KTWS (Klippel‐Trenaunay‐Weber syndrome): A systematic presentation of a rare disease

Klippel‐Trenaunay‐Weber syndrome (KTWS) is a rare disease with a wide range of manifestations. KTWS is characterized by a clinical triad of varicosities of the extremities, cutaneous vascular malformations, and hypertrophy of soft tissues and long bones. The diagnosis is made clinically supplemented with magnetic resonance imaging and computed tomography.


Patient:
We report the case of a 47-year-old male with KTWS, who presented with various symptoms such as rectorrhagia since childhood, digestive problems and abnormal lateral vascular malformations of the left buttock which extended all the way to the leg, vascular malformations of the left fourth and fifth toes as well as soft tissue swelling of the left foot.There was no evidence of other clinical presentations.The patient was hospitalized with severe rectorrhagia and a hemoglobin level of 3/9.Physical examination revealed a blood pressure of 85/55 and pulse rate of 115.Ruptured aneurysm of the superior mesenteric artery was found on angiography and subsequently treated with embolization.Dermatologic evaluation showed pitting edema of the left leg and foot and multiple vascular lesions.Thus a diagnosis of KTWS was established.
Pulsed dye laser therapy and compression bandage was performed for the patient.The patient's follow-up was done 3 months after discharge for which the patient was again consulted by a dermatologist and gastroenterologist.Lymphedema of the left leg had improved to a great extend so treatment with compression bandage was continued.Colonoscopy was repeated for the patient to evaluate and control possible active sources of bleeding, due to potential life-threating complications.
Results: According to previous findings, there have been few case reports of KTWS presenting with gastrointestinal manifestations, fewer of which have covered acute life-threatening bleedings associated with this system.Other than the classic triad of a combined vascular malformation of capillaries, veins, and lymphatic vessels; congenital venous abnormalities; and limb hypertrophy, its association with neurovascular abnormalities has been reported but is infrequent, and the presence of intracranial arteriovenous malformations (AVMs) are extremely rare. 2 The incidence of genitourinary manifestations in Klippel-Trenaunay syndrome is 30%. 3e overall genitourinary symptoms in patients with the KTWS seem to occur in the more severe cases and usually involve cutaneous vascular malformations of the trunk, pelvis, and genitalia. 4 mentioned above, lymphatic system abnormalities as examined with MRL are commonly associated with KTS and are likely to play a significant role in the disorder. 5ippel-Trenaunay syndrome patients often suffer degenerative joint disease at an early age.Performing arthroplasty in these patients is particularly difficult for a number of reasons. 6e arteriovenous malformations that occur in this syndrome turn the approach into a challenging one due to potential bleeding risks which can be life-threatening, similar to our patient case, who suddenly presented with severe GI bleeding and a very low hemoglobin level. 7nagement is largely conservative and the extent of diagnostic evaluation is determined by the planned treatment.Among palliative treatment options are elastic compression therapy for swelling as well as lymphedema and laser therapy for vascular lesions.In rare cases, surgery is also performed. 8,9 reported in this case, many KTWS patients present with gastrointestinal bleeding due to vascular malformations which can manifest as rectorrhagia. 10

| C A S E REP ORT
We report the case of a 47-year-old male who presented with rectorrhagia since childhood as well as digestive problems, grade 2 hemorrhoid and abnormal lateral vascular malformations of the left buttock all the way to the leg and vascular malformations of the fourth and fifth left toes (Figure 1).He also has a history of amputation of the second and third left toes and soft tissue swelling of the left foot (Figure 2).Cherry angioma and senile angioma were seen in the abdomen (Figure 3).

