The association between Klippel Trenaunay syndrome and discoid eczema observed in two patients. Shaikah A. Al-Aojan PROVISIONAL PDF

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1 Al-Aojan 1 ACCEPTED CASE SERIES MANUSCRIPT PEER PEER REVIEWED REVIEWED PROVISIONAL OPEN ACCESS PDF The association between Klippel Trenaunay syndrome and discoid eczema observed in two patients Shaikah A. Al-Aojan Disclaimer: This manuscript has been accepted for publication in International Journal of Case Reports and Images (IJCRI). This is a pdf file of the provisional version of the manuscript. The manuscript will under go content check, copyediting/proofreading and content formating to conform to journal s requirements. Please note that during the above publication processes errors in content or presentation may be discovered which will be rectified during manuscript processing. These errors may affect the contents of this manuscript and final published version of this manuscript may be extensively different in content and layout than this provisional PDF version. ABSTRACT Introduction: Klippel Trenaunay syndrome (KTS) is defined as a triad of port-wine stain, varicose veins or venous malformations, and bony or soft tissue hyperplasia of an extremity. KTS is associated with a variety of inherited and acquired disorders. Case series: This article discusses 2 patients with Klippel Trenaunay syndrome who were also found to have discoid eczema, an association that was not described previously. Conclusion: The recognition of this association will help in the early diagnosis and management of patients with Klippel Shaikah A. Al-Aojan Affiliation: Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Corresponding Author: Dr. Shaikah A. Al-Aojan, Prince Sultan Military Medical City, Riyadh, Saudi Arabia; s.auj@hotmail.com Received: 04 August 2017 Accepted: 29 November 2017 Published: 01 February 2018 Trenaunay syndrome, as well as, further understanding and comprehending the disease. Keywords: Discoid eczema, Eczema, Klippel Trenaunay syndrome, Varicose veins How to cite this article Al-Aojan SA. The association between Klippel Trenaunay syndrome and discoid eczema observed in two patients. Int J Case Rep Images 2018;9():** **. Article ID: Z CS10095SA ********* doi: /ijcri CS INTRODUCTION Klippel Trenaunay syndrome (KTS) is defined as a triad of port-wine stain, varicose veins or venous malformations, and bony or soft tissue hyperplasia of an extremity. It is one of the many overgrowth syndromes that each have unique clinical, behavioral, and genetic features, but at times these features may overlap, causing diagnostic difficulty. In this case, cutaneous manifestations may aid in distinguishing these disorders [1]. Klippel Trenaunay syndrome is associated with a variety of inherited and acquired disorders. Nummular eczema is an idiopathic inflammatory skin disorder that is characterized by multiple coin-shaped eczematous lesions, most commonly found over the trunk and extremities [2]. To the best of our knowledge, discoid eczema in association with Klippel Trenaunay syndrome has not been reported in the medical literature so far.

