Parkes Weber syndrome (PWS) is a
congenital disorder
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...
of the
vascular system
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
. It is an extremely rare condition, and its exact prevalence is unknown.
It is named after British dermatologist
Frederick Parkes Weber
Frederick Parkes Weber (8 May 1863 – 2 June 1962) was an English dermatologist and author who practiced medicine in London.
Background
Weber's father, Sir Hermann David Weber (1823–1918), was a personal physician to Queen Victoria.
...
, who first described the syndrome in 1907.
In the body, the vascular system consists of
arteries
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
,
vein
Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenat ...
s and
capillaries
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
. When abnormalities such as
vascular malformation
A vascular malformation is a blood vessel or lymph vessel abnormality. Vascular malformations are one of the classifications of vascular anomalies, the other grouping is vascular tumors. They may cause aesthetic problems as they have a growth cyc ...
,
capillary arteriovenous malformations (AVMs),
arteriovenous fistula
An arteriovenous fistula is an abnormal connection or passageway between an artery and a vein. It may be congenital, surgically created for hemodialysis treatments, or acquired due to pathologic process, such as trauma or erosion of an arterial ...
s (AVFs) and overgrowth of a limb occur together in combination and disturb the complex network of blood vessels of the vascular system, it is known as PWS.
The capillary malformations and AVFs are known to be present from the birth. In some cases, PWS is a genetic condition where the
''RASA1'' gene is mutated and displays an
autosomal dominant inheritance pattern.
If PWS is genetic then most patients show multiple capillary malformations. Patients who do not have multiple capillary malformations most likely did not inherit PWS and do not have RASA1 mutations. In such cases, the cause of PWS is often unknown and is sporadic as most cases often are.
PWS is often confused with
Klippel–Trénaunay syndrome
Klippel–Trénaunay syndrome, formerly Klippel–Trénaunay–Weber syndrome and sometimes angioosteohypertrophy syndrome and hemangiectatic hypertrophy, is a rare congenital medical condition in which blood vessels and/or lymph vessels fail t ...
(KTS). These two diseases are similar, but they are distinct. PWS occurs because of vascular malformation that may or may not be because of genetic mutations, whereas Klippel-Trénaunay syndrome is a condition in which blood vessels and or lymph vessels do not form properly.
PWS and KTS almost have the same symptoms, except PWS patients are seen with both AVMs and AVFs occurring with limb hypertrophy.
Symptoms
Major symptoms of PWS include:
Birthmarks: Affected PWS patients have large, flat, pink staining on the skin. This staining is a result of the capillary malformations that have the tendency to increase the blood flow near the surface of the skin causing the staining. Because of the staining color they are sometimes referred to as "
port-wine stain
A port-wine stain (''nevus flammeus'') is a discoloration of the human skin caused by a vascular anomaly (a capillary malformation in the skin). They are so named for their coloration, which is similar in color to port wine, a fortified red wi ...
s". "Port-wine stain" or discoloration of the skin due to vascular malformation is also referred as
nevus flammeus.
Hypertrophy:
Hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J. ...
refers to excessive growth of the bone and soft tissue. In PWS patients a limb is overgrown and hypertrophy is usually seen in the affected limb.
Multiple arteriovenous fistulas: PWS patients also have multiple AVFs that occur in conjunction with capillary malformations. AVFs occur because of abnormal connections between arteries and veins.
Normally, blood flows from arteries to capillaries then to veins. But for AVF patients, because of the abnormal artery and vein connections, blood flows directly from arteries into the veins completely bypassing the capillaries.
These irregular connections affect the
blood circulation
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
and may lead to life-threatening complications such as abnormal bleeding and
heart failure. AVFs can be identified by: large, purplish bulging veins, swelling in limbs, decreased in
blood pressure,
fatigue and
heart failure.
Capillary arteriovenous malformations: Vascular system disorder is the cause of the capillary malformations. Here, the capillaries are enlarged and increase the blood flow towards the surface of the skin.
Because of the capillary malformations, the skin has multiple small, round, pink or even red dots.
For most of the affected individuals, these malformations occur on the face, arms and or legs. The spots may be visible right from birth itself or they may develop during childhood years.
If capillary malformations occur by themselves, it is not a huge threat to life. But when these occur in conjunction with AVFs then it is a clear indicator of PWS and may be serious depending on the severity of the malformations.
The Human Phenotype Ontology (HPO) reports of additional symptoms in PWS patients. HPO is an active database that collects and researches on the relationships between phenotypic abnormalities and biochemical networks.
