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40 years!
Last updated:
October 03, 2022
Years published: 2022
NORD gratefully acknowledges Adrienne M. Hammill, MD, PhD, Cancer and Blood Diseases Institute, Division of Hematology, Hemangioma & Vascular Malformation Program, Cincinnati Children’s Hospital Medical Center; Associate Professor, Department of Pediatrics, University of Cincinnati, for assistance in the preparation of this report.
Summary
PIK3CA-related overgrowth spectrum (PROS) includes a group of genetic disorders that leads to overgrowth of various body parts due to changes (mutations) in the gene PIK3CA. This gene is involved in making a protein that helps regulate cell growth, division and survival. A broad array of disorders falls within this spectrum, with some overlap of symptoms between the different disorders. Syndromes within the spectrum may also overlap genetically, meaning they may share specific PIK3CA gene mutations in cells in the areas of the body that are affected. Since PIK3CA mutations in these disorders are not present in all cells, only certain areas of the body are overgrown, ranging from isolated digits to whole limbs, trunk, or brain. Different tissues may be involved individually or in combination such as fat, muscle, bone, nerve, brain and blood vessels. Genetic mutations that cause these disorders are not passed down from parent to child but instead result from changes to genes during development in the womb. Symptoms associated with these disorders can be present at birth (congenital) or appear later in early childhood. Overgrowth may stop in childhood or continue into adulthood.
Different subtypes within PROS include: CLAPO syndrome, CLOVES syndrome, DCMO, DMEG, FAH/FAO/HHML, FAVA, FIL, HMEG, Klippel-Trenaunay syndrome (KTS), LON, macrodactyly, MCAP and muscular hemihyperplasia (HH). Symptoms vary widely and depend on which part of the body overgrows, ranging from intellectual disability, seizures and autism when the brain is involved to blood clots when blood vessels are affected. Some PROS syndromes affect a wider range of body systems while others are more limited in which parts of the body overgrow.
CLAPO Syndrome
CLAPO is an acronym for the multiple features that can co-occur in this syndrome: capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of face and limbs and partial or generalized overgrowth involving one or more body segments. This syndrome was first described in 2008. Features that distinguish CLAPO from other PROS syndromes with similar signs, like MCAP syndrome, are the presence of capillary malformations on the lower lip and the absence of neurological symptoms since CLAPO does not affect the brain. Capillary malformations in MCAP are most frequently found on or above the upper lip instead. Overgrowth in CLAPO may be difficult to detect and what may appear as overgrowth of fatty tissue may be asymmetry between body parts due to vascular changes.
CLOVES Syndrome
CLOVES syndrome is a rare disorder first described as a distinct syndrome in 2007. It is characterized by tissue overgrowth and complex vascular anomalies. CLOVES stands for Congenital Lipomatous (fatty) Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies. It can affect soft tissue, blood vessels, bone and internal organs, and symptoms can range from mild to severe. This syndrome has many potential symptoms, but these are among the most common ones:
1. Lipomatous overgrowth where soft fatty masses are present at birth on the trunk (back, flanks, axilla, abdomen or buttocks). These overgrowths can appear on one or both sides of the body.
2. Vascular malformations may be found overlying these masses or elsewhere on the body, most often as a red-pinkish birthmark called a capillary malformation (also known as a port-wine stain). Other skin abnormalities in this syndrome include moles, prominent veins and epidermal nevi (slightly raised often rough areas of skin with light brownish color).
3. Patients with CLOVES are more susceptible to blood clots, including pulmonary embolism (clots in the lungs), due to abnormal malformed veins (usually residual embryonic dilated veins) in the chest and upper and lower extremities. Abnormal veins may also cause localized pain and inflammation.
4. Swellings of lymph fluid, known as lymphatic malformations, can also occur within the fatty masses or elsewhere in body (abdomen, chest, extremities).
5. Overgrowth of one or more extremities (arms and legs) is common. Large wide hands or feet, large fingers or toes, wide space between digits (sandal gap deformity) and uneven size of extremities (length and/or girth discrepancy) are common. This can also occur in the face and head when those areas are involved.
