About segmental overgrowth
Segmental overgrowth means excessive growth confined to only some parts of the body. It is almost invariably asymmetrical. It is a feature of a heterogeneous group of rare disorders which often carry a significant burden of morbidity and mortality. Affected patients commonly develop distorting or restricting overgrowth leading to marked functional impairments.
Mosaic activating mutations in segmental overgrowth conditions
We and others have identified somatic activating mutations in components of the phosphatidylinositol-3-kinase (PI3K)-PTEN-AKT-mTOR signalling pathway in many patients with different forms of segmental overgrowth. Proteus syndrome, one of the better defined but rarer subtypes of segmental overgrowth (although the label is also often loosely applied to other types) was first shown to be due to a mosaic activating mutation in AKT1, a gene responsible for cell growth (Lindhurst et al.,NEJM, 2011). Subsequently different somatic mutations have been identified in several other genes in the same cell growth pathway (PIK3CA, PIK3R2, AKT3 and mTOR (Poduri et al., 2012), (Lindhurst et al., 2012),(Rivière et al., 2012), (Ho Lee et al 2012),(Rios et al., 2013)), and have been associated with a diverse array of overgrowth syndromes. Mosaic loss of heterozygosity of PTEN has also been shown to lead to mosaic overgrowth, and forms part of the PTEN harmatoma tumour syndrome spectrum (Caux et al 2007)
PIK3CA related overgrowth spectrum
PIK3CA encodes p110α, the catalytic subunit of phosphatidylinosotide-3-kinase (PI3K). This signalling enzyme is critical for growth, survival and metabolism of most cells, and is one of the most commonly mutated genes found in cancers. “The PIK3CA-related overgrowth spectrum” is a term adopted to encompass a wide spectrum of clinical phenotypes ranging from isolated digit enlargement to extensive overgrowth of the limbs, abdomen or brain, often in association with vascular malformations. Previously described syndromes that have now been shown to be caused in many cases by somatic PIK3CA mutations include:
- CLOVES (Congenital lipomatous overgrowth, vascular malformations and epidermal naevi, scoliosis and skeletal deformities)
- HHML (Hemihyperplasia-multiple lipomatosis syndrome)
- Fibroadipose hyperplasia
- Macrodystrophica lipomatosa
- Infiltrating facial lipomatosis
- Macrocephaly-capillary malformation (MCM)
- Megalencephaly, polymicrogyria, and hydrocephalus syndrome (MPPH)
- Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP)
- Macrocephaly-cutis marmorata telangiectasia congenita (M-CMTC)
- Klippel-Trenauney Syndrome (KTS)
- Isolated lymphatic malformations
- Isolated vascular malformations
- Complex epidermal naevus syndrome
Current rapid identification and study of new patients with mutations in the PI3K/AKT pathway mean that definitive re-classification is likely to occur when the full disease spectrum and any genotype-phenotype correlations have been discovered.
Who should be referred for genetic testing*?
Patients with any of the above diagnoses, PTEN harmatoma tumour syndrome (Cowden), Proteus syndrome or those with any of the below clinical features should be referred for genetic testing. Tissue from an affected site of overgrowth will be required (skin biopsy or previously removed surgical tissue), alongside germline DNA from lymphocytes or saliva. In patients with facial or abdominal overgrowth, salivary or urine DNA respectively may carry the causative mutation. Please contact us if you wish to refer a patient for genetic testing. We are currently able to screen for common variants in PIK3CA, PIK3R2, PTEN, AKT1, AKT2, and AKT3 and related pathway genes.
1. Overgrowth: adipose, skin, muscle, nerve, skeletal, e.g.:
- Isolated macrodactyly
- Overgrown splayed feet/ hands or limbs
- Truncal adipose overgrowth
- Linear naevus
2. Vascular malformations: capillary, venous, arteriovenous malformation, lymphatic.
- Isolated large truncal capillary vascular malformations
- Large lymphatic malformations (NOT cystic hygroma)
3. Hemimegalencephaly/ dysplastic megalencephaly/ focal cortical dysplasia
4. Any of the above features arising in association with hypoglycaemia or other endocrine abnormalities
What is the management for segmental overgrowth?
Surgical debulking, liposuction and interventional radiology for vascular malformations remain the mainstay of treatments for these conditions. There are no clinically approved pharmacotherapies, however the genetically activated pathway is targeted by a variety of drugs in clinical development, and a handful in current use. Specifically, mTOR inhibitors theoretically could be effective therapies to slow excessive growth. Sirolimus (rapamycin) has been reported to be effective in isolated case-reports of allied conditions (Hammill et al), (Marsh et al), but long-term safety data are currently lacking. mTOR inhibitors should only be considered if there is an urgent clinical need to retard excessive growth.
We are planning clinical trials of sirolimus and other experimental drugs for PIK3CA-related overgrowth, aiming to start a pilot study in 2015. If you have a patient who would be suitable for the trial, or if you wish to discuss mTOR inhibitor therapy off licence please get in touch.
Other important issues which need bespoke treatment in some patients relate to thrombosis or haemorrhage risk, or potential complications such as airway obstruction related to the anatomical site of the overgrowth.
Is there an increased risk of cancer*?
Activating mutations in the PI3K-AKT signalling pathway are amongst the most common variants found in cancers (COSMIC). From existing reports, there appears to be a relatively low frequency of cancers (1%) in patients with somatic PIK3CA mutations, with all reported cases to date being Wilms tumours in children. For mosaic PIK3R2, AKT2, AKT3 and MTOR mutations, only small numbers of patients have been reported to date making it difficult to evaluate cancer risk at present. Proteus syndrome (AKT1) has been associated with the development of benign tumours of the thyroid and parathyroid (Biesecker 2006). We recommend that surveillance strategies appropriate to the patient’s syndrome remain in place until this risk can be fully evaluated.
PHTS or Cowden syndrome (PTEN) has been associated with an increased risk of malignancy; the lifetime risk for breast cancer has been reported to approach 85% in women, and the lifetime risks of thyroid and endometrial cancer are estimated to be 35% and 28% respectively – see Eng 2011 for further details.
How should patients be screened*?
PIK3CA-related overgrowth (and PIK3R2/AKT3/MTOR)
Imaging should be tailored to the clinical presentation in this highly varies disease spectrum. However the following is offered as a guide:
- Whole body MRI scan – if there is truncal overgrowth to screen for complex vascular malformations
- For infants 6-12 months (earlier age if symptomatic): use non-contrast study
- For older patient: as a baseline study with contrast (contrast may not be required depending on experience)
- Brain MRI scan – if there is facial or neurologic involvement
- Plain radiographs of affected areas
- Spine series – if there is curvature on examination
- Spinal ultrasound as baseline in infants in first months of life and in patients with truncal involvement to screen for tethered cord
- Renal ultrasound at baseline, then every 3 months until age 8 years
*Adapted from guidelines developed in the 2013 PIK3CA workshop; Bethesda, USA
PHTS/Cowden (PTEN) (Eng et al)
- All adults and children < 18 years: annual thyroid and skin examination
- Women: from age 30 years
- Monthly self-examination breasts
- Annual breast screening e.g. mammogram
- Annual transvaginal US and/or endometrial biopsy
- Men and women:
- Colonoscopy from age 35 years (frequency thereafter dependent on degree of polyposis
- Renal CT/MRI from age 40 years every two years
- Families with specific cancers – consider screening 5-10 years before earliest age of occurrence
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.