This is a useful database as it has information and data on some of the rarest diseases such as PWS. According to HPO, the symptoms which are reported very frequently in PWS patients include: abnormal bleeding, hypertrophy of the lower limb, hypertrophy of the upper limb,
nevus flammeus or staining of the skin, peripheral arteriovenous fistula,
telangiectasia
Telangiectasias, also known as spider veins, are small dilated blood vessels that can occur near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. These dilated blood vessels can develop anywhere on ...
of the skin. Frequent to occasional symptoms include:
varicose veins
Varicose veins, also known as varicoses, are a medical condition in which superficial veins become enlarged and twisted. These veins typically develop in the legs, just under the skin. Varicose veins usually cause few symptoms. However, some indiv ...
,
congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
,
glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
and
headache.
Abnormal bleeding: some skin lesions are prone to bleed easily.
Peripheral arteriovenous fistula: abnormal communication between artery and vein that is a direct result of the abnormal connection or wiring between the artery and vein.
Telangiectasia of the skin:
Telangiectasia
Telangiectasias, also known as spider veins, are small dilated blood vessels that can occur near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. These dilated blood vessels can develop anywhere on ...
is a condition where tiny blood vessels become widened and form threadlike red lines and or patterns on the skin.
Because of their appearance and formation of web-like patterns they are also known as spider veins. These patterns are referred as telangiectases.
Varicose veins
Varicose veins, also known as varicoses, are a medical condition in which superficial veins become enlarged and twisted. These veins typically develop in the legs, just under the skin. Varicose veins usually cause few symptoms. However, some indiv ...
: Enlarged, swollen and twisted veins.
Congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
: This is a condition in which the heart's ability to meet the requirements of the body is diminished. The
cardiac output is decreased and the amount of blood pumped is not adequate enough to keep the circulation from the body and
lungs going.
Glaucoma:
Glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
is a combination of diseases that cause damage to the optic nerve and may result in vision loss and blindness.
Headache: pain in the head.
Causes
The causes for PWS are either genetic or unknown. Some cases are a direct result of the RASA1 gene mutations. And individuals with RASA1 can be identified because this genetic mutation always causes multiple capillary malformations.
PWS displays an autosomal dominant pattern of inheritance.
This means that one copy of the damaged or altered gene is sufficient to elicit PWS disorder. In most cases, PWS occurs in people that have no family history of the condition. In such cases the mutation is sporadic. And for patients with PWS with the absence of multiple capillary mutations, the causes are unknown.
According to Boston's Children Hospital, no known food, medications or drugs can cause PWS during pregnancy. PWS is not transmitted from person to person. But it can run in families and can be inherited. PWS affects both males and females equally and as of now no racial predominance is found.
Mechanism
The causes for PWS without capillary malformations are currently unknown. Some cases of PWS are a result of mutations on the
RASA1 gene which is located on chromosome 5 at position 14.3.
This mutation is only applicable to patients with capillary malformations. RASA1 gene is responsible for making p120-RasGAP protein.
This protein regulates the
RAS/MAPK signaling pathway. RAS/MAPK signaling pathway is used for transmitting signals from the outside the cell to the cell's nucleus. This pathway is very important as it directs cell functions such as growth, proliferation and controls the cell movement.
The p120-RasGAP protein regulates the RAS/MAPK pathway by acting as a negative regulator of the signaling pathway.
It turns off signals.
Mutations in the RASA1 gene disrupt the normal formation of p120-RasGAP protein and result in a nonfunctional protein.
The protein no longer regulates the RAS/MAPK signaling pathway. However, according to NIH Genetics Home Reference, it is still unclear how exactly the disruption of p120-RasGAP protein formation leads to vascular abnormalities and limb overgrowth. But it is a known fact that somehow p120-RasGAP protein is crucial for the normal development of the vascular system and its complex network of blood vessels such as arteries, veins and capillaries.
Based on current knowledge, disruption of p120-RasGAP protein is the reason behind blood vessel malformations which in turn lead to all sorts of problems such as: overgrowth in limbs, excess blood flow near the surface of the skin which leads to port wine stains and even heart failure can occur. The severity of the symptoms is based on extent of the malformations.
Diagnosis
Making a correct diagnosis for a genetic and rare disease is oftentimes very challenging. So the doctors and other healthcare professions rely on the person's medical history, the severity of the symptoms, physical examination and lab tests to make and confirm a diagnosis.
There is a possibility of interpreting the symptoms of PWS with other conditions such as AVMs and or AVFs. This is because AVMs and AVFs also involve the characteristic overgrowth in soft tissue, bone and brain.
Also PWS can be misdiagnosed with Klippel–Trenaunay syndrome (KTS).
However, KTS consists of the following: triad capillary malformation, venous malformation, and
lymphatic malformation.
