Parkes Weber syndrome

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 stains". "Port-wine stain" or discoloration of the skin due to vascular malformation is also referred as nevus flammeus. Hypertrophy: Hypertrophy 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. These irregular connections affect the blood circulation 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. Because of the capillary malformations, the skin has multiple small, round, pink or even red dots. 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 of the skin. Frequent to occasional symptoms include: varicose veins, congestive heart failure, glaucoma 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 is a condition where tiny blood vessels become widened and form threadlike red lines and or patterns on the skin. Glaucoma: Glaucoma 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. == 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. 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 and gene-targeted deletion/duplication analysis can be performed to identify possible RASA1 gene mutations. 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, ultrasound, CT/CAT scan, angiogram, and echocardiogram. 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 • Proteus syndrome • Macrodystrophia lipomatosa • Neurofibromatosis 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. Laser therapy 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, occupational therapists 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 ==