What is Segmental Overgrowth & PROS (PIK3CA Related Overgrowth Spectrum)

Segmental overgrowth describes a condition where there is an excess of growth in different parts of the body, but normal growth elsewhere.

  • PIK3CA related overgrowth spectrum (PROS) is an umbrella term for rare syndromes characterised by malformations and tissue overgrowth caused by somatic mutations in PIK3CA gene[1][2][3]. Within the PROS condition malformations are seen in several different tissues such as skin, vasculature, bones, fat and brain tissue depending on the specific disease. 
  • Some patients may fit in to one or more of the categories below, but there will also be those people who don’t & therefore carry with them a diagnosis of just PROS.

Within the PROS umbrella we see the following sub PROS conditions:

 Hemihyperplasia multiple lipomatosis (HHML)

  • Hemihyperplasia-multiple lipomatosis syndrome is a rare, genetic overgrowth syndrome characterized by non- progressive, asymmetrical, moderate hemihyperplasia (frequently affecting the limbs) associated with slow growing, painless, multiple, recurrent, subcutaneous lipomatous masses distributed throughout entire body (in particular back, torso, extremities, fingers, axillae). Superficial vascular malformations may also be associated. Increased risk of intra-abdominal embryonal malignancies may be associated.
  • For more details see link: https://en.wikipedia.org/wiki/Hemihyperplasia%E2%80%93multiple_lipomatosis_syndrome

 

(FAH) FibroAdipose Hyperplasia/(FAO) FibroAdipose Overgrowth

  • Fibroadipose hyperplasia (FAH) also known as (FAO) FibroAdipose Overgrowth manifests as patchy overgrowth of a limb or part of the body. The overgrowth is due to fatty, fibrous and/or blood vessel overgrowth in a particular region of the body. This is usually not evident at birth and the overgrowth typically gets worse over time.
  • FAO often overlaps with signs and symptoms associated with Macrodactyly, HHML, Muscular HH, and CLOVES syndrome..
  • See link for further explanation

 

Macrodactyly  

 

(FAVA) Fibro-Adipose Vascular Anomaly is a rare vascular anomaly occurring when the body’s own tissue infiltrates a muscle, creating a tumor-like mass typically found in one or more limbs.  

  • “We all have fatty tissue – called adipose tissue – in our bodies.  Adipose tissue serves the important function of storing fat.  And we all have muscles in our extremities – our arms, hands, legs, and feet.  Our muscles are made up of collections of muscle cells called muscle fibers, along with blood vessels, tendons, and nerves.  The current hypothesis among experts is that in a patient with a fibro- adipose vascular anomaly, there is a disproportionate increase in fat in one or more muscles, combined with fibrous scar tissue, which disorganizes the normal pattern of muscle fibers.”
  • https://www.projectfava.org/whatisfava

 

(HH) Muscle hemihyperplasia

  • Hemihyperplasia, formerly called hemihypertrophy, is a rare disorder in which one side of the body grows more than the other due to an excess production of cells, causing asymmetry. In a normal cell, there is a mechanism that turns off growth once the cell reaches a certain size. However, in hemihyperplasia, the cells on one side aren’t able to stop growing. This causes the affected body area(s) to continue growing or enlarge abnormally. The disorder is congenital, which means that it is evident at birth.
  • See link for more details: https://en.wikipedia.org/wiki/Hemihypertrophy

 

Facial Infilitrating lipomatosis

  • Facial infiltrating lipomatosis (FIL), also referred to as congenital infiltrating lipomatosis of the face or facial infused lipomatosis, is an ultra-rare craniofacial overgrowth condition caused by a genetic mutation of the PIK3CA gene. The condition is a part of the PIK3CA related overgrowth spectrum (PROS).[2] The disease is congenital and non-hereditary.
  • For this disease the mutation causes overgrowth of half of the face (hemifacial). It affects both soft and hard tissue (facial skeleton). The condition is noticeable at birth by the asymmetrical cheeks, with one cheek being prominently larger than the other.
  • See link for more details: FIL

 

(CLOVES) Congenital  lipomatous overgrowth, vascular malformations, epidermal  naevi and skeletal abnormalities

  • Congenital lipomatous overgrowth: Fatty masses are present at birth, typically on the trunk or buttocks. They may appear on one or both sides of the body.
  • Vascular malformations: These may include red or purplish birthmarks, prominent veins, or problems with blood clots. Problems with blood vessels can lead to pain and inflammation in the affected areas, as well as bleeding in the skin, stomach, intestines, or bladder.
  • Epidermal nevi: These are also known as moles.
  • Scoliosis/skeletal/spinal abnormalities: Limb overgrowth (often uneven), wide hands or feet, large fingers or toes, and curving of the spine are common.
  • See for more details: CLOVES Syndrome

 