2 Al-Aojan 2 Figure 1: Showing the discoid eczema lesions overlying port wine stain. Note the presence of varicose veins. CASE SERIES Case 1 We report a 28-year-old man from Saudi Arabia, who was diagnosed with Klippel Trenaunay syndrome at the age of six years. He was noted to have a port wine stain over his right thigh and leg since birth, he also had a hypertrophy of the right lower limb along with varicose veins. The patient had an occluded anterior and posterior tibial veins along with an absent superficial femoral vein over the mid-calf. No arterio-venous fistula was detected. At the age of 17 years he developed a deep venous thrombosis. He underwent multiple sessions of Pulsed Dye laser targeting the port wine stain and it partially improved. The patient was referred to our clinic from vascular surgery with the complaint of itchy skin lesions over right leg and thigh for two years, these lesions were intermittent, improving after using topical steroids for a couple of days then recurring again. The patient claimed that pruritus was disturbing his sleep and his daily activity were greatly affected by his skin condition. He denies the use of any topical preparations prior to the eruption and he doesn t recall any history of insect bite. His family history is negative for similar complaints. Upon examination, he had a well-defined pink-red patches extending from the right thigh to the right leg Figure 2: Showing port wine stain and varicose veins of left flank in patient 2. with superimposed multiple ill-defined coin-shaped erythematous crusted plaques, multiple enlarged venous veins and hypertrophy of the left lower limb (Figure 1). Nails, scalp, mucus membranes and lymph nodes were normal. The patient underwent a biopsy of one of the discoid lesions which showed a spongiotic dermatitis with irregular acanthosis and parakeratosis. A superficial dermal perivascular lymphohistiocytic inflammatory infiltrate, swelling of endothelial cells, and papillary dermal edema were seen. Special stains for fungal organisms were negative. The patient was reassured about the benign nature of the disease. A thorough search for possible triggers of discoid eczema did not reveal a cause in this patient. He was started on a sedative antihistamine to relieve the pruritus in addition to potent topical steroid. He was seen 2 weeks after starting treatment and the lesions completely resolved. Case 2

3 Al-Aojan 3 Figure 3: Showing discoid eczema lesions over right arm of patient 2. Figure 4: Close up view of the lesions over the arm. The second patient is a 35-year-old male who was diagnosed with Klippel Trenaunay syndrome at 10 years of age. He was following in our clinic for Pulsed dye laser treatment of his port wine stain over the left flank. The patient was otherwise well until he developed multiple itchy skin lesions over his back and right arm for 1 week. Lesions were especially itchy at night. He claimed that the lesions were soothed with the application of wet compresses. He denies any history of contact with animals, topical formulations or insect bite prior to the appearance of his lesions. He is not known to have any allergies. On examination, he had a port wine stain and varicose veins over the left flank extending to the left thigh with limb hypertrophy (Figure 2) as well as multiple coinshaped erythematous scaly plaques over right arm and back (Figure 3, 4). The patient was diagnosed with discoid eczema and was started on betamethasone dipropionate ointment twice per day with rapid improvement after 2 weeks. DISCUSSION Klippel Trenaunay syndrome, or angio osteohypertrophy, was first described by Klippel and Trenaunay in 1900 [3]. The cause of KTS is still unknown, however, one plausible theory is at the time of vascular differentiation, an intrauterine insult resulted in malformation of the venous drainage of the extremity [4]. Servelle, by experimental induction of venous stasis, lead to the hypothesis that the etiologic factor in hypertrophied and elongated extremities could be the lack of normal venous drainage [5]. While others have suggested the role of the nervous system and the loss of sympathetic tone by intrauterine injury to the sympathetic ganglia or intermediate lateral tract, resulting in arteriovenous shunt dilation and subsequent venous engorgement [6]. A related theory holds that during fetal development, an underlying mesodermal defect leads to the abnormal maintenance of microscopic arteriovenous fistula [7]. Evidence of a hereditary factor is supported by a few of the familial cases that have been reported [8,9]. Major findings that will most often be seen are presented in Table 1 [10]. Onset in childhood is typical, and the location of the varicosities is characteristically over the lateral aspect of the limb, sweeping medially at the groin. Chronic venous insufficiency is common during the second and third decades of age, and associated venous stasis ulcers can also be found in atypical locations. Generally, only one lower limb is affected and that limb is often noticeably warmer. The association of such venous disease with a port-wine stain and limb hypertrophy should lead to a diagnosis of KTS. Venous abnormalities can extend into the pelvis and abdomen, giving rise to colonic or bladder arteriovenous malformations which might result in rectal bleeding and hematuria, respectively. Lymphedema, orofacial anomalies and congenital bony abnormalities, including

