PIK3CA-related overgrowth spectrum (NORD): Year of the Zebra
PIK3CA-related overgrowth spectrum, or PROS, is a group of disorders caused by mutations in the PIK3CA gene, which plays a role in regulating cell growth and division.
As a result, mutations can result in uncontrolled growth of affected tissues.There are many subtypes of PROS, based on the areas and tissues affected.
CLAPO syndrome involves Capillary malformation, also known as “port wine stain”, in the lower lip, Lymphatic malformation in the face and neck, Asymmetry of the face and limbs, and Partial or generalized Overgrowth of one or more body segments.CLOVES syndrome involves Congenital Lipomatous Overgrowth resulting in fatty swellings on the trunk and/or overgrowth of arms and/or legs that leads to asymmetric enlargement; Vascular malformations including capillary, venous, and/or lymphatic malformations and/or combinations of all of those; Epidermal nevi, presenting as brown bumpy birthmarks on the skin; and Scoliosis, Skeletal, or Spinal anomalies.Klippel-Trenaunay Syndrome, or KTS, includes capillary malformation, abnormal veins, and limb overgrowth.
People with KTS often have lymphatic malformations as well, so depending on the distribution may have some overlap with CLOVES syndrome.Diffuse Capillary Malformation with Overgrowth, or DCMO, involves capillary malformation over a large area of the body with accompanying overgrowth, often increased size of an involved limb due to increased muscle and bone, but does not include venous or lymphatic malformation.Fibro-Adipose Vascular Anomaly, or FAVA, is characterized by the development of a mass of blood vessels and fatty tissue within muscles, which can be painful and reduce mobility.
Fibroadipose Hyperplasia, or FAH, results from overgrowth of connective tissues. In a related disorder, Hemihyperplasia Multiple Lipomatosis Syndrome, or HHML, is characterized by multiple fatty growths, along with hemihyperplasia, which is abnormal enlargement of one limb or one side of the body.
Macrodactyly is isolated enlargement of a digit or digits – fingers or toes, due to overgrowth of bone and soft tissue, which can be painful and reduce mobility or dexterity.Muscular hemihyperplasia, or HH, causes an overgrowth of muscles on one side of the body, so may overlap with HHML, FAH, and macrodactyly.
HH is usually present at birth.Facial Infiltrating Lipomatosis, or FIL, leads to overgrowth of bone and fatty tissue in the face, causing asymmetrical facial enlargement, tongue and teeth enlargement, and rarely nerve tumors.
In Lipomatosis of Nerve, or LON, there is overgrowth of fatty tissue around nerve bundles causing pain or numbness, called neuropathy.
It most commonly affects the median nerve, which controls the forearm, leading to complications like carpal tunnel syndrome.Some subtypes of PROS affect the brain.
Overgrowth of the brain can compress the drainage of the cerebrospinal fluid resulting in herniation or hydrocephalus, which in turn, can cause seizures, abnormal muscle tone, and various cognitive and behavioral disabilities.
Conditions include: Dysplastic Megalencephaly, known as DMEG, which causes enlargement of both cerebral hemispheres; Hemimegalencephaly, or HME, causes enlargement of one side of the brain, which results in asymmetrical enlargement and can lead to severe seizures; and Megalencephaly-Capillary malformation–MCAP–syndrome which involves brain enlargement in conjunction with skin vascular changes, usually capillary malformations, which may take on a particular lacy net-like pattern, called cutis marmorata telangiectatica congenita or CMTC.
Abnormal brain development can lead to growth hormone deficiency, which may cause low blood sugar levels.PROS is due to somatic, or non-inherited, mutations in the PIK3CA gene, which encodes p110α.
This is a subunit of the enzyme phosphoinositide 3-kinase, or PI3K which regulates cell growth, division, and survival. These mutations result in hyperactivity of PI3K, which accelerates cell division and stimulates the production of growth factors and hormones, contributing to tissue overgrowth.Careful exam by a doctor familiar with vascular anomalies and overgrowth syndromes is often sufficient to make a clinical diagnosis.
However, the definitive diagnosis of PROS involves a biopsy of affected tissue to identify a PIK3CA mutation. Imaging studies may be performed to detect bony overgrowth, brain abnormalities, or other internal lesions.
Prenatal ultrasound sometimes detects growth abnormalities associated with these conditions.The majority of people with PROS would benefit from interdisciplinary evaluation by medical providers familiar with these diagnoses.
The treatment of PROS depends on the subtype and the symptom severity. Extensive or involved lesions are usually treated with medicines designed to slow down or turn off the hyperactivity of the PI3K and the downstream pathway.
Several different medicines have been used, but alpelisib was approved in 2022 by the FDA as a treatment for severe cases of PROS in adults and children two years of age or older.
In the case of simple localized lesions, overgrown tissue may be surgically excised; in larger lesions, debulking (removal of part of the lesion) may be performed.
Sclerotherapy, where a chemical is injected into the defective vessel causing it to scar down and close off; or embolization, where injections are given to clot off the defective vessel artificially may be performed.
Bony overgrowth in children which results in limb length discrepancy can be treated with epiphysiodesis, or surgical closure of the growth plate.
Hydrocephalus may be treated by placing a shunt to drain excess cerebrospinal fluid; brain stem herniation may require decompression surgery.
Physical, occupational, and speech therapies might be helpful for individuals with motor and/or intellectual disabilities related to their PROS disease.Alright, as a quick recap, PROS is a group of rare genetic disorders caused by mutations in the PIK3CA gene which causes uncontrolled growth of affected tissues such as muscle, bone, nerve, brain, and blood and lymphatic vessels.
PROS is diagnosed through tissue biopsy and genetic testing, and treatment often requires a multidisciplinary approach.
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