PIEZO1-gene gain-of-function mutations with lower limb lymphedema onset in an adult: Clinical, scintigraphic, and noncontrast magnetic resonance lymphography findings.

Primary lymphedema, a rare disease, has a genetic cause in ~40% of patients. Recently, loss-of-function mutations in PIEZO1, which encodes the mechanotransducer protein PIEZO1, were described as causing primary lymphedema, when gain-of-function PIEZO1 mutations were attributed to dehydrated hereditary stomatocytosis type-1 (DHS), a dominant red cell hemolytic disorder, with ~20% of patients having perinatal edema. Lymphedema was diagnosed in a 36-year-old man from a three-generation DHS family, with a PIEZO1-allele harboring 3 missense mutations in cis. Four affected family members had severe fetal and neonatal edema, most severe in the proband, whose generalized edema with prevailing ascites resolved after 8 months. Our patient's intermittent lower limb-lymphedema episodes during hot periods appeared at puberty; they became persistent and bilateral at age 32. Clinical Stemmer's sign confirmed lymphedema. Lower leg lymphoscintigraphy showed substantial dermal backflow in both calves, predominantly on the right. Noncontrast magnetic resonance lymphography showed bilateral lower limb lymphedema, dilated dysplastic lymphatic iliac, and inguinal trunks. Exome-sequencing analysis identified no additional pathogenic variation in primary lymphedema-associated genes. This is the first description of well-documented lymphedema in an adult with PIEZO1-DHS. The pathophysiology of PIEZO1-associated primary lymphedema is poorly understood. Whether it infers overlapping phenotypes or different mechanisms of gain- and loss-of-function PIEZO1 mutations deserves further investigation.

Blood Flow and Shear Stress Allow Monitoring of Progression and Prognosis of Tumor Diseases.

In the presence of tumor angiogenesis, blood flow must increase, leading to an elevation of blood flow velocities (BFVels) and wall shear stress (WSS) in upstream native arteries. An adaptive arterial remodeling is stimulated, whose purpose lies in the enlargement of the arterial inner diameter, aiming for normalization of BFVels and WSS. Remodeling engages delayed processes that are efficient only several weeks/months after initiation, independent from those governing expansion of the neovascular network. Therefore, during tumor expansion, there is a time interval during which elevation of BFVels and WSS could reflect disease progression. Conversely, during the period of stability, BFVels and WSS drop back to normal values due to the achievement of remodeling processes. Ovarian peritoneal carcinomatosis (OPC), pseudomyxoma peritonei (PMP), and superficial arteriovenous malformations (AVMs) are diseases characterized by the development of abnormal vascular networks developed on native ones. In OPC and PMP, preoperative blood flow in the superior mesenteric artery (SMA) correlated with the per-operative peritoneal carcinomatosis index (OPC: n = 21, R = 0.79, p < 0.0001, PMP: n = 66, R = 0.63, p < 0.0001). Moreover, 1 year after surgery, WSS in the SMA helped in distinguishing patients with PMP from those without disease progression [ROC-curve analysis, AUC = 0.978 (0.902-0.999), p < 0.0001, sensitivity: 100.0%, specificity: 93.5%, cutoff: 12.1 dynes/cm2]. Similarly, WSS in the ipsilateral afferent arteries close to the lesion distinguished stable from progressive AVM [ROC-curve analysis, AUC: 0.988, (0.919-1.000), p < 0.0001, sensitivity: 93.5%, specificity: 95.7%; cutoff: 26.5 dynes/cm2]. Blood flow volume is indicative of the tumor burden in OPC and PMP, and WSS represents an early sensitive and specific vascular marker of disease progression in PMP and AVM.