4 Al-Aojan 4 Table 1: adapted from Muluk et al. [9] Major findings that led to diagnosis of Klippel Trenaunay syndrome Long-standing varicose veins Soft tissue and bony hypertrophy of left leg and arm Vascular nevus Syndactyly Long-standing lymphedema syndactyly, pelvic nonfusion, talipes equinovarus, spina bifida, and scoliosis can also be seen. Although deep venous thrombosis is not uncommon, reports of pulmonary embolism are fortunately rare [11]. While the diagnosis of KTS is clinical, imaging of the extremity s venous system can be used as an adjunctive tool. Contrast venography has been the usual imaging modality, while magnetic resonance imaging is considered as an alternative. Findings seen in these modalities include hypoplastic or absent deep venous system, venous obstruction by either fibrous bands or adjacent arteries, and incompetent venous valves [5, 12]. In some patients, pelvic venous anatomy may have to be assessed for colonic and bladder arteriovenous malformations. Another useful diagnostic tool is arteriography, to assess for the presence of a clinically important AVF [9]. Some studies highlighted that a marked improvement in many patients occurred after surgical relief of venous obstruction. However, other authors have found that only a minority of venous obstructions are amenable to surgical correction [4, 8]. Management of venous insufficiency in patients with mild symptoms includes lifelong compression stocking therapy. When symptoms are more problematic, surgical correction of venous obstruction can be done when such obstruction is demonstrated and when a correctable situation exists [9]. Although some authors report improvement of symptoms after ligation and stripping of superficial veins, others have noted worsening of symptoms, which could be attributed to the reduction of an already compromised venous drainage [5, 8]. Treatment of thromboembolic events in patients with KTS includes warfarin anticoagulation, with caval filter placement for warfarin failures. Primary filter placement is also important for patients with significant pulmonary compromise [13]. When filters are used, all possible sources of emboli must be considered, with suprarenal caval filter placement a consideration if supported by venous anatomic findings [13, 14]. Nummular eczema is an idiopathic inflammatory skin disorder that is characterized by multiple coin-shaped eczematous lesions, most commonly found over the trunk and extremities [2]. The cause of nummular eczema is unclear [15]. Possible aetiological factors are divided into internal and external factors. The internal factors are dry skin, stasis, emotional stress and atopic dermatitis in children [14, 16 18]. The external factors include autoeczematization from allergens or Staphylococcus, seasonal variation, alcohol intake and drugs. The commonly attributed allergens were rubber chemicals, formaldehyde, neomycin, chrome, nickel and mercury in dental amalgam, as well as Dermatophagoides farinae and the house dust allergen in elderly patients [19 21]. Staphylococcus and Micrococcus are implemented as possible direct causes of hypersensitivity reactions [22]. The peak frequency of lesions in the winter when the hydration state is low, which makes the stratum corneum become drier than usual supports seasonal variation as an external cause of nummular eczema [21]. Oral systemic drugs such as gold and isotretinoin were shown to relate to this form of eczema [23, 24]. The patch test should be considered for patients with severe or persistent disease, while routine laboratory tests are usually normal [25]. No association was reported in the literature so far between KTS and discoid eczema. We hypothesize that the impaired venous circulation with resultant stasis is most likely responsible for the observed association of KTS with discoid eczema in our patients. CONCLUSION Klippel Trenaunay syndrome (KTS) and discoid eczema are two dermatological diseases with various associations. The occurrence of the two disorders simultaneously was never reported in the medical literature. We report two patients with KTS who also developed discoid eczema. Whether this association is primary or secondary to venous stasis seen in KTS patients remain to be determined. REFERENCES 1. Nafday SM, Heiden RA, Rai DB. Unusual case of Klippel-Trenaunay syndrome a case report and review of the literature. Int J Angiol 2000 Oct;9(4): Rollins TG. From xerosis to nummular dermatitis: The dehydration dermatosis. JAMA 1968 Oct 14;206(3): Klippel M, Trenaunay P. Osteohypertrophic varicose nevus. Arch Gen Med Paris 1900;185: Gloviczki P, Hollier LH, Telander RL, Kaufman B, Bianco AJ, Stickler GB. 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