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.