Lymphedema results from impaired flow of the lymph fluid and is characterized by excess fluid accumulation and swelling. Many cases of lymphedema are acquired and secondary to other circumstances (e.g. lymph node damage or removal during cancer treatment) (Brouillard et al., 2014). However, primary or familial lymphedema is present at birth and caused by underlying defects in the lymphatic system. These conditions are clinically and genetically heterogeneous. Some are associated with broader syndromic features, and a thorough history and physical evaluation is important in the initial assessment (Pateva et al., 2022).

Evaluation of primary lymphedema, including when genetic analysis should be pursued based on a patient’s symptoms and family history, may be guided by the St. George’s classification algorithm for primary lymphatic anomalies (Gordon et al., 2020; Connell et al., 2013; Connell et al., 2010). The presence of other features such as growth disturbances, cutaneous malformations, and/or vascular anomalies can direct testing toward syndromic causes. Age of onset can also be used to help guide the differential (Gordon et al., 2020). Hereditary lymphedema should also be considered in cases of nonimmune hydrops fetalis/fetal edema when common etiologies have been ruled out (Boudon et al., 2015). Pathogenic/likely pathogenic (P/LP) variants in genes included in the VEGFR3 signaling pathway account for up to one third of familial lymphedema, including syndromic and non-syndromic forms (Mendola et al., 2013). Some of the specific genes associated include FLT4 (VEGFR3), GJC2, FOXC2, SOX18, GATA2, CCBE1, VEGFC, PTPN14, and CEFSR1 (Gordon et al., 2020). Biallelic PIEZO1 P/LP variants have been reported to cause nonimmune hydrops fetalis (Datkhaeva et al., 2018).

Milroy disease (also known as hereditary lymphedema type I) is characterized by neonatal-onset primary lymphedema. The lymphedema is typically bilateral and confined to the feet/lower extremities. Lymphography shows hypoplasia of lymphatic vessels. Features such as cellulitis, hemangiomas, papillomas, upslanting toenails, prominent veins, and hydrocele in males are also commonly observed. Milroy disease is inherited in an autosomal dominant manner with variable expressivity and 80-90% penetrance (Van Zanten et al., 2006). This condition is associated with heterozygous inactivating P/LP variants in the FLT4 (VEGFR3) gene. The proportion of individuals with Milroy disease who test positive for variants in FLT4 is not currently known, but studies indicate it may be as high as 75% (Van Zanten et.al, 2006). There is evidence for additional locus heterogeneity, as many affected individuals have negative FLT4 testing. Primary treatment of Milroy disease focuses on the management of edema and prevention of cellulitis. Patients are prone to foot infections (athlete’s foot and infected eczema) and prompt treatment for early cellulitis with appropriate antibiotics and sometimes intravenous antibiotics is important. In addition, some clinicians consider prophylactic antibiotics to be a standard of care (Van Zanten et.al, 2006).