Mutations in EPHB4 cause human venous valve aplasia.

Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex "organization" of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.

After Superficial Ablation for Superficial Reflux Associated with Primary Deep Axial Reflux, Can Variable Outcomes be Caused by Deep Venous Valve Anomalies?

OBJECTIVE: To identify which deep anatomical anomalies can explain variable hemodynamic outcomes in patients with superficial reflux associated with primary deep axial reflux who underwent isolated superficial vein ablation without improvement. METHODS: This is a retrospective study of deep venous valve anomalies in patients who underwent superficial vein ablation for superficial and associated deep reflux. A group of 21 patients who were diagnosed with saphenous reflux associated with primary deep axial reflux, were submitted to great saphenous vein ablation. In 17 patients the deep reflux was not abolished. In this subgroup, surgical exploration of the deep valve was carried out using venotomy for possible valve repair. RESULTS: Among the 17 subgroup patients, four post-thrombotic lesions were discovered intra-operatively in four patients; they underwent different surgical procedures. In 13 of the subgroup patients, primary valve incompetence was confirmed intra-operatively. In 11 cases the leaflets were asymmetrical and in only two were they symmetrical. After valvuloplasty, deep reflux was abolished in all 13 patients. Clinical improvement was obtained in 12/13 patients (92%). It is noteworthy that abolition of deep reflux was associated with significant improvement in air plethysmography data as well as with improvement in clinical status measured on CEAP class, VCSS and the SF-36 questionnaire. CONCLUSION: Failure to correct deep axial reflux by superficial ablation in patients with superficial and associated primary deep axial reflux may be related to asymmetry in the leaflets of the incompetent deep venous valve.

Pre-pubertal presentation of peritoneal inclusion cyst associated with congenital lower extremity venous valve agenesis.

Peritoneal inclusion cysts are uncommon lesions that usually occur in the pelvis of reproductive-age females. The case of a 7-year-old girl with an inflamed peritoneal inclusion cyst with unusual right paracolic localization and congenital lower extremity superficial and deep venous valve agenesis is presented. Inflammation of the peritoneal inclusion cyst was responsible for the signs of acute abdomen and subsequent presentation at our center. The cystic structure was initially diagnosed using ultrasonography, and its complete extent (8cm x 6.5cm x 4cm) was evident after magnetic resonance imaging. The minimal access approach was opted for to resect the entire cyst from the lateral border of the ascending colon. Afterwards, the cyst was punctured to reduce its size and to retrieve the cyst wall using an endoscopic specimen retrieval bag. Minimal access surgery precautions in this patient with congenital lower extremity venous valve agenesis are discussed.

Neovalve construction in deep venous incompetence.

OBJECTIVES: The purpose of this study is to assess the outcome of neovalve construction in two consecutive series of patients affected by postthrombotic syndrome and valve agenesis. The technique was modified in the second series so as to correct a cause of failure. METHODS: Between December 2000 and June 2007, 40 neovalve constructions were carried out in 36 patients (19 males, 17 females, median age 57, range, 29-82) affected by deep venous insufficiency. Thirty-two patients were affected by postthrombotic syndrome and 4 by valve agenesis. The 32 patients with postthrombotic syndrome were selected from among 76 patients with resistant ulcers classified C (6,S) E (S) A (S,D,P) P (R,RO) and the 4 patients with valve agenesis were selected from among 28 affected by resistant ulcers classified as C (6,S) E (C) A (S,D,P) P (R). The patients were subdivided into 2 groups. The first group included 19 operations performed in the period between December 2000 and December 2004, with a median follow-up of 54 months (range, 31-78). The second group included 21 patients operated on between January 2005 and June 2007, with a median follow-up of 5 months (range, 2-29). In the second group, a surgical variation was applied in order to prevent flap collapse and to maintain the continence of the neovalve. RESULTS: In the first series, ulcer healing was observed in 16 cases out of 19 (84%). Recurrent ulcers were observed in one case after 3 years. Valve competence was ascertained in 13 cases per 803 patient-months (1.6/100 patient-months). With regard to the second series, competence was achieved in all cases with a cumulative rate of 21 per 228 patient-months (9.2/100 patient-months). In the second series, the ulcer failed to heal in one case and recurred in two cases, with an intention-to-treat ulcer recurrence rate of three cases per 209 patient-months. Postoperative deep-venous thrombosis was observed in 3 patients in the first series. None was detected in the second series. The mortality rate was 0 and in neither group was pulmonary embolism detected. CONCLUSION: The modified technique applied to the second group seemed to improve valve continence results significantly. However, a longer follow-up period is required for the latter group to validate this technical enhancement.