Primary lymphedema

Primary lymphedema is chronic swelling of one or more limbs caused by a developmental or inherited abnormality of the lymphatic system, in the absence of surgery, radiation, infection, malignancy, or other acquired causes of lymphatic obstruction

It is a rare, lifelong condition that usually begins in childhood or early adulthood, and it predisposes to recurrent cellulitis, progressive fibrosis, and considerable functional and psychological burden

The condition is coded Q82.0 in ICD-10 and BD93.0 in ICD-11, catalogued as ORPHA:77240 by Orphanet and MONDO:0019175 by the Monarch Initiative, and indexed in Wikidata as Q7243149

Terminology and classification

• Primary lymphedema is classified by the age at onset into congenital lymphedema, present before 1 year of age
• Congenital hereditary lymphedema is known as Milroy disease, whereas the familial form beginning around puberty is called Meige disease or lymphedema praecox
• Primary lymphedema may occur as an isolated finding or as part of a syndromic disorder such as lymphedema-distichiasis, hypotrichosis-lymphedema-telangiectasia, Hennekam syndrome, or Klippel-Trenaunay syndrome
• The ICD-11 block BD93 separates primary lymphoedema (BD93.0) from secondary lymphoedema (BD93.1), a distinction that drives investigation, prognosis, and access to specialised care
• Orphanet recognises primary lymphedema as a rare disease and distinguishes more than twenty genetic subtypes, whereas MONDO groups them under a single parent concept with links to the causative genes
• The term lymphedema is preferred to the older term elephantiasis, which is reserved for advanced, fibrotic, and massively enlarged limbs and is often associated with filarial infection

History

• Sir William Milroy described a family with hereditary congenital swelling of the lower legs in 1892, and the eponym Milroy disease has been used ever since
• Henri Meige described the familial form beginning around puberty in 1898, which became known as lymphedema praecox or Meige disease
• Lymphoscintigraphy was developed in the 1970s and 1980s and provided the first reliable functional assessment of lymphatic transport in vivo
• Mutations in FLT4, encoding vascular endothelial growth factor receptor 3, were identified in Milroy disease in the late 1990s, establishing the first molecular cause of primary lymphedema
• FOXC2 mutations were linked to lymphedema-distichiasis around 2000, SOX18 to hypotrichosis-lymphedema-telangiectasia in 2003, and CCBE1 to Hennekam syndrome in 2009, progressively expanding the genetic architecture
• The International Society of Lymphology published its consensus document on the diagnosis and treatment of peripheral lymphedema in 2020, harmonising staging, compression, and surgical referral across centres

Epidemiology

• Primary lymphedema is rare, with Orphanet estimating a prevalence of approximately 1 to 9 per 100,000 in the general population, although this figure excludes undiagnosed mild cases
• Females predominate in most series, with an 80% female proportion in older reports and 58% to 70% in more recent cohorts, particularly for lymphedema praecox
• Approximately 10% of cases are present at birth, about 80% begin before 35 years of age, and the remaining 10% begin after 35 years, although the proportions vary with case ascertainment
• Congenital Milroy disease affects males and females equally, whereas praecox and tarda forms show a clear female excess, suggesting hormonal or sex-specific genetic influences
• The lower limbs are involved in 80% to 90% of patients, with unilateral swelling more frequent than bilateral in praecox disease and bilateral involvement more typical of congenital syndromes
• A positive family history is obtained in roughly 20% to 30% of cases, and the proportion rises when first-degree relatives are examined and when genetic testing is performed
• Primary lymphedema is much less common than secondary lymphedema worldwide, where filarial infection, cancer surgery, and radiotherapy account for the vast majority of cases
• Because mild ankle swelling is often attributed to obesity or venous disease, the true prevalence is probably higher than clinic-based estimates, and diagnostic delay of several years is common

Pathophysiology

• Primary lymphedema results from hypoplasia, aplasia, or hyperplasia of lymphatic vessels and lymph nodes, or from impaired intrinsic contractility of lymphangions, leading to inadequate drainage of interstitial fluid
• FLT4 mutations reduce VEGFR-3 signalling required for lymphangiogenesis, producing hypoplastic superficial lymphatic capillaries and a reduced number of functional collectors in Milroy disease
• FOXC2 mutations impair valve formation and collector patterning, which explains the coexistence of lymphedema with distichiasis in lymphedema-distichiasis syndrome
• Accumulation of protein-rich interstitial fluid raises tissue oncotic pressure, stimulates fibroblast proliferation and adipose deposition, and eventually produces non-pitting fibrosis
• Stagnant lymph is poorly populated by immune cells and provides a favourable medium for bacterial growth, which explains the high frequency of cellulitis and erysipelas in affected limbs
• Chronic inflammation and impaired immune surveillance are also thought to underlie the rare but feared development of lymphangiosarcoma, known as Stewart-Treves syndrome, in long-standing lymphedema

