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Overgrowth

Megalencephaly-capillary malformation syndrome

MCAP is a complex condition where certain tissues grow excessively, particularly the brain, leading to developmental differences. It typically involves unusual vascular marks on the skin and can present with a wide range of other symptoms affecting multiple body systems.

Somatic / Mosaic Overgrowth Tier C OMIM:602501
Rare
Prevalence
Population estimate
1
Associated genes
PIK3CA

Overview

Megalencephaly-capillary malformation syndrome (MCAP), sometimes known as MCAP syndrome, is a rare genetic condition characterised by overgrowth of the brain (megalencephaly) and vascular malformations, which are abnormalities of blood vessels. It is part of a group of conditions caused by changes in the PIK3CA gene, often referred to as PIK3CA-related overgrowth spectrum (PROS) [PMID:22933465]. The condition affects individuals differently, with varying degrees of severity and a wide range of associated features.

MCAP is not inherited in the typical sense, as the genetic change usually occurs spontaneously during early development in only some of the body's cells. This is known as somatic mosaicism. The condition typically manifests from birth or early childhood, affecting development and growth in multiple areas of the body.

While MCAP is considered rare, its exact prevalence is not well established. Awareness and understanding of MCAP continue to evolve, leading to improved diagnosis and management strategies for affected individuals.

Symptoms & clinical features

The symptoms of MCAP are diverse and can vary significantly among individuals. Key features often include megalencephaly, which means an unusually large brain, leading to a larger head circumference. This can sometimes be associated with developmental delay, learning difficulties, or epilepsy. Vascular malformations are another hallmark feature, frequently appearing as pink or purple birthmarks (capillary malformations) on the skin, particularly on the head and face [PMID:22933465].

Beyond these core features, individuals with MCAP may experience a range of other symptoms. These can include asymmetry, where one side of the body or a limb grows larger than the other. Connective tissue abnormalities, such as joint laxity or unusual skin texture, may also be present. Some individuals might develop polydactyly (extra fingers or toes) or syndactyly (fused fingers or toes). Other potential issues include eye abnormalities, such as glaucoma, and gastrointestinal problems. Hydrocephalus, an accumulation of fluid in the brain, can also occur.

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Affected organs

MCAP primarily affects the brain, leading to megalencephaly and sometimes hydrocephalus. The condition also commonly impacts the skin and blood vessels, resulting in capillary malformations and other vascular anomalies. Bones and connective tissues can be affected, sometimes causing skeletal overgrowth or asymmetry. The eyes may be involved, potentially leading to conditions like glaucoma. In some cases, internal organs can also show signs of overgrowth or malformation, though this is less common than the brain and skin manifestations.

Multiple body systems
Multiple body systems
Systemic involvement
Cellular impact
Cellular impact
Mechanism at cellular level

Risks & severity

The severity of MCAP varies considerably, ranging from mild forms with limited symptoms to more severe presentations involving significant developmental challenges and multiple medical complexities. The degree of brain overgrowth and the extent of vascular malformations do not always correlate directly with developmental outcomes. Some individuals with significant megalencephaly may have typical development, while others might experience severe developmental delay or intellectual disability.

Potential risks associated with MCAP include epilepsy, which can occur due to the brain changes, and the development of hydrocephalus requiring intervention. The vascular malformations, particularly those affecting the brain (cerebral malformations), may carry risks of bleeding or other neurological complications, though these are less common [PMID:22933465]. There is also a small, increased risk of certain benign tumours, though the evidence for this is still emerging and often specific to the type of PIK3CA variant [PMID:33675037]. Regular monitoring is important to manage these potential risks.

Genetic causes

Megalencephaly-capillary malformation syndrome is caused by pathogenic variants in the PIK3CA gene. This gene provides instructions for making a protein called p110 alpha, which is a crucial component of the PI3K enzyme. The PI3K enzyme plays a vital role in cell growth, proliferation, and survival by initiating signalling pathways within cells.

In MCAP, the PIK3CA variants are typically somatic, meaning they occur after fertilisation in some, but not all, of the body's cells. This leads to a mosaic distribution of the genetic change, where some tissues have the variant and others do not. The presence of these variants leads to overactivity of the PI3K pathway, causing uncontrolled cell growth and proliferation in the affected tissues, which explains the overgrowth features seen in MCAP [PMID:22933465].

  • PIK3CA
    phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
    The PIK3CA gene provides instructions for a crucial enzyme involved in fundamental cellular processes such as growth, division, and survival.

Inheritance pattern

MCAP typically follows a somatic mosaic inheritance pattern. This means the genetic change in the PIK3CA gene is not present in every cell of the body but is found only in certain cells or tissues. The variant arises spontaneously during early embryonic development, rather than being inherited from a parent.

Because the variant is somatic and mosaic, individuals with MCAP generally do not pass the condition on to their children. It is considered a de novo (new) event in the affected individual. However, if a parent has an extremely low level of mosaicism for the PIK3CA variant in their reproductive cells (germline mosaicism), there could be a very small theoretical chance of passing it on, but this is exceedingly rare and usually not a concern. Genetic counselling can provide specific risk assessments for families.

