b'these conditions has been published via the St.iii) One condition caused by pathogenic variants inGeorges Classification Algorithm of Primary LymphaticGATA2 may present with childhood-onset of Anomalies, with its latest update in 2020. Geneticlymphedema, often in one leg and the genitalcauses and testing can be structured around thisarea (GATA2 deficiency or Emberger syndrome). classification. Genetic testing is appropriate andThis condition is particularly important to diagnose, helpful in the diagnosis and management of childrenas it can be complicated by immunodeficiency, and adults with primary lymphatic disorders, so themyelodysplasia, and leukemia. Surveillance for patient may need to be referred to a genetic specialist.these complications is indicated.This field is developing rapidly, and a growing numberiv) There are several genes resulting in a generalizedof genetic causes are being identified each year 47 . lymphatic dysplasia (swelling of all four limbs, A specific genetic diagnosis can inform about thegenitals, and face) with internal (systemic) lymphatic natural history and prognosis of the condition,problems (intestinal lymphangiectasia, pleural or surveillance for associated complications, andpericardial effusions or may present antenatallyrecurrence risk for offspring or siblings of the proband.with fetal hydrops. These genes are usually The availability of genetic testing varies from oneinherited in an autosomal recessive manner.center/country to another, although this is rapidlyThese genes include CCBE1, FAT4, ADAMTS3, improving. Genetic testing is not usually indicated inFBXL7 and PIEZO1.those with secondary lymphedema with clear causes.A child (or adult) may present with lymphedema of the However, some cases of primary lymphedema mayextremities but also with intellectual disability, autism, present after minor trauma e.g., a sprained ankle,structural malformations, and or dysmorphic features which leads to persistent swelling, where the degree of(unusual facial features). These patients should be trauma would not usually be expected to cause chroniccarefully evaluated for the underlying cause. It is swelling. Similarly, persistent swelling after an episodepossibly due to a chromosome abnormalitywhich of cellulitis may indicate an underlying primarywould be detected by a test called an array CGH lymphatic dysplasia 51 . (comparative genomic hybridization). However, some Many of the primary lymphedema cases are single- other single-gene disorders may present in this way gene disorders. These can be diagnosed on DNA(e.g., Noonan syndrome). In some centers, the genes extracted from blood lymphocytes from an affectedfor these syndromic conditions may be included inindividual. Testing can either be for single genesthe lymphedema gene panel. (targeted) or a panel of genes, including many or Finally, some patients may have a localized genetic all the genes currently known to be associated withdisorder presenting with swelling, segmental lymphedema. This is usually done by next-generationovergrowth and vascular malformations (e.g., Klippel-sequencing, also known as massive parallel sequencing. Trenaunay syndrome (KTS)). Testing the DNA extracted The most frequent causes of primary lymphedema from blood lymphocytes rarely identifies the under-are listed below:lying genetic cause. In this group, DNA extracted from a skin biopsy from the affected limb is much more i)The FLT4 gene encodes for the Vascular likely to identify the cause, e.g., gain of functionEndothelial Growth Factor Receptor 3 (VEGFR3).pathogenic variants in PIK3CA.Pathogenic variants in this gene are responsible Differential Diagnoses: Primary versusfor Milroy Disease. This presents as congenitalSecondary Lymphedemalymphedema, particularly of the dorsum of the feetusually bilateral but may be asymmetrical.In adults, causes of secondary lymphedema need toMales have an increased risk of hydroceles (at be considered. However, primary lymphedema is not any age) and minor urethral abnormalities (e.g.,simply a diagnosis of exclusion. The age of onset, hypospadias). There is rarely swelling of any otherfamily history, and clinical features as described inextremity. This condition is autosomal dominant. the algorithm (Figure 5) should be sought and mayii)Pathogenic variants in the FOXC2 gene causeaid the diagnosis.lymphedema distichiasis syndrome (LDS). ThisThe onset of primary lymphedema beyondpresents with lymphedema of the lower limbs inthe age of 35 years is rare (previously knownlate childhood or adulthood, varicose veins at aas lymphedema tarda), and considerationyoung age of onset, distichiasis from birth (extraof secondary causes in this age group iseyelashes arising from the inner aspect of theimportant in making an accurate diagnosis.eyelids), and an increased incidence of congenital heart disease, renal abnormalities, cleft palate, Primary lymphedema in infants is sometimes difficultand spinal cysts. This condition is also autosomalto diagnose when the foot and lower leg are chubby; dominant. the diagnosis becomes clearer over the following | Standardized Approach for the Diagnosis and Management of Lymphedema (LE) and Lymphatic Diseases (LD)|16'