Clinical features

• The hallmark is painless, progressive swelling of a limb, typically the foot and lower leg, which is firm, non-pitting, and often more marked distally with a buffalo-hump contour over the dorsum of the foot
• Stemmer sign, the inability to pinch and lift a fold of skin at the base of the second toe, is a useful bedside sign of lymphatic rather than venous edema
• Over time the skin becomes thickened and hyperkeratotic, with papillomatosis, deep creases, lymphangiectatic vesicles, and a tendency to fungal intertrigo between the toes
• Recurrent cellulitis or erysipelas is the most important complication, presenting with acute redness, warmth, pain, fever, and sometimes lymphangitic streaks, and each episode may further damage lymphatic function
• Syndromic forms have additional features, such as distichiasis in FOXC2 disease, yellow nails and pleural effusions in yellow nail syndrome, or capillary malformations and overgrowth in Klippel-Trenaunay syndrome
• Complications include recurrent infection, progressive limb enlargement, reduced mobility, cosmetic distress, and rare malignant transformation

Diagnosis

• Diagnosis begins with history and examination to establish age at onset, family history, syndromic features, and to exclude acquired causes such as cancer treatment, trauma, filariasis, and obesity
• Lymphoscintigraphy with technetium-99m-labelled colloid is the functional reference standard, showing delayed uptake, reduced transit, dermal backflow, or absent visualisation of lymphatics
• Indocyanine green lymphography provides real-time, high-resolution mapping of superficial lymphatic channels and is increasingly used for surgical planning
• Magnetic resonance lymphangiography and duplex ultrasonography add anatomical information, including vessel calibre, node size, and the presence of venous obstruction
• Genetic testing with a lymphatic disorders panel is appropriate in congenital, familial, syndromic, or early-onset cases and can identify FLT4, FOXC2, SOX18, CCBE1, GJC2, KIF11, and PIK3CA variants
• The differential diagnosis includes secondary lymphedema, chronic venous insufficiency, deep vein thrombosis, lipedema, systemic causes of edema such as heart failure and nephrotic syndrome, and obesity-related swelling

Management

• There is no cure, and management aims to reduce limb volume, prevent progression, and prevent and treat infection through complete decongestive therapy delivered by trained therapists
• Complete decongestive therapy combines manual lymphatic drainage, multilayer short-stretch bandaging during the intensive phase, compression garments during maintenance, remedial exercise, and meticulous skin care
• Intermittent pneumatic compression and night-time compression devices can be added for patients who cannot tolerate bandaging or who have persistent swelling despite standard therapy
• Diuretics such as furosemide are ineffective and potentially harmful in lymphedema, and benzopyrones such as diosmin or coumarin are not recommended because of hepatotoxicity and lack of proven benefit
• Cellulitis should be treated promptly with antibiotics such as penicillin or amoxicillin-clavulanate, and patients with recurrent episodes may benefit from prophylactic penicillin or from decongestive therapy to reduce stasis
• Surgery is offered to selected patients and includes lymphaticovenous anastomosis for localized obstruction, vascularized lymph node transfer for proximal defects, and debulking procedures such as the Charles operation for massive fibrotic limbs
• Patients should avoid venepuncture, blood pressure cuffs, and trauma in the affected limb, maintain a healthy weight, and receive pneumococcal and influenza vaccination advice when splenic function or immunity is compromised
• The prognosis is lifelong but generally favourable for limb function when patients adhere to compression and skin care, whereas recurrent infection, delayed diagnosis, and obesity accelerate fibrosis and disability

Research and controversies

• More than twenty genes have now been implicated, yet a causative variant is found in only a minority of unselected patients, suggesting that non-coding, epigenetic, and environmental factors remain undiscovered
• The relative value of lymphoscintigraphy, indocyanine green lymphography, and magnetic resonance lymphangiography for staging and surgical selection has not been established in comparative trials
• Outcomes of lymphaticovenous anastomosis and vascularized lymph node transfer are reported mainly from single-centre case series, and patient selection, outcome measures, and follow-up duration vary widely
• Whether early prophylactic compression in asymptomatic or minimally symptomatic children slows progression is unknown, and paediatric evidence is particularly scarce
• Stem cell therapy and gene therapy for lymphatic regeneration remain experimental, and no trial has yet demonstrated durable restoration of lymphatic transport in humans with primary lymphedema