Usually a specific set of symptoms such as capillary and arteriovenous malformations occur together and this is used to distinguish PWS from similar conditions. Arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs) are caused by RASA1 mutations as well. Therefore, if all the other tests (discussed below) fail to determine PWS, which is highly unlikely,
genetic testing such as
sequence analysis
In bioinformatics, sequence analysis is the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. Methodologies used include sequence alig ...
and gene-targeted deletion/duplication analysis can be performed to identify possible RASA1 gene mutations.
PWS can be distinguished from other conditions because of its defining port-wine stains that are large, flat and pink. The port-wine stains and physical examination are enough to diagnose PWS.
But additional testing is necessary to determine the extent of the PWS syndrome. The following tests may be ordered by physicians to help determine the appropriate next steps:
MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
,
ultrasound
Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...
,
CT/CAT scan,
angiogram
Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins, and the heart chambers. Modern angiography is performe ...
, and
echocardiogram
An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart.
It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound.
Echocardiography has become routinely used in th ...
.
MRI: This is a high-resolution scan that is used to identify the extent of the hypertrophy or overgrowth of the tissues. This can also be used to identify other complications that may arise a result of hypertrophy.
![Angiogram](https://upload.wikimedia.org/wikipedia/commons/3/38/Angiogram.jpg)
Ultrasound: this can be necessary to examine the vascular system and determine how much blood is actually flowing through the AVMs.
CT/CAT scan: this scan is especially useful for examining the areas affected by PWS and is helpful for evaluating the bones in the overgrown limb.
Angiogram: an angiogram can also be ordered to get a detailed look at the blood vessels in the affected or overgrown limb. In this test a physician injects a dye into the blood vessels that will help see how the blood vessels are malformed.
Echocardiogram: depending on the intensity of the PWS syndrome, an echo could also be ordered to check the condition of the heart.
PWS often requires a multidisciplinary care. Depending on the symptoms, patients are dependent on:
dermatologists
Dermatology is the branch of medicine dealing with the skin.''Random House Webster's Unabridged Dictionary.'' Random House, Inc. 2001. Page 537. . It is a speciality with both medical and surgical aspects. A dermatologist is a specialist medical ...
,
plastic surgeons
Plastic surgery is a surgical specialty involving the restoration, reconstruction or alteration of the human body. It can be divided into two main categories: reconstructive surgery and cosmetic surgery. Reconstructive surgery includes craniofa ...
,
general surgeons,
interventional radiologists
Interventional radiology (IR) is a medical specialty that performs various minimally-invasive procedures using medical imaging guidance, such as Fluoroscopy, x-ray fluoroscopy, CT scan, computed tomography, magnetic resonance imaging, or ultraso ...
,
orthopedists,
hematologists,
neurosurgeons,
vascular surgeons
Vascular surgery is a surgical subspecialty in which diseases of the vascular system, or arteries, veins and lymphatic circulation, are managed by medical therapy, minimally-invasive catheter procedures and surgical reconstruction. The specialty ...
and
cardiologists
Cardiology () is a branch of medicine that deals with disorders of the heart and the cardiovascular system. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart d ...
.
Since the arteriovenous and capillary malformations cannot be completely reconstructed and depending on the extent and severity of the malformations, these patients may be in the care of physicians for their entire lives.
Differential diagnosis
*
Klippel–Trénaunay syndrome
Klippel–Trénaunay syndrome, formerly Klippel–Trénaunay–Weber syndrome and sometimes angioosteohypertrophy syndrome and hemangiectatic hypertrophy, is a rare congenital medical condition in which blood vessels and/or lymph vessels fail t ...
*
Proteus syndrome
Proteus syndrome is a rare disorder with a genetic background that can cause tissue overgrowth involving all three embryonic lineages. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development.Freedberg, et al. ...
*
Macrodystrophia lipomatosa Macrodystrophia lipomatosa (ML) is a rare congenital disorder characterized by localised overgrowth of a part of an extremity or less commonly a whole extremity. The involvement of more than one extremity is even more uncommon. There is a slight pre ...
*
Neurofibromatosis
Neurofibromatosis (NF) is a group of three conditions in which tumors grow in the nervous system. The three types are neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis. In NF1 symptoms include light brown sp ...
type 1
Prevention
At the moment, there are no known measures that can be taken in order to prevent the onset of the disorder. The Genetic Testing Registry is a resource for patients with PWS as it provides information on genetic tests that could be done to see if the patient has the necessary mutations.
If PWS is sporadic or does not have RASA1 mutation, then genetic testing will not work and there is not a way to prevent the onset of PWS.
Treatment
There is no cure for PWS.
Treatment differs from person to person and depends on the extent and severity of the blood vessels malformations and the degree of correction possible. The treatments can only control the symptoms and often involve a multidisciplinary care as mentioned in diagnosis.