Diagnosis & testing

Diagnosis of MCAP is usually suspected based on characteristic clinical features, such as megalencephaly, capillary malformations, and other signs of overgrowth or asymmetry. Imaging studies, particularly MRI scans of the brain, are often used to confirm megalencealy and assess for other brain anomalies, including hydrocephalus or cerebral vascular malformations.

Confirmation of MCAP is made through genetic testing to identify pathogenic variants in the PIK3CA gene. Because the variants are mosaic, testing may need to be performed on affected tissues (e.g., skin biopsies from a vascular malformation) rather than just a blood sample, which might not detect the variant if it's not present in blood cells. Referral to a clinical genetics service in the UK is the standard pathway for individuals suspected of having MCAP. The NHS Genomic Medicine Service offers genomic testing, often aligned with R-codes such as R189 for PIK3CA-related overgrowth spectrum conditions.

Management & lifestyle

Management of MCAP focuses on addressing the specific symptoms and complications experienced by each individual, as there is no single cure for the condition. A multidisciplinary team of specialists, including paediatricians, neurologists, dermatologists, orthopaedic surgeons, and geneticists, is often involved. Regular monitoring for potential complications such as hydrocephalus, epilepsy, and glaucoma is important.

Treatment approaches may include medications to manage epilepsy, surgical interventions for hydrocephalus (e.g., shunt placement), or orthopaedic procedures for limb length discrepancy or skeletal issues. Laser therapy can be used to treat some capillary malformations. Research is ongoing into targeted therapies that inhibit the overactive PI3K pathway, showing promise in some cases. Families in the UK can access support and guidance through their local NHS clinical genetics service and genetic counsellors, who can help coordinate care and provide information about condition management and support networks.

UK care pathway

In the UK, individuals suspected of having MCAP are typically referred to a clinical genetics service. These services are part of the NHS Genomic Medicine Service (GMS), which provides comprehensive genomic testing and genetic counselling. Genetic specialists will assess clinical features, coordinate appropriate diagnostic tests, including genomic analysis (often under relevant R-codes for PIK3CA-related conditions), and help families understand the diagnosis. Genetic counsellors provide essential support, explaining inheritance patterns, discussing implications for the family, and signposting to relevant support organisations.

Frequently asked questions

Is MCAP inherited from my parents?

MCAP is typically not inherited. The genetic change usually happens spontaneously during early development, meaning it's only present in some of your body's cells. This is called somatic mosaicism, and it's generally not passed down to children.

What kind of doctors will be involved in my child's care?

A team of specialists will likely be involved, tailored to your child's specific needs. This might include a paediatrician, neurologist, dermatologist, orthopaedic surgeon, and a clinical geneticist, among others. A genetic counsellor can help coordinate care.

Will my child's symptoms get worse over time?

The progression of MCAP symptoms varies widely. Some symptoms, like brain overgrowth, are often present from birth, while others may evolve or require ongoing management. Regular medical check-ups are important to monitor any changes and address them proactively.

Can diet or lifestyle changes help manage MCAP?

There is no specific diet or lifestyle change known to cure or prevent MCAP. However, maintaining a healthy lifestyle, including a balanced diet and appropriate physical activity, is generally beneficial for overall well-being and can support specific therapeutic interventions.

Is there a cure for MCAP?

Currently, there is no cure for MCAP. Management focuses on treating individual symptoms and complications to improve quality of life. Research into targeted therapies that specifically address the underlying genetic pathway is ongoing and shows promise for future treatments.

References

  1. Adam MP, Bick S, Mirzaa GM. PIK3CA-Related Overgrowth Spectrum. 1993. PMID: 23946963
  2. Alamar M, Candela S, Flor-Goikoetxea A. Megalencephaly-capillary malformation syndrome and associated hydrocephalus: treatment options and revision of the literature. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2021. PMID: 34047857
  3. Porwal M, Anderson D, Razzak AN. Prenatal diagnosis and delivery of megalencephaly-capillary malformation syndrome. BMJ case reports. 2022. PMID: 36572450
  4. Deleu T, Jansen K, Calenbergh FV. Brain overgrowth associated with megalencephaly-capillary malformation syndrome causing progressive Chiari and syringomyelia. Surgical neurology international. 2022. PMID: 35673641
  5. Döcker D, Schubach M, Menzel M. Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP)--pure coincidence? European journal of human genetics : EJHG. 2015. PMID: 24939587
  6. Davis S, Ware MA, Zeiger J. Growth hormone deficiency in megalencephaly-capillary malformation syndrome: An association with activating mutations in PIK3CA. American journal of medical genetics. Part A. 2020. PMID: 31729162
  7. Segal D, Heary RF, Sabharwal S. Severe holocord syrinx in a child with megalencephaly-capillary malformation syndrome. Journal of neurosurgery. Pediatrics. 2016. PMID: 27035547
  8. Happle R. Capillary malformations: a classification using specific names for specific skin disorders. Journal of the European Academy of Dermatology and Venereology : JEADV. 2015. PMID: 25864701
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor.