Primary lymphoedema

• The clinical features of lymphoedema depend on the specific condition and affected body part(s). Most forms are associated with chronic swelling, often affecting one or more limbs, with possible additional features including dysplastic nails and/or skin papillomatosis.
• Lymphoedema is associated with a risk of complications, particularly infection of the skin and subcutaneous tissue (cellulitis).
• Lymphoedema affecting internal compartments of the body can present with additional symptoms (for example, shortness of breath in chylothorax or diarrhoea and abdominal discomfort with intestinal lymphangiectasia).
• The clinical features and age of onset are variable, depending on the underlying diagnosis. Primary lymphoedema is a heterogenous condition, and careful delineation of a patient’s phenotype can help guide testing and management. The St George’s classification divides lymphoedema into five broad groups, as outlined below.

Lymphatic malformations

• Lymphatic malformations affect a defined segment of the body, often associated with segmental overgrowth and/or other vascular malformations.
• Isolated lymphatic malformations are often caused by somatic variants (such as PIK3CA or genes of the RAS-MAPK pathway). This has implications for genomic testing: the causative variant may not be identified on testing of constitutional (germline) DNA (such as a blood sample), and testing of a somatic sample (such as a skin biopsy) may be required.
• Some lymphatic malformations can be caused by a constitutional (germline) variant – for example, those seen in capillary malformation/arteriovenous malformation syndrome (caused by variants in RASA1 and/or EPHB4).

Lymphoedema with prenatal or postnatal systemic involvement

• Some forms of lymphoedema feature involvement of internal body compartments (such as the pleural cavity in chylothorax or the abdomen in chylous ascites). They can present prenatally as non-immune fetal hydrops.
• There is a further distinction between generalised lymphatic dysplasia (GLD), in which the distribution is widespread (that is, it affects most of the body), and multi-segmental lymphatic dysplasia, in which the distribution is patchy (that is, it affects several body parts but spares others). GLD is more likely to be associated with a constitutional (germline) genetic cause (such as variants in PIEZO1, EPHB4, SOX18, FAT4 or ADAMTS3).

Congenital-onset lymphoedema

• Some forms of lymphoedema present at birth (including those diagnosed antenatally) or develop within the first year of life. The most common form is Milroy disease (caused by variants in the FLT4 gene), which presents with lower-limb lymphoedema (bilateral but often asymmetric) and can be associated with genital anomalies (such as hydrocele or urethral malformations in males).
• Less common causes of congenital lymphoedema include variants in PIEZO1 and VEGFC. Some patients present with syndromic features that suggest a specific diagnosis – for example, microcephaly and chorioretinopathy (caused by variants in KIF11) or hypotrichosis, telangiectasia and renal defects (caused by variants in SOX18).

Late-onset lymphoedema

• Late-onset lymphoedema presents after the first year of life. The age of onset, severity and extent of limb involvement can be variable.
• Some patients present with isolated lymphoedema (caused by variants in the GJC2 and/or CELSR1 genes), while others have additional features that suggest a specific diagnosis – for example, additional eyelashes arising from the inner eyelid (distichiasis) in lymphoedema-distichiasis syndrome (caused by variants in FOXC2) or myelodysplasia and/or hearing loss in Emberger syndrome (caused by variants in GATA2).

Syndromic lymphoedema

• Syndromic lymphoedema presents as part of a complex syndrome in which lymphoedema is not the dominant feature.
• Syndromic causes of lymphoedema include chromosomal conditions (such as Turner syndrome and Phelan-McDermid syndrome), tuberous sclerosis, single-gene conditions (such as Noonan syndrome and other conditions of the Ras-MAPK pathway, including neurofibromatosis type 1) and imprinting conditions (such as Prader-Willi syndrome). Due to the genetic heterogeneity of these conditions, investigation in syndromic lymphoedema should be guided by the patient’s phenotype.

• Recurrence of primary lymphoedema depends on the underlying cause. If a constitutional (germline) single-gene condition is identified, the recurrence risk is 25%–50% depending on the inheritance pattern. Penetrance can be incomplete.
• Isolated lymphatic malformations are often caused by somatic variants, which occur after conception rather than being inherited from a parent. The recurrence risk in siblings is therefore extremely low.

Consider referral to a specialist lymphoedema clinic (St George’s University Hospitals or University Hospitals of Derby and Burton) for assessment and management. This will include:

• nuclear lymphoscintigraphy and/or MRI lymphangiography to assess lymphatic drainage;
• compression bandaging or hosiery for limb oedema;
• advice about good skin care to reduce risk of infection;
• low threshold for antibiotic treatment of suspected cellulitis;
• prophylactic antibiotics in patients with recurrent cellulitis;
• multidisciplinary management of complications (with input from, for example, dermatology and urology);
• genomic testing (depending on clinical features) and genomic counselling to discuss recurrence risks; and
• consideration for targeted treatment for some conditions (such as mTOR inhibitors for PIK3CA-related conditions).

For clinicians

• NHS England: National Genomic Test Directory
• St George’s University Hospitals lymphoedema service
• University Hospitals of Derby and Burton lymphoedema service

References:

• Gordon K, Varney R, Keeley V and others. ‘Update and audit of the St George’s classification algorithm of primary lymphatic anomalies: A clinical and molecular approach to diagnosis‘. Journal of Medical Genetics 2020: volume 57, issue 10, pages 653–659. DOI: 10.1136/jmedgenet-2019-106084

For patients

• NHS Health A to Z: Lymphoedema
• Noonan Syndrome Association