Lymphatic malformation (generalised)

Overview

Generalised lymphatic malformation (GLM) is a rare condition where the lymphatic vessels, which are crucial for draining fluid and transporting immune cells, do not form or function correctly across multiple body areas. This can lead to swelling, fluid build-up, and a range of associated health issues. The lymphatic system is a network of tissues and organs that help rid the body of toxins, waste, and other unwanted materials, playing a vital role in immunity and maintaining fluid balance [PMID:33678739].

Unlike localised lymphatic malformations that affect a single area, GLM is characterised by its widespread nature, often impacting several organ systems. The severity can vary significantly among individuals, from mild swelling to more complex health challenges. While GLM is present from birth, its signs and symptoms may become apparent at different stages of life, often in infancy or early childhood.

Symptoms & clinical features

The symptoms of generalised lymphatic malformation arise from the impaired function of the lymphatic system. Affected individuals commonly experience persistent swelling, known as lymphoedema, in various body parts. This swelling can be present at birth or develop shortly afterwards and may worsen over time [PMID:33678739]. The affected areas can feel soft and doughy, and in some cases, the skin overlying the malformation may appear thickened or discoloured.

Depending on the location of the malformations, other symptoms can include pain, discomfort, and restricted movement if joints are affected. Internal lymphatic malformations can lead to fluid accumulation in body cavities, such as around the lungs (chylothorax) or in the abdomen (chylous ascites), potentially causing breathing difficulties or digestive issues [PMID:27376483]. Recurring infections in affected areas are also a concern due to impaired lymphatic drainage. The specific presentation of GLM varies widely, making diagnosis challenging.

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Affected organs

Generalised lymphatic malformation can affect a wide range of organs and body systems due to the widespread nature of the lymphatic network. Commonly affected areas include the limbs, trunk, head, and neck, leading to noticeable swelling and disfigurement. Internal organs can also be involved, presenting more complex health issues.

When the lungs or surrounding areas are affected, it can cause chylothorax, a build-up of lymphatic fluid around the lungs, which can impact breathing. Involvement of the intestines can lead to chylous ascites (lymphatic fluid in the abdomen) or protein-losing enteropathy, affecting nutrient absorption. Bone involvement can result in lesions, and in rare cases, the central nervous system may be affected. The diverse range of potential organ involvement underscores the complexity of this condition.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of generalised lymphatic malformation can vary substantially, ranging from relatively mild lymphoedema in limited areas to severe, life-threatening complications. The extent of lymphatic vessel malformation and the specific organs involved determine the overall impact on an individual's health. Early onset and extensive involvement are often associated with a more significant clinical picture.

Life-long management is typically required, and individuals may face a heightened risk of recurrent infections in affected areas, chronic pain, and potential functional limitations. While GLM is present from birth, its full clinical spectrum may not be apparent immediately. Age of onset of symptoms can vary, though most are observed in infancy or early childhood. The exact prevalence of generalised lymphatic malformation is not well established, but it is considered a rare condition.

Genetic causes

Generalised lymphatic malformation is understood to have a genetic basis, with several genes being associated with its development. It is often inherited in an autosomal recessive pattern. Pathogenic changes in genes such as ADAMTS3, CCBE1, and PIEZO1 have been identified in individuals with lymphatic malformation. These genes play critical roles in the formation and function of the lymphatic system.

For example, the CCBE1 gene provides instructions for a protein that is involved in guiding the formation of new lymphatic vessels. When there are pathogenic variants in CCBE1, this guidance can be disrupted, leading to abnormal lymphatic development [PMID:27376483]. Similarly, ADAMTS3 is important for the structural integrity and development of lymphatic vessels. The PIEZO1 gene encodes a protein that forms a mechanosensitive ion channel, important for processes like fluid balance and the development of blood and lymphatic vessels. Pathogenic variants in these genes can impair these crucial developmental processes, resulting in the widespread lymphatic abnormalities seen in GLM.