6. Spinal anomalies include scoliosis (curving of the spine), fatty masses pushing on the spinal cord and tethered cord (spinal cord fixed by abnormal band). Rarely, patients may suffer from arteriovenous malformations around the area of the spinal cord, which can be quite aggressive and difficult to treat.
7. The size of the kidneys may be asymmetric (one is larger) and may show some abnormal features on imaging studies. Wilms tumor has been noted in a small number of young patients with CLOVES syndrome so screening with serial ultrasound examinations during childhood is recommended.
Additional findings can occur in CLOVES syndrome including bleeding from abnormal vessels in the skin, gastrointestinal tract (the stomach and intestines) and/or the genitourinary tract (urinary bladder and urethra). (For more information on this disorder, choose “CLOVES Syndrome” as your search term in the Rare Disease Database).
Diffuse Capillary Malformation with Overgrowth (DCMO)
DCMO patients have multiple and/or extensive capillary malformations associated with facial asymmetry, limb overgrowth and hand or foot deformities. These capillary malformations form a blotchy network of birthmarks that may lighten over the first several months and are typically lighter than birthmarks in KTS. Capillary malformations in DCMO extend beyond just one body region. They may be present on the abdomen but never on the back. Limb overgrowth in DCMO does not progress, so vascular complications are not expected to occur.
Dysplastic Megalencephaly (DMEG)
Dysplastic megalencephaly, or bilateral hemimegalencephaly, causes overgrowth of both hemispheres of the brain, leading to abnormal development. Symptoms include seizures that don’t respond well to medications, severe neurological impairment, abnormal muscle tone and developmental delays in motor, language and cognitive skills. DMEG may also be associated with cardiac failure during fetal development.
Fibroadipose Hyperplasia (FAH)/Fibroadipose Overgrowth (FAO)
First reported in 2012 as a PIK3CA-related condition, this 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 fatty tissue below the skin and around the abdomen. Although extra fingers or toes may be present at birth, overgrowth in fibroadipose hyperplasia is not usually apparent at birth and tends to progress over time. Functional limitations with completing everyday tasks may occur due to anatomical differences between body parts and limited movement of enlarged body parts.
Hemihyperplasia Multiple Lipomatosis (HHML) Syndrome
When the overgrowth is more diffuse it may present as hemihyperplasia multiple lipomatosis (HHML) syndrome, a rare disorder characterized by the development of multiple benign fatty tumors (lipomas) and the abnormal enlargement of one side or structure of the body (hemihyperplasia). Hemihyperplasia may present as asymmetry between just one limb as compared to the other side, or between one half of the body and the other. Hemihyperplasia may be mildly progressive as the result of asymmetric (more rapid) growth on the affected side.
Fibro-Adipose Vascular Anomaly (FAVA)
FAVA is a rare mass of blood vessels and fatty tissue that develops within a muscle. It normally leads to overgrowth of a single limb, most commonly in the lower extremities about 90% of the time but may also form in the upper extremities and the trunk. It tends to cause pain as its most prominent symptom, but may present as reduced mobility, swelling, or visible veins. Diagnosis with FAVA may be delayed into late childhood or even adulthood. FAVA is three times more common in females than males. As of 2020, there were only 20 patients with FAVA reported in the medical literature.
Facial Infiltrating Lipomatosis (FIL)
Facial infiltrating lipomatosis (FIL) results in overgrowth in areas of the face due to invasion by mature fat cells (lipocytes). One side of the face becomes swollen and enlarged over time due to enlargement of bones and soft tissues. Other features may include early development of teeth, enlarged teeth (macrodontia), tongue enlargement on the affected side and nerve tumors (neuromas) in areas around the tongue and lips.