AVMs and AVFs are treated with surgery or with
embolization
Embolization refers to the passage and lodging of an embolus within the bloodstream. It may be of natural origin ( pathological), in which sense it is also called embolism, for example a pulmonary embolism; or it may be artificially indu ...
.
If there are differences in the legs because of overgrowth in the affected limb, then the patient is referred to an orthopedist.
If legs are affected to a minimal degree, then the patient may find heel inserts to be useful as they adjust for the different lengths in the legs and can walk normally. The port-wine stains may be treated by dermatologists.
Supportive care is necessary and may include
compression garment
Compression garments are pieces of clothing that fit tightly around the skin. In medical contexts, compression garments provide support for people who have to stand for long periods or have poor circulation. These come in varying degrees of co ...
s. These garments are tight-fitting clothing on the affected limb and helps with reducing pain and swelling.
This can also help with protecting the limb from bumps and scrapes that cause bleeding. Again, based on the symptoms, the doctors may recommend antibiotics or pain medications.
Surgical care might also be an option for PWS patients. Surgeons may perform debulking procedure in which abnormal and overgrown tissues are removed.
If PWS is affecting a foot or leg, the limbs can become quite large. And orthopedic surgeon can operate on the limb to reshape the limb. If the growth of the limb is more than one inch a procedure called
epiphysiodesis
Epiphysiodesis is a pediatric orthopedic surgery procedure that aims at altering or stopping the bone growth naturally occurring through the growth plate also known as the physeal plate. There are two types of epiphysiodesis: temporary hemiepiphy ...
may be performed.
This procedure interrupts the growth of the leg and stops the leg from growing too big.
Other treatment options include: embolization and laser therapy. Embolization includes a substance injected by an interventional radiologists that can help in the elimination of the abnormal connections between the arteries and veins.
According to "Parkes Weber syndrome—Diagnostic and management paradigms: A systematic review", published in July 2017, embolization alone or in combination with surgical removal of arteriovenous malformations leads to significant clinical improvement.
Laser therapy
Laser medicine consists in the use of lasers in medical diagnosis, treatments, or therapies, such as laser photodynamic therapy, photorejuvenation, and laser surgery.
Lasers
Lasers used in medicine include in principle any type of laser, but ...
can also help lighten capillary malformations and can speed up the healing process of the bleeding lesions.
Other specialists are needed for dealing with the progression of the disease, such as:
physical therapists
Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patien ...
,
occupational therapist
Occupational therapists (OTs) are health care professionals specializing in occupational therapy and occupational science. OTs and occupational therapy assistants (OTAs) use scientific bases and a holistic perspective to promote a person's abi ...
s and counselors.
Physical therapists can help ease the pain and increase the range of movements of the arm or leg that is overgrown. Occupational therapists could help with the development of motor skills impeded by physical problems. The classic port-wine stains may make the patient feel uncomfortable and counselors can help with the psychological and social issues.
Prognosis
PWS is a progressive condition and advances with age. It is dependent on the extent of the disease and overgrowth, condition of the patient's heart, if the blood vessels are responsive to treatment, overall health of the patient, tolerance of medications and treatments. Based on these factors the prognosis is fair to good.
The deformity and overgrowth tend to progress with time until
epiphyseal closure. A lot of medical attention is needed to correct the blood vessels.
Recent research
According to NIH clinical trials.gov, research on the port-wine stain and its relation to
polymorphisms of RASA1 has commenced in November 2010 and expected to end in November 2019.
The purpose of the study is to assess how the port-wine stains can lead to complex syndromes such as PWS. Currently there is little knowledge about the epidemiology of the stains and how they progress with the disease. The research is ongoing and the results are yet to be published.
In another review published in July 2017 (discussed in treatments and prognosis), Banzic et al. discussed clinical findings that embolization works really well in patients with PWS. Also, embolization along with surgical resection that targets arteriovenous malformations reliably leads to significant clinical improvements.
See also
*
Klippel–Trénaunay syndrome
Klippel–Trénaunay syndrome, formerly Klippel–Trénaunay–Weber syndrome and sometimes angioosteohypertrophy syndrome and hemangiectatic hypertrophy, is a rare congenital medical condition in which blood vessels and/or lymph vessels fail t ...
*
List of skin conditions
Many skin conditions affect the human integumentary system—the organ system covering the entire surface of the body and composed of skin, hair, nails, and related muscle and glands. The major function of this system is as a barrier against ...
References
Further reading
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External links
{{Deficiencies of intracellular signaling peptides and proteins
Vascular-related cutaneous conditions
Syndromes
Diseases named for discoverer