PIK3CA-RELATED OVERGROWTH SPECTRUM (PROS)

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PIK3CA-Related Overgrowth Spectrum, abbreviated as PROS, is a rare genetic disorder characterized by abnormal tissue growth in various parts of the body. This condition is caused by mutations in the PIK3CA gene, which plays a crucial role in regulating cell growth and division.

These genetic mutations can lead to overgrowth in multiple tissues and organs throughout the body, including the skin, blood vessels, bones, fat, and brain. As a result, individuals with PROS may exhibit diverse symptoms depending on the specific type of syndrome and the affected body regions.

Symptoms of PROS may be evident at birth, allowing for early diagnosis by healthcare professionals. However, in some cases, symptoms may manifest later in childhood.

The diverse manifestations of PROS underscore its classification as a spectrum disorder, highlighting the variability in clinical presentation and severity among affected individuals.

Causes

PROS is primarily caused by somatic mutations in the PIK3CA gene, which lead to uncontrolled activation of the PI3K/AKT/mTOR pathway. This pathway is involved in cell proliferation, survival, and metabolism. When mutations occur in the PIK3CA gene, it results in excessive cell growth and tissue overgrowth.

Understanding PIK3CA and PROS

PIK3CA-related overgrowth spectrum (PROS) arises due to alterations in the PIK3CA gene, which plays a crucial role in normal bodily functions. Like many genes, PIK3CA contains instructions for producing a specific protein. This protein regulates various signaling pathways within the body, which are essential for controlling processes such as cell growth, division, movement, and programmed cell death.

When mutations occur in the PIK3CA gene, the resulting protein is unable to perform its functions effectively. As a consequence, errors in cell growth regulation occur. Cells may proliferate excessively or persist for longer durations than necessary, leading to abnormal growth or structural changes in affected body parts.

Importantly, the manifestations of PROS vary among individuals because the genetic mutations typically occur only in certain cells rather than all cells in the body. This explains why unusual growth patterns may be observed in specific regions while other areas remain unaffected.

It’s noteworthy that PROS is not inherited in a typical Mendelian manner, where the condition is passed from parent to child. Instead, the mutations in the PIK3CA gene typically arise spontaneously in affected individuals, meaning that having a child with PROS does not necessarily imply that the parent carries the same genetic anomaly or that other offspring will develop the condition.

Prevalence

PROS is considered a rare disorder, with an estimated prevalence of 1 in 100,000 individuals. However, the exact prevalence may vary due to underdiagnosis and limited awareness of the condition.

Types of PROS

Physicians may diagnose PIK3CA-related overgrowth spectrum (PROS) directly or identify specific syndromes falling within the PROS spectrum. These include:

1. Fibroadipose Hyperplasia: Characterized by patchy growths on limbs or other body parts due to excessive growth of fatty or fibrous tissue and blood vessels. These growths tend to worsen over time, potentially leading to mobility issues.
2. CLOVES Syndrome: An acronym representing congenital, lipomatous, overgrowth, vascular malformations, epidermal nevus, and spinal/skeletal problems. Symptoms include visible fatty masses, vascular malformations, epidermal nevi, and skeletal abnormalities like scoliosis.
3. Megalencephaly-Capillary Malformation (MCAP) Syndrome: Results in overgrowth of the brain, blood vessels, and facial features. Individuals may experience developmental delays and exhibit distinctive fingers and toes.
4. Hemihyperplasia-Multiple Lipomatosis (HHML) Syndrome: Commonly affecting the growth of limbs, characterized by slow-growing, painless fatty masses under the skin in various body regions. These masses typically occur on the back, torso, legs, arms, and fingers, alongside unusual blood vessel formation.
5. Hemimegalencephaly: Involves abnormal enlargement of all or part of the brain, often accompanied by alterations in blood vessels. Children with hemimegalencephaly may experience seizures, paralysis, and developmental delays.
6. Facial Infiltrating Lipomatosis: Presents with painless swelling or overgrowth of facial structures, typically occurring unilaterally. Masses may arise from nerves, tongue enlargement may occur, and bone and teeth abnormalities might be observed.