| DISCUSS ION
KTWS is a severe congenital anomaly in which mutations of the AGGG1 gene have been identified to play a key role. 1 KTWS is a complex vascular syndrome associated with hypertrophy of the limbs and patients are diagnosed on the basis of physical examination.Some patients may present with acute life-threatening complications such as VTE.Varying involvement of cutaneous capillaries, veins, and lymphatics along with hypertrophy of the soft tissue and bones of the affected limb is seen. 11,12though involvement of the lower limbs is very common, there have been case reports without lower limb involvement. 13 a cohort study, 173 KTWS patients were examined, 43 of whom had arm involvement.Out of the 19 patients who only had arm involvement, 12 patients were examined by duplex ultrasonography (CDU).Nine of the twelve had venous malformations. 14 is believed that deep vein abnormalities as a result of obstruction of venous flow lead to venous hypertension, varicose veins, and organ hypertrophy. 15t in this disease, intracerebral arteriovenous abnormalities are very rare. 2 Urogenital involvement in these patients is not very rare and shows itself with hematuria or changes in the skin of the external genitalia. 16ong the rare associations of KTWS is glioblastoma multiforme (grade IV astrocytoma). 17so hemi-megalencephaly, characterized by the enlargement of all or part of the hemispheres of the brain, is in rare cases associated with KTWS.The damaged hemisphere may have focal neural migration defects or areas of polymicrogyria, pachygyria, and heterotopia. 18rmatologic management is mainly conservative.Laser can be used to treat port wine stains and elastic compression wraps can help with lymphedema and limb swelling. 8ninvasive pulsed dye laser is the current gold standard for the treatment of port wine stains.However, most port wine stains are not completely cleared after pulsed dye laser therapy, owing to insufficient photocoagulation and laser-induced vascular regeneration and reperfusion. 19st patients did well without treatment or with elastic compression only.Surgical treatment for vascular malformations in KTS is rarely needed and it continues to be controversial. 10nce his syndrome commonly presents with involvement of superficial and deep vessels, stenting can be used in the veins, especially in the Iliofemoral vein, in cases which conservative therapy has failed. 20mphaticovenular anastomosis (LVA) has also proven to be effective in the treatment of cellulitis in these patients. 21strointestinal involvement in KTWS disease is rare but very life-threatening, so in a study by Servelle et al., of 588 KTWS patients, only six had gastrointestinal bleeding and in cases where the patient has severe bleeding, it may be necessary to remove a part of the digestive system. 22ually, in KTWS patients, vascular abnormalities do not involve all parts of the digestive system. 23d because the patient presents with intermittent bleeding, it is even possible to be confused with hemorrhoids.Although there are some reports of KTWS globally, our report presents a case of higher severity involving the gastrointestinal system particularly, emphasizing the importance of acute gastrointestinal bleeding followed by severe anemia in such patients, which seems to be a less expected manifestation.However, it should be kept in mind, that although KTWS is an uncommon cause for this clinical picture, that it still falls in the category of its differential diagnoses.More importantly, patients diagnosed with KTWS should be closely observed for gastrointestinal sources of bleeding, which also raises the question of possible screenings in such individuals.

AUTH O R CO NTR I B UTI O N S
Ramin Mofarrah has contributed to the conception and design of this paper as well as analysis and interpretation of data and revision of the drafted manuscript.Ramina Mofarrah, Sadaf Emadi and Sueshianth Ghobadi Aski have each made substantial contributions to drafting the manuscript.Peyman Gooranorimi has made critical revisions on this manuscript.All authors have given their approval of the version to be submitted for publication and have participated sufficiently in the work to take public responsibility for appropriate portions of the content and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

E TH I C S S TATEM ENT
Hereby we confirm that the human studies have been reviewed and approved by the appropriate institutional ethics committee and have therefore been performed in accordance with the ethical standards laid down in the World Medical Association Declaration of Helsinki or other comparable standards.Also all persons gave their informed consent prior to their inclusion in the study.

CO N S E NT
The examination of the patient was conducted according to the principles of the Declaration of Helsinki.The authors certify that they have obtained all appropriate patient consent forms, in which the patients gave their consent for images and other clinical information to be included in the journal.The patients understand that their names and initials will not be published.

K
E Y W O R D S hypertrophy, KTWS, port wine stain 1 | INTRODUC TI ON Klippel-Trenaunay-Weber syndrome (KTWS) is a severe congenital disorder characterized by capillary malformations, venous malformations or varicose veins, and hypertrophy of the affected tissues.1 He also had a history of ischemic stroke and his hair had whitened for 30 years.There was no evidence of other clinical presentations.The patient was initially diagnosed with hereditary hemorrhagic telangiectasia (HHT) and underwent several packed cell transfusions and was started on octreotide.But 2 years later he was hospitalized with severe rectorrhagia and a hemoglobin level of 3/9.Patient's vital signs revealed a blood pressure of 85/55 and a pulse rate of 115.Pallor, thready pulse and cold extremities were detected on examination.Colonoscopy was performed but did not identify the source of bleeding so subsequent angiography was done for the patients which revealed a F I G U R E 1 Vascular malformations of the fourth and fifth left toes.F I G U R E 2 Soft tissue swelling of the left foot.ruptured aneurysm of the superior mesenteric artery.Treatment was done with embolization.Dermatology and gastrointestinal services were consulted and KTWS was confirmed.Soft tissue swelling and lymphedema were managed with compression bandages.Pulsed dye laser was recommended for vascular lesions and angiomas, but was never performed due to the patient's lack of financial resources.The patient's follow-up was done 3 months after discharge for which the patient was again consulted by a dermatologist and gastroenterologist.Lymphedema had improved extensively so compression bandages were continued.Colonoscopy was repeated for the patient to evaluate and control comorbid sources of active bleeding, due to potential life-threating complications.

4 |
CON CLUS IONIn conclusion we describe a case of KTWS with systemic symptoms.KTWS is a severe congenital disorder with a wide range of manifestations.It is characterized by a clinical triad of extremity varicosities, cutaneous vascular malformations, and hypertrophy of soft tissues and long bones.

F I G U R E 3
Cherry angioma and senile angioma were seen in the abdomen.