• ADAMTS3
  ADAM metallopeptidase with thrombospondin type 1 motif 3
• CCBE1
  collagen and calcium binding EGF domains 1
  The CCBE1 gene provides instructions for a protein crucial in the development and maintenance of the lymphatic system, a vital part of the body's immune and fluid balance systems.
• PIEZO1
  piezo type mechanosensitive ion channel component 1 (Er blood group)
  PIEZO1 encodes a mechanosensitive ion channel protein critical for sensing physical forces and regulating cell volume, particularly in red blood cells.

Inheritance pattern

Generalised lymphatic malformation is typically inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of a gene - one from each parent - to develop the condition. If a person inherits only one altered copy, they are considered a 'carrier' and generally do not show symptoms of the condition themselves.

For parents who are both carriers of a pathogenic variant in the same gene associated with GLM, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered copies and develop the condition. There is a 2 in 4 (50%) chance that their child will be a carrier, and a 1 in 4 (25%) chance that their child will inherit two unaffected copies and neither have the condition nor be a carrier.

Diagnosis & testing

A diagnosis of generalised lymphatic malformation usually begins with a clinical evaluation based on the presence of characteristic symptoms like widespread swelling and fluid accumulation. Imaging techniques, such as ultrasound, MRI (magnetic resonance imaging), or lymphoscintigraphy, are often used to visualise the extent and location of the lymphatic abnormalities and confirm the diagnosis [PMID:33678739].

Genetic testing is crucial for confirming the underlying cause of GLM, especially given its genetic basis. This testing can identify pathogenic variants in genes like ADAMTS3, CCBE1, or PIEZO1. In the UK, genetic testing for suspected inherited lymphatic conditions may be accessed via the NHS Genomic Medicine Service (GMS) through R-codes, such as R253 for inherited lymphoedema. Referrals for genetic testing are typically made by clinical geneticists or specialists who suspect a genetic cause for the lymphatic malformation.

Management & lifestyle

The management of generalised lymphatic malformation focuses on alleviating symptoms, preventing complications, and improving quality of life, as there is currently no cure. Treatment plans are highly individualised and depend on the specific symptoms, location, and severity of the malformations. A multidisciplinary team, which may include lymphoedema specialists, geneticists, radiologists, and surgeons, often provides care.

Conservative management strategies often include compression therapy, manual lymphatic drainage, and meticulous skin care to manage lymphoedema and reduce the risk of infection. Medications, such as sirolimus, have shown promise in some cases by helping to reduce the size of malformations or manage symptoms [PMID:27376483]. Surgical intervention may be considered for specific, well-defined malformations that are causing significant problems, but this is less common for generalised forms. Regular monitoring and follow-up are essential within the NHS care pathway to adapt treatment as needed and address any emerging complications.

UK care pathway

In the UK, individuals suspected of having a generalised lymphatic malformation would typically enter the NHS Genomic Medicine Service (GMS) pathway. Referral to a clinical genetics service is a key step, where genetic counsellors can provide support and information regarding the condition, its inheritance, and implications for the family. Diagnostic genetic testing, guided by NHS R-codes such as R253 for inherited lymphoedema, is undertaken to identify the specific genetic cause.

Ongoing management involves a network of specialist care, often including paediatricians (for children), lymphoedema clinics, and other relevant specialists depending on the affected organs. Genetic counsellors play an important role in explaining complex genetic information and supporting families through diagnosis and beyond.

Related conditions

Several conditions can present with overlapping features to generalised lymphatic malformation or involve similar genetic pathways. Hennekam syndrome, for instance, is another rare genetic disorder characterised by lymphoedema and other developmental abnormalities, and it can be caused by pathogenic variants in the CCBE1 gene, among others [PMID:27376483].

Distinguishing generalised lymphatic malformation from other forms of lymphoedema, such as primary lymphoedema (which might be localised) or secondary lymphoedema (resulting from injury or infection), is important for accurate diagnosis and management. Conditions like Klippel-Trénaunay syndrome, which involves vascular malformations, varicose veins, and limb overgrowth, also share some features and require careful differential diagnosis.

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Frequently asked questions