Hemimegalencephaly (HME)
Hemimegalencephaly (HME) is a rare neurological condition in which one-half of the brain, or one side of the brain, is abnormally larger than the other. The structure of the brain on the affected side may be markedly abnormal or show only subtle changes. In either case, because of this size and structural difference, the enlarged brain tissue causes frequent seizures, often associated with cognitive or behavioral disabilities. Seizures in association with HME often begin in early infant life, including infantile spasms. Hemimegalencephaly may occur as an isolated or sporadic brain malformation, or it may be associated with other neurodevelopmental syndromes; it has been observed in some patients with CLOVES syndrome when the face/head are involved. Thus, when detected, HME should prompt a search for other syndromic diagnoses.
Anti-seizure medications are not typically effective in controlling seizures in HME and surgery is often recommended to control the seizures. If the affected side is surgically removed (anatomic hemispherectomy) or disconnected from the other brain structures (functional hemispherectomy) early in life, the remaining side of the brain may gradually take over the functions normally performed by the affected side.
Any combination of altered mental status, seizures, enlarged head and /or colored birthmark should prompt consideration of HME. In general, the presence of HME is definitively diagnosed by brain MRI. With the evolution of more widespread fetal imaging including ultrasound and MRI, many HME cases are detected prenatally. (For more information on this disorder, choose “Hemimegalencephaly” as your search term in the Rare Disease Database).
Klippel-Trenaunay Syndrome (KTS)
Originally described in the early 1900s according to a set of symptoms, many but not all patients with KTS have since been found to have PIK3CA gene mutations. KTS is present at birth and is characterized by a triad of cutaneous capillary malformation (port-wine stain) and abnormal veins in association with limb overgrowth, and patients often show lymphatic malformations as well. KTS occurs typically in one lower limb and may extend into the pelvis. KTS affects males and females equally. There is some overlap with symptoms of CLOVES syndrome depending on the extent of involvement. (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database).
Lipomatosis of Nerve (LON)
Lipomatosis of nerve occurs when nerve bundles enlarge from overgrown fat that impacts nerve function. LON may be associated with bone or soft tissue overgrowth in areas served by but at somewhat of a distance from the affected portion of the nerve. This means LON may occur with other overgrowth conditions like macrodactyly or muscular hemihyperplasia. Overgrowth progresses slowly so patients usually do not present with symptoms until childhood or young adulthood and symptoms are usually of a neurological dysfunction. LON most often affects the median nerve that controls the forearm and hand so patients can present with carpal tunnel syndrome. Other nerves more frequently affected are the ulnar and plantar nerves serving the arm and feet, respectively. LON affects males and females equally.
Macrodactyly
Macrodactyly refers to abnormally large fingers or toes present at birth due to overgrowth of bones and soft tissue. It can occur as a feature of other PROS syndromes or in isolation. Macrodactyly occurs more often in the hands than feet but can affect both in one individual. It may also affect one or more digits and may occur on one or both sides of the body. Growth of the enlarged digits may occur at the same or at a much faster rate than unaffected digits and growth rates can vary across time in the affected individual. Webbed fingers and toes, known as syndactyly, may co-occur in patients with macrodactyly. Other accompanying symptoms in macrodactyly include stiffness, reduced mobility, swelling and rarely, pain. PIK3CA gene mutations are a primary cause of isolated macrodactyly.
Megalencephaly-Capillary Malformation (MCAP) Syndrome
Megalencephaly-capillary malformation syndrome (MCAP), formerly known as macrocephaly-capillary malformation (M-CM), is a complex disorder that usually presents at birth and involves many organ systems, including the brain; skin; blood vessels; connective tissue and others. Some patients with this syndrome have mild symptoms while others have more severe ones.
Most affected individuals have a disproportionately large head and vascular malformations on the skin, typically light pink vascular markings on the midline face, trunk, and sometimes limbs.
