Milroy lymphoedema

Overview

Milroy lymphoedema is a rare, inherited disorder that affects the lymphatic system. The lymphatic system is a vital part of the immune system and helps to maintain fluid balance in the body by draining excess fluid, proteins, and waste products from tissues. In Milroy lymphoedema, the lymphatic vessels do not develop or function correctly, leading to a build-up of fluid, typically in the legs. This build-up causes chronic swelling, known as lymphoedema [PMID:15714705].

This condition is usually present from birth (congenital) or develops in early childhood. The swelling can vary in severity and may affect one or both lower limbs. While the primary symptom is swelling, associated skin changes can also occur over time due to the persistent fluid retention. Milroy lymphoedema is classified as a primary lymphoedema, meaning it is not caused by injury, infection, or other medical conditions, but rather by an inherent problem with the lymphatic system itself.

Symptoms & clinical features

The main symptom of Milroy lymphoedema is chronic swelling, usually of the ankles, feet, and legs. This swelling can be present at birth or may develop shortly after. While the lower limbs are most commonly affected, in some individuals, other parts of the body might also experience swelling, though this is less typical.

The swelling associated with Milroy lymphoedema is generally soft and pits when pressed, particularly in the early stages. Over time, if left unmanaged, the affected skin can become thicker, harder, and may develop a rough, 'cobblestone' appearance. Skin folds can deepen, and there may be an increased risk of skin infections (cellulitis) in the affected areas due to compromised skin integrity and reduced immune function locally [PMID:15714705]. The degree of swelling can vary significantly between individuals, even within the same family.

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Affected organs

The primary body system affected in Milroy lymphoedema is the lymphatic system, specifically the lymphatic vessels that are responsible for draining fluid from tissues. This dysfunction directly leads to swelling in the affected limbs. The skin in areas of chronic swelling can also be significantly impacted, becoming thickened, fibrotic, and more prone to infection. While other organs are not typically directly affected by the lymphatic malformation itself, complications like recurrent infections can have broader implications for overall health.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of Milroy lymphoedema can vary, ranging from mild swelling that is barely noticeable to significant and disabling oedema. The swelling is generally chronic and progressive if not managed. Individuals with Milroy lymphoedema have an increased risk of recurrent bacterial infections of the skin and underlying tissues, known as cellulitis [PMID:15714705]. These infections can be painful and may require antibiotic treatment. Rarely, long-standing lymphoedema can be associated with an increased risk of a rare type of cancer called lymphangiosarcoma, although this is extremely uncommon in Milroy lymphoedema.

The condition typically presents at birth or in early childhood. While the swelling is often present from a young age, its progression and potential complications can evolve throughout an individual's life. Exact prevalence figures are not well established, but it is considered a rare condition.

Genetic causes

Milroy lymphoedema is caused by pathogenic variants (sometimes called mutations) in the FLT4 gene. This gene provides instructions for making a protein called Fms-related tyrosine kinase 4, also known as vascular endothelial growth factor receptor 3 (VEGFR-3). This protein plays a crucial role in the development and maintenance of the lymphatic system.

The VEGFR-3 protein is found on the surface of cells that line lymphatic vessels and acts as a receptor. When a specific growth factor binds to this receptor, it triggers signalling pathways essential for the formation and function of lymphatic vessels, particularly during embryonic development. Pathogenic variants in FLT4 disrupt the normal function of the VEGFR-3 protein, leading to impaired development or improper functioning of the lymphatic vessels [PMID:10091880]. This in turn results in the inadequate drainage of fluid and the characteristic swelling seen in Milroy lymphoedema.

• FLT4
  fms related receptor tyrosine kinase 4

Inheritance pattern

Milroy lymphoedema typically follows an autosomal dominant inheritance pattern. This means that a person only needs to inherit one copy of the altered FLT4 gene from either parent to develop the condition. If one parent has Milroy lymphoedema, there is a 50% chance with each pregnancy that their child will inherit the pathogenic variant and therefore also develop the condition.

In some cases, a new (de novo) pathogenic variant may occur in the FLT4 gene in an individual with no family history of the condition. In such situations, the parents are typically unaffected, but the individual with the de novo variant can still pass it on to their children. Genetic counselling can provide detailed information about inheritance patterns and risks for family members.

Diagnosis & testing

A diagnosis of Milroy lymphoedema is often suspected based on the characteristic clinical features, particularly the presence of congenital or early-onset lymphoedema, usually in the lower limbs. A physical examination by a healthcare professional will assess the extent and nature of the swelling.

Confirmation of the diagnosis, and differentiation from other forms of lymphoedema, is typically achieved through genetic testing for pathogenic variants in the FLT4 gene. The NHS Genomic Medicine Service provides genetic testing for primary lymphoedema, often initiated by a clinical genetics service or a specialist paediatrician or lymphoedema clinic. Referrals for genetic testing typically follow an R-code pathway, such as R249 Primary lymphoedema, as part of the National Genomic Test Directory. Imaging techniques, such as lymphoscintigraphy, may also be used to visualise the lymphatic system and confirm impaired drainage, though genetic testing is key for specific diagnosis.

Management & lifestyle

While there is currently no cure for Milroy lymphoedema, management focuses on controlling the swelling and preventing complications. The primary aim is to reduce fluid build-up and maintain skin health. Treatment strategies often include conservative measures such as compression therapy, using specialist garments or bandages to help reduce swelling and support the affected tissues. Manual lymphatic drainage, a specialised massage technique performed by trained therapists, can also help to move fluid.

Exercise, skin care, and elevation of the affected limb are also important components of management. Regular skin care is crucial to prevent infections, and prompt treatment with antibiotics is necessary for any episodes of cellulitis. Individuals with Milroy lymphoedema are often supported by specialist lymphoedema clinics, typically found within NHS hospitals or community services, where they can receive ongoing advice and care. Genetic counselling is also recommended to discuss the genetic aspects and inheritance patterns of the condition.

UK care pathway

In the UK, individuals suspected of having Milroy lymphoedema would typically be referred by their GP or another specialist to an NHS clinical genetics service or a specialist lymphoedema clinic. These services can provide a comprehensive assessment and coordinate appropriate investigations. Genetic testing, covered under the NHS Genomic Medicine Service, is performed through a specific R-code pathway (e.g., R249 Primary lymphoedema) to identify the underlying genetic cause. Genetic counsellors play a vital role in explaining the condition, inheritance patterns, and implications for families, as well as supporting individuals through their diagnostic journey.

Related conditions

Milroy lymphoedema is one type of primary lymphoedema. Other genetic conditions can also cause primary lymphoedema, sometimes affecting different parts of the body or having additional associated features. For example, Meige lymphoedema (lymphoedema praecox) typically presents later in childhood or adolescence and is often associated with pathogenic variants in other genes, although clinical overlap can exist. Understanding the specific genetic cause helps to differentiate Milroy lymphoedema from other forms of primary lymphoedema and guides management and genetic counselling.

Frequently asked questions