PIK3CA-Related Overgrowth Spectrum - An Overview

What Is the PIK3CA-Related Overgrowth Spectrum?

PIK3CA-related overgrowth spectrum (PROS) is a group of genetic disorders, which leads to overgrowth of various body parts due to mutation in the gene called PIK3CA. This particular gene is related to protein synthesis and is responsible for regulating cell growth, and survival of the cells. There are a wide variety of disorders that fall under the PIK3CA-related overgrowth spectrum. These disorders present the symptoms based on the site and degree of mutation in the PIK3CA gene, based on this degree of mutation symptoms range from localized overgrowth or the overgrowth seen in a particular tissue. In some cases, overgrowth is observed during childhood but the growth pattern is normal during adulthood. These disorders or genetic mutations are not inherited but occur during intrauterine life. Multiple syndromes that are a part of the PIK3CA-related overgrowth spectrum include:

What Is the PIK3CA-Related Overgrowth Spectrum?

PIK3CA-related overgrowth spectrum (PROS) is a group of genetic disorders, which leads to overgrowth of various body parts due to mutation in the gene called PIK3CA. This particular gene is related to protein synthesis and is responsible for regulating cell growth, and survival of the cells. There are a wide variety of disorders that fall under the PIK3CA-related overgrowth spectrum. These disorders present the symptoms based on the site and degree of mutation in the PIK3CA gene, based on this degree of mutation symptoms range from localized overgrowth or the overgrowth seen in a particular tissue. In some cases, overgrowth is observed during childhood but the growth pattern is normal during adulthood. These disorders or genetic mutations are not inherited but occur during intrauterine life. Multiple syndromes that are a part of the PIK3CA-related overgrowth spectrum include:

Clapo Syndrome: CLAPO syndrome is a rare vascular disorder identified by lower lip capillary malformation, predominantly facial and neck lymphatic malformation, asymmetry, and partial featuresor generalized overgrowth.

Cloves Syndrome: CLOVES syndrome is a recently described rare disorder characterized by tissue overgrowth and complex vascular anomalies. CLOVES stands for congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal nevi, and scoliosis or skeletal or spinal anomalies.

Diffuse Capillary Malformation With Overgrowth (Dcmo): Diffuse capillary malformation with overgrowth (DCMO) is a clinical diagnosis describing patients with multiple, extensive capillary malformations (CMs) associated with overgrowth and foot anomalies.

Dysplastic Megalencephaly (Dmeg): Dysplastic megalencephaly, also known as bilateral hemimegalencephaly, is a rare cerebral malformation characterized by bilateral cerebral hemisphere overgrowth and extensive malformation of cortical development.

Fibroadipose Hyperplasia (Fah) or Fibroadipose Overgrowth (Fao): Overgrowth syndrome affects connective tissues (including fat, skin, ligaments, tendons, and blood). Body parts that may enlarge are the trunk, an individual limb, or fingers and toes. Fat, bone, and muscle may overgrow, but most commonly, overgrowth is seen in the fatty tissue below the skin and around the abdomen.

Hemihyperplasia Multiple Lipomatosis (Hhml) Syndrome: Hemihyperplasia-multiple lipomatosis syndrome (HHML) is a condition characterized by nonprogressive, asymmetrical overgrowth, the presence of multiple lipomas, and superficial vascular malformations.

Some of the other conditions that result in the overgrowth include:

• Fibro-Adipose Vascular Anomaly (Fava).

• Facial Infiltrating Lipomatosis (Fil).

• Hemimegalencephaly (Hme).

• Klippel-Trenaunay Syndrome (Kts).

• Lipomatosis of Nerve (Lon).

• Macrodactyly.

• Megalencephaly-Capillary Malformation (McAp) Syndrome).

• Muscular Hemihyperplasia (Hh).

What Are the Causes Of the PIK3CA-Related Overgrowth Spectrum?

PIK3CA-related overgrowth spectrum results from the mutation during intrauterine life. This mutant gene is either associated with a particular syndrome or can overlap multiple syndromes. The type of mutation that occurs in the PIK3CA gene is termed somatic mosaic mutation, here somatic refers to all the body cells excluding the germ cells that divide and are passed on to offspring, and hence this condition is not inherited. Mosaic refers to the occurrence of mutation only in certain cells or tissues which results in localized overgrowth. These somatic mutations can occur during any cycle of cell division either during lifetime or during prenatal life. In the case of PIK3CA-related overgrowth spectrum disorders, these mutations occur during prenatal life.

The PIK3CA gene is responsible for the formation of a protein called p110 alpha. This protein secretes an enzyme called PI3K, which is responsible for cell growth and division; mutation in these genes leads to abnormal growth of the bone, soft tissue, and blood cells. Recent studies have noted the same mutation to be associated with some malignancies of the lower GI (gastrointestinal) tract, ovaries, breast, brain, and liver. The mutations with the PIK3CA gene are not commonly malignant, but in some cases are responsible for causing a condition called Wilms tumor, which is one of the most common pediatric kidney cancers in very young children.

What Are the Signs and Symptoms of PIK3CA-Related Overgrowth Spectrum?

The specific symptoms can vary greatly among individuals, but some common features of PROS may include:

• Overgrowth: The overgrowth can affect various tissues, including bones, muscles, skin, and blood vessels. The affected areas may appear larger or have asymmetrical growth compared to the unaffected side.

• Vascular Malformations: PROS can lead to the development of abnormal blood vessels or lymphatic vessels, known as vascular or lymphatic malformations. These malformations can cause swelling, discoloration, or disfigurement in the affected areas.

• Skeletal Abnormalities: Some individuals with PROS may have skeletal abnormalities, such as limb length discrepancies, scoliosis (curvature of the spine), or abnormal bone growth.

• Skin Abnormalities: PROS can cause various skin abnormalities, including thickened or bumpy skin, lipomas (benign fatty tumors), or epidermal nevi (raised or thickened patches of skin).

• Intellectual Disability: In some cases, individuals with PROS may have developmental delays or intellectual disability. However, the extent and severity of intellectual impairment can vary widely.

• Other Features: PROS can also present with additional features like macrocephaly (abnormally large head size), macrodactyly (enlarged fingers or toes), asymmetry of facial features, or abnormalities of the genitourinary system.

How Are PIK3CA-Related Overgrowth Spectrum Diagnosed?

Diagnosis relies on evaluating the clinical symptoms of the condition, clinical abnormality, or overgrowth when suspected various diagnostic tests to determine the mutation are carried out. Some of the most common diagnostic tests include biopsy and sequencing of the DNA.

Biopsy of the tissue over the affected area or the excision of overgrown tissue is collected and is genetically tested for somatic mutation at the PIK3CA coding regions. Various other diagnostic tests are used to determine the condition based on the region of mutation. Some of the other diagnostic tests include:

• Blood culture.

• Saliva testing.

• Performing an MRI of the affected area is necessary to ascertain or determine vascular changes.

• Brain imaging to determine the structural changes in cases with neurological symptoms.

• X-ray to analyze any bone changes.

How Are PIK3CA-Related Overgrowth Spectrum Treated?

The treatment in patients with PIK3CA mutation mainly aims at treating the condition symptomatically and in some cases might require a multidisciplinary approach.

The drug of choice in patients with overgrowth, functional abnormalities, and other vascular lesions is considered to be a medication called Alpelisib in children between two to eighteen years the recommended doses are 50 mg once a day, and children above the age of six are recommended to increase the dose to 125 mg once daily after 24 weeks from the onset of treatment. The efficacy of this drug in treating neurological symptoms still remains unknown. This drug was approved in 2022 by the U.S. Food and Drug Administration (FDA). In cases with severe vascular abnormalities laser ablation is used. Surgical removal of the vascular anomaly and skin grafting are other treatment modalities.

Conclusion:

PIK3CA-related overgrowth spectrum is a group mutation disorder or condition that leads to overgrowth of the body of certain organs or parts of the body. These conditions can be diagnosed during intrauterine life. The prognosis of the disorder is good and early diagnosis allows for the possibility of effective treatment. Various radiographic methods help in the diagnosis. If the condition is still encountered after birth it is treated symptomatically.