Most children with MCAP have an enlarged brain (megalencephaly) and other findings on brain MRI scans with associated neurological problems. One particularly common type of malformation of the brain’s cortex in MCAP is polymicrogyria (PMG), which refers to abnormally small and numerous folds of the cortical surface. The corpus callosum (a midline structure that joins the two cerebral hemispheres) is usually twice as thick as normal. Head overgrowth tends to progress with time, and brain overgrowth within the skull can even lead to brain herniation. Brain overgrowth can interfere with drainage of cerebrospinal fluid, leading to abnormal widening of the ventricles and excessive accumulation of this fluid (hydrocephalus). Chiari malformation may also occur when megalencephaly causes portions of the cerebellum of the brain to become dislodged and compress the brainstem. Symptoms of hydrocephalus and Chiari malformation include headaches, lethargy, breathing abnormalities and recurrent vomiting; when this occurs, neurosurgical intervention is needed urgently.
Most infants with this syndrome have some degree of body overgrowth at birth that tends to stabilize or normalize with age, although others may have body growth deficiency later. Body growth may also be uneven between the two halves of the body, ranging from very noticeable to very subtle.
Specific skin findings are associated with MCAP syndrome. These light-pink vascular markings, known as capillary malformations, are most commonly at the midline face (on the forehead or above the upper lip) in MCAP, but they can also be found in children who don’t have this syndrome. They may fade as children with MCAP get older. MCAP-associated capillary malformations often show a lacy or reticulated pattern (resembling a net or web) called cutis marmorata.
Children with MCAP syndrome may also have low blood sugar levels (hypoglycemia). This is from growth hormone deficiency caused by abnormal brain development. (For more information on this disorder, choose “Megalencephaly-Capillary Malformation” as your search term in the Rare Disease Database).
Muscular Hemihyperplasia (HH)
Formerly known as muscular hemihypertrophy, muscular hemihyperplasia is an overgrowth of muscle tissue on one side of the body and usually present at birth. It can overlap with features of macrodactyly, HHML and FAO.
PROS is caused by somatic mutations in the PIK3CA gene. There are a variety of activating mutations of the PIK3CA gene associated with each syndrome with some genetic overlap between the different syndromes.
During prenatal development, mutations known as somatic and germline mutations can occur. Germline mutations are genetic changes in sperm or egg cells (germ cells) that are passed down during conception to affect offspring. Somatic mutations are genetic changes in any body cell other than germ cells and, therefore, cannot be passed down to offspring. Somatic mutations can occur during prenatal development and any time during the lifespan.
In the case of PROS, these somatic mutations occur during prenatal development and are said to be somatic mosaic mutations. Mosaic refers to these mutations being present in only certain body cells that affect only certain areas of the body rather than in all body (somatic) cells, which is why overgrowth appears in only certain body regions or asymmetrically.
The PIK3CA gene provides instructions for making the protein known as p110α, and mutations in this gene result in an abnormally active PI3K enzyme. With this increase in activity, affected cells grow and divide more than they should, leading to abnormal bone, soft tissue and blood vessel growth. PIK3CA mutations may also cause overgrowth by influencing the effects of growth factors and hormones on nearby and distant cells.
Since 2004, mutations in the PIK3CA gene have been found in certain cancers of the lower GI tract, the ovaries, breasts, brain and liver. Currently, most patients with PROS do not appear to be at a significantly higher risk for cancer. The only cancer reported in PROS to date has been Wilms tumor, the most common pediatric kidney cancer in very young children.
Because PROS includes several different syndromes, the exact incidence and prevalence rates are not known. These syndromes are typically diagnosed at birth or in early childhood. Many syndromes such as MCAP, CLOVES and KTS affect males and females in equal numbers.
Diagnosis of PROS is based on genetic testing for PIK3CA genetic variants. Testing for somatic conditions includes biopsy of tissue affected by overgrowth. Detection of a PIK3CA mutation in biopsied tissue may be difficult because these mutations are detected at widely varying levels in affected cells and tissues.
For MCAP, however, diagnostic testing may be done with blood and saliva samples because the PIK3CA mutations in this syndrome may be found in more cells.
A combination of clinical features that help doctors suspect PROS and order PIK3CA genetic testing include:
• overgrowth symptoms either at birth or during early childhood
• tissue overgrowth that is patchy and irregular
• overgrowth in fat, muscle, nerve or skeletal tissue
• vascular malformations in capillaries, veins, arteries or lymphatic vessels
• epidermal nevus
• congenital neurological disorders
Symptoms may present in isolation or with two or more of the above features.
