What is segmental overgrowth?

Segmental overgrowth describes abnormally increased growth affecting only some parts of the body, with normal growth elsewhere. This is nearly always asymmetrical. Segmental overgrowth is highly variable, and spans a wide variety of disorders which have often had different clinical names given to them in the past.  Examples of these include:

• CLOVES (Congenital lipomatous overgrowth, vascular malformations and epidermal naevi, scoliosis and skeletal deformities)
• Proteus syndrome
• Cowden or PTEN harmatoma tumour syndrome (PHTS)
• HHML (Hemihyperplasia-multiple lipomatosis syndrome)
• Fibroadipose hyperplasia
• Macrodactyly
• Macrodystrophica lipomatosa
• Infiltrating facial lipomatosis
• Klippel-Trenauney Syndrome (KTS)
• Isolated lymphatic malformations
• Isolated vascular malformations
• Complex epidermal naevus syndrome
• Hemimegalencephaly
  • Macrocephaly-capillary malformation (MCM)
  • Megalencephaly, polymicrogyria, and hydrocephalus syndrome (MPPH)
  • Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP)
  • Macrocephaly-cutis marmorata telangiectasia congenita (M-CMTC)

What causes segmental overgrowth?

Segmental overgrowth disorders have recently been shown to be caused in many cases by changes in genes (genetic mutations) which are involved in controlling the way cells and tissue grow.   The changes mean that growth of affected tissues continues at a rate faster than normal, not properly controlled by the usual mechanisms of the body.  The genes in which these mutations have been found include;

• PIK3CA
• PIK3R2
• PTEN
• mTOR
• AKT1
• AKT3

Is this an inherited condition?

Current evidence tells us that, in the vast majority of cases these conditions are not inherited from parents, and are equally not passed onto children. The genetic mutation usually occurs early in pregnancy in a single cell of an embryo, which is just a tiny ball of cells. As just one cell is affected at this time, only some parts of the body are affected, whilst other parts grow normally. The genetic mutation occurs because the cell makes a mistake in copying DNA when dividing to create a new cell; there are no known triggers for this.

Will the overgrowth ever stop?

In some patients, overgrowth continues into early adulthood and then slows down or stops, but in others, growth continues into adult life. At present there is no way of predicting whether someone will keep growing or not, but research efforts are underway to answer this question.

Is there an increased risk of cancer?

Many of the genetic mutations found in segmental overgrowth conditions are also found in cancers. However, cancers have lots of different genetic mutations and current scientific evidence suggests that in most forms of segmental overgrowth the risk of cancer is very low, though probably slightly higher than in the general population.  However future research studies are needed to determine the true risk, and in the meantime your doctors will monitor you or your child for this in a way appropriate to the clinical condition and site of the overgrowth.

For some conditions, and in particular Cowden syndrome or PHTS, the risk of getting certain types of cancers (breast, thyroid, uterus and to a lesser extent kidney and bowel cancer) have been found to be higher. It is therefore important that patients with confirmed genetic changes in the gene PTEN are regularly seen by their local specialist for surveillance.

Are there any available treatments?

At present the main treatment for overgrowth is surgical removal of tissue, or operations to slow down growth. However, finding the genetic cause of these conditions has opened up the possibility of treatments with drugs that may be able to stop or slow down overgrowth. If you or your child is severely affected, your doctor may discuss with you a treatment called sirolimus (rapamycin) or everolimus. These drugs may theoretically be beneficial, and a very small amount of published experience supports this. However the balance of risks and benefits of this treatment are not properly tested, and urgent efforts are underway to fill in this gap in knowledge.

We are currently planning treatment trials in patients with PIK3CA related overgrowth (PROS) to assess if sirolimus or other experimental treatments will reduce overgrowth, and to assess who should be offered treatment. If you are interested in treatments or wish to know more about our trial please get in touch and you can check our clinical trials page for more details.

How do I get myself or my child tested?

As part of our research study, we can test for the gene changes commonly found in segmental overgrowth conditions, and can be contacted directly to organise this via our contact form. Alternatively, you can discuss testing with your GP or local doctor. In order to test, doctors will need to look at DNA taken from an affected area of overgrowth, and this may require taking a small sample of skin (skin biopsy).

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After 3 years of recruiting patients and investigating gene changes causing patchy, asymmetric forms of overgrowth, we have made major progress in identifying the genetic cause in many patients. We have now turned this knowledge into genetic tests available on the NHS*, and are focussing on ensuring that patients and their specialists know how to access these services. We are now seeing far fewer new patients on our research facility, however we remain interested in unusual cases, and are happy to discuss this further.

If you are a new participant, we would still like to hear from you, and you will soon be able to sign up to our study via the Rare Disease secure online RUDY database – Expected to go live January 2018.  This is an excellent platform enabling participants to self-enrol to our study and collate their medical history and add other relevant information, while providing us with a point of contact for follow-up, future cohort studies and clinical trials.

*Genetic diagnostic testing for Segmental Overgrowth is now available on the NHS via the UK Genetic Testing Network in Cambridge and Manchester.