These distinct manifestations within the PROS spectrum underscore the diverse range of clinical presentations associated with mutations in the PIK3CA gene.

Symptoms

Symptoms of PROS can vary widely depending on the affected tissues and organs. Common symptoms may include:

• Overgrowth of limbs, leading to asymmetry or disproportionate growth
• Vascular malformations
• Skin abnormalities such as epidermal nevi or lipomas
• Skeletal abnormalities
• Neurological complications such as seizures or developmental delays

Risk Factors

The primary risk factor for PROS is the presence of somatic mutations in the PIK3CA gene. These mutations are typically not inherited but occur sporadically during early embryonic development.

Diagnosis

Diagnosing PROS can be challenging due to its rarity and variable presentation. However, it typically involves a combination of clinical evaluation, imaging studies (such as ultrasound or MRI), genetic testing to identify mutations in the PIK3CA gene, and biopsy of affected tissues.

Treatment

While there’s currently no cure for PIK3CA-related overgrowth spectrum (PROS), several management strategies can help alleviate symptoms:

1. Surgery: Surgical intervention may be recommended to remove overgrowths, especially if they impede movement or daily activities. Additionally, surgery can address complications such as brain pressure, scoliosis correction, or other associated problems.
2. Medications: Some medications may be prescribed to manage specific symptoms of PROS, such as seizures or other neurological manifestations.
3. Regular Monitoring: Routine medical follow-ups are essential to monitor the progression of the condition and address any emerging issues promptly.
4. Interventional radiology procedures to address vascular malformations
5. Physical therapy or occupational therapy to improve mobility and function

Home Care Tips

While there are no specific home care tips for treating PROS, individuals with this condition may benefit from supportive care measures such as:

• Regular monitoring of symptoms and complications
• Following a healthy lifestyle, including regular exercise and a balanced diet
• Seeking emotional support from family, friends, or support groups

Prevention

Since PROS is caused by somatic mutations that occur spontaneously, there are currently no known ways to prevent the condition. However, early diagnosis and intervention can help manage symptoms and improve outcomes for affected individuals.

When to See a Doctor

If you or your child experience unusual or disproportionate growth, skin abnormalities, or other symptoms suggestive of PROS, it is essential to consult a healthcare professional for further evaluation and diagnosis.

Outlook/Prognosis

PROS is a lifelong condition with a variable clinical course, as it can affect different body parts and systems uniquely in each individual. Consequently, the outlook and symptoms can vary significantly from one person to another. For instance:

• Brain involvement in PROS can lead to developmental delays and learning differences, impacting your child’s cognitive and educational development.
• Individuals with PROS may have an increased risk of developing certain types of cancer. Changes in the PIK3CA gene, implicated in PROS, are also observed in tumors of individuals with cancer who do not have PROS. It’s crucial to discuss your child’s current and future cancer risk with their healthcare provider.

Navigating the challenges associated with PROS requires comprehensive medical care, ongoing monitoring, and support tailored to your child’s individual needs. Collaborating closely with your child’s healthcare team can help optimize their quality of life and well-being despite the complexities of this condition.

Sources

1. Photo credit: MDPI.com
2. Keppler-Noreuil, K. M., Parker, V. E., Darling, T. N., & Martinez-Agosto, J. A. (2015). Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. American journal of medical genetics. Part C, Seminars in medical genetics, 169(3), 260–271.
3. National Center for Advancing Translational Sciences Genetic and Rare Diseases Information Center
4. CLOVES Syndrome Community
5. Texas Children’s Hospital: “Fibroadipose hyperplasia (FH).”
6. Orphanet: “Hemihyperplasia-multiple lipomatosis syndrome.”
7. Journal of Indian Society of Pedodontics and Preventive Dentistry: “Congenital infiltrating lipomatosis of the face: Case report and review of the literature.”
8. Rivière, J. B., Mirzaa, G. M., O’Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., Ward, T. R., Butler, H. E., Kramer, N. A., Albrecht, B., Armour, C. M., Armstrong, L., Caluseriu, O., … Dobyns, W. B. (2012). De novo germline and postzygotic mutations in AKT3, PIK3R2, and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature Genetics, 44(8), 934–940.