(MCAP/MCM) Megalencephaly-Capillary Malformation 

  • Megalencephaly-capillary malformation syndrome (MCAP) is a disorder characterized by overgrowth of several tissues in the body. Its primary features are a large brain (megalencephaly) and abnormalities of small blood vessels in the skin called capillaries (capillary malformations).
  • Many people with this condition have a disproportionately large head and discoloration of the skin. Enlargement of the brain, known as megalencephaly, can lead to problems such as headaches, seizures, behavioral problems, and trouble breathing.
  • See link for more details: https://ghr.nlm.nih.gov/condition/megalencephaly-capillary-malformation-syndrome

 

(KTS) Klippel-Trenaunay Syndrome

 

(DCMO) Diffuse capillary malformation with overgrowth

 

CLAPO Syndrome

 

(LON) Lipomatosis Of Nerve

 

(DMEG) Dysplastic Megalencephaly Enlargement

  • A congenital brain malformation where one or both cerebral hemispheres are abnormally large and malformed. It is often used interchangeably with hemimegalencephaly (HME), especially when the overgrowth is one-sided.

  • Brain overgrowth and malformation: The brain’s hemispheres are enlarged and have a dysplastic, or malformed, structure.

  • Developmental delays: Affected individuals typically experience early and significant developmental delays.

  • Intractable epilepsy: Severe seizures often begin in the first few months of life and can be difficult to control with medication.

  • Intellectual disability: A high degree of intellectual disability is common.

  • Physical signs: A disproportionately large head is common, and other symptoms can include body asymmetry and defects in muscle tone.

  • https://www.icliniq.com/articles/neurological-health/megalencephaly

 

(ILM) Isolated Lymphatic MalformationLymphatic malformations are rare, non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by the abnormal development of the lymphatic system. These malformations can affect any area of the body (except the brain), but most commonly affect the head and neck. They tend to be soft, spongy, non-tender masses & vary in size depending on location: https://rarediseases.org/rare-diseases/lymphatic-malformations/

 

PIK3CA – related nonvascular lesions: 

  • Epidermal Nevi: An epidermal nevus (plural: nevi) is an abnormal, noncancerous (benign) patch of skin caused by an overgrowth of cells in the outermost layer of skin (epidermis). Epidermal nevi are typically seen at birth or develop in early childhood. See link: Epidermal Nevus
  • Seborrheic keratoses are usually brown, black or light tan. The growths look waxy, scaly and slightly raised. They usually appear on the head, neck, chest or back.  Seborrheic keratoses are harmless and not contagious. They don’t need treatment, but you may decide to have them removed if they become irritated by clothing or you don’t like how they look. Seborrheic keratose: A seborrheic keratosis (seb-o-REE-ik ker-uh-TOE-sis) is a common noncancerous skin growth. People tend to get more of them as they get older. See link: https://www.mayoclinic.org/diseases-conditions/seborrheic-keratosis/symptoms-causes/syc-20353878
  • Benign lichenoid keratoses: Lichenoid keratosis (LK) is a common benign skin growth that typically presents as an evolving single discrete papule on the trunk or upper extremities of adultsLK occurs almost always as a solitary skin growth; however, two or three lesions can occasionally be present. Approximately 8% of patients with LK will have two discrete lesions, 1% with three; more than three lesions are exceedingly rare. see link: https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/lichenoid-keratosis-lichenoid-keratosis-lichen-planus-like-keratosis/
  • Focal cortical dysplasia: https://pmc.ncbi.nlm.nih.gov/articles/PMC3403799/

 

What causes segmental overgrowth?

The underlying cause of many of these conditions are genetic changes in the genes important for controlling growth e.g PIK3CA, PIK3R2, AKT1, AKT3 and mTOR. The gene changes are not inherited or passed on to children, and are only found in the parts of the body that are affected by the overgrowth.

What kind of problems do patients with segmental overgrowth have?

Patients may have overgrowth of any part of their body. This could be an enlarged toe, finger, arm or leg, or more extensive overgrowth affecting both legs, the brain or one side of the the body. Tissues in the body affected my include fat, muscle, bone, blood vessels, skin and nerves. For most patients, overgrowth is present at birth or develops in early childhood and for some the growth will slow down or stop in early adulthood, but for others the growth may carry on into adult life.

What treatments are available?

Until the last few years treatment was very limited with surgery being one of the available options but this varied in success. In recent years there have been a small number of drug trials (tablets) aimed at those with overgrowth conditions. This includes Sirolimous & more recently Alpelisib. There is more information about these in our (research in to PROS section, please click on the link below)

How do I get myself or child tested?

To get tested for these gene changes, doctors will need to look at genes in the affected tissue and this may involve taking a small skin biopsy. You can speak to your local doctor about getting tested, any specialist or consultant you are under or alternatively the RDCN (Rare Disease Collaborative Network) Please see link to the RDCN page for more information.

Research in to PROS
RDCN
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