AbstractPurpose To provide an in‐depth re‐examination of assumed causes of tissue hypertrophy, port‐wine stains and the Sturge‐Weber and related syndromes to support an alternative unifying pathophysiologic mechanism of venous dysplasia producing focal venous hypertension with attendant tissue responses and to propose a novel etiological hypothesis for the venous dysplasia in these syndromes with supportive evidence.Methods Data from twenty patients with port‐wine stains was collected prospectively by the author in an institutional referral‐based practice. The literature was searched using Medline.Results Newly obtained dermatologic, corneal pachymetry, fundus ophthalmoscopic, ocular and orbital venous Doppler ultrasonography, and magnetic resonance imaging findings in patients with the Sturge‐Weber syndrome or isolated port‐wine stains, along with published data, reveal diffusely thickened tissues and neural atrophy in all areas associated with venous congestion.Conclusion Contrary to traditional understanding, signs and symptoms in the Sturge‐Weber and related syndromes, including both congenital and acquired port‐wine stains are shown to arise from effects of localized primary venous dysplasia or acquired venous obstruction rather than neural dysfunction, differentiating these syndromes from actual phacomatoses. Effects of focal venous hypertension are transmitted to nearby areas via compensatory collateral venous channels in the above conditions. Conclusion: A novel underlying etiology—prenatal venous thrombo‐occlusion—may be responsible for the absence of veins with persistence and enlargement of collateral circulatory pathways with data in the literature backing this offshoot hypothesis. The mechanism for isolated pathologic tissue