J, Lakes N, et al.

    Angiogenesis 2020; (23(3)):425-442 doi:10.1007/s10456-020-09722-0.

    PMID: 32350708
  16. 16

    Kaposiform hemangioendothelioma further broadens the phenotype of PIK3CA-related overgrowth spectrum.

    Carli D, Kalantari S, Manicone R, et al.

    Clinical genetics 2021; (100(5)):624-627 doi:10.1111/cge.14047.

    PMID: 34402524
  17. 17

    A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer.

    Anderson EJ, Mollon LE, Dean JL, et al.

    International journal of breast cancer 2020; (2020()):3759179 doi:10.1155/2020/3759179.

    PMID: 32637176

This page explains the genetics of hemifacial hyperplasia for educational purposes only. Always consult a geneticist or your healthcare team to discuss your or your child's specific diagnosis and testing needs.

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