For patients with megalencephaly and neurological symptoms, brain imaging techniques are part of the diagnostic workup and are frequently used for monitoring structural changes. Vascular anomalies are detected with imaging studies, usually MRI of the affected regions with contrast to show vascular details. Prenatal ultrasound may reveal some features of these conditions.
Treatment depends on symptoms present for each syndrome and, for those patients with multiple features, requires collaboration between an interdisciplinary team of physicians and specialists.
Diagnosis of PROS disorders with involvement below the skin typically requires imaging. This is most often MRI for soft tissue and vasculature, but may include x-rays to follow changes in bones, or ultrasounds for organ surveillance.
Extensive or involved lesions are usually treated with drugs designed to slow down or turn off the hyperactivity of the PI3K enzyme and the PI3K/Akt/mTOR pathway. Several different medicines have been used, and alpelisib was approved in 2022 by the U.S. Food and Drug Administration (FDA) as a treatment for severe cases of PROS in adults and children two years of age or older.
Laser ablation may be used to treat vascular anomalies in the skin. In more severe cases, surgical removal of a skin vascular malformation followed by a skin graft may be helpful. For deeper malformations, sclerotherapy (for venous or lymphatic malformations) or embolization (for arterial lesions) may be performed as single therapy or in conjunction with/prior to surgery. For patients with abnormal embryonic veins at high risk of clot, veins are often ablated prior to surgery if possible. Anticoagulation therapy is often used around large surgeries to prevent clotting and risk of embolism in the perioperative period.
For bulky tissue overgrowth of limbs, digits or soft tissues, surgical removal or debulking may be an option but can be complicated by vascular changes in these tissues. Abnormal tissue can also regrow, requiring repeated surgical interventions during a lifetime.
Orthopedic measures such as surgical closure of the growth plate (epiphysiodesis) at joints, most commonly the knee, may equalize leg length. This can also be performed in digits (fingers or toes) with overgrowth. Shoe lifts on the shorter leg’s foot can also correct unequal leg length until timing is appropriate for epiphysiodesis in order to prevent scoliosis (spine curvature) that might occur otherwise.
Megalencephaly usually warrants referral to a neurosurgeon, especially if hydrocephalus or Chiari malformation occurs. Hydrocephalus is treated with shunt placement to drain excess cerebrospinal fluid; brain overgrowth with threated herniation may also be treated with laminectomy for decompression. In patients with hemimegalencephaly, seizures are often poorly controlled with medication, so surgery to separate the hemispheres is usually undertaken. The connection between the two hemispheres may be severed while leaving the abnormal hemisphere within the skull (hemispherotomy) or the abnormal hemisphere may be removed altogether (hemispherectomy).
Treatment with physical, occupational and speech therapies along with special education services may be beneficial depending on motor and intellectual disabilities present.
Imaging studies should also be used to monitor for tumor development since Wilms tumor has been reported in patients with PROS. Ultrasound monitoring is recommended every 3-4 months until age 7 years.
Other drugs that inhibit the PI3K/Akt/mTOR pathway are under investigation for the treatment of PROS. These drugs have been repurposed for the treatment of PROS but were originally developed to treat cancer and/or prevent organ rejection after transplant. Some have been approved for other uses. These drugs include the mTOR inhibitor sirolimus and the Akt inhibitor miransertib.
Sirolimus has been used for over a decade for disease control in many different vascular malformations, including several PROS diagnoses. It has been shown in prospective studies to improve pain and functional limitation in many patients with lymphatic, venous or combined malformations (including PROS). While it has not been FDA-approved for the treatment of PROS, it has been approved in several related diseases including tuberous sclerosis and lymphangioleiomyomatosis.
Miransertib is currently being studied in prospective studies of Proteus syndrome and PROS and has been reported to lessen pain and stabilize skin lesions in PROS without significant reported adverse events.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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INTERNET
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