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Lymphoedema-distichiasis
This inherited disorder primarily affects the lymphatic system, leading to chronic swelling, typically in the legs. It also causes distichiasis, which means having an extra row of eyelashes. The condition is present from birth, although symptoms may develop later in life.
Overview
Lymphoedema-distichiasis is a rare inherited condition. Its main features are lymphoedema, which is chronic swelling due to a problem with the lymphatic system, and distichiasis, which is the presence of an extra row of eyelashes [PMID:16124177]. The lymphatic system is a network of vessels and nodes that helps to drain fluid (lymph) from tissues, fight infection, and absorb fats. When this system doesn't work correctly, fluid can build up, causing swelling.
While distichiasis is often noticeable at birth or in early childhood, lymphoedema typically develops during puberty or early adulthood, although it can appear earlier or later [PMID:20301323]. The severity of both lymphoedema and distichiasis can vary significantly between affected individuals, even within the same family.
Symptoms & clinical features
The primary symptoms of lymphoedema-distichiasis are lymphoedema and distichiasis. Lymphoedema most commonly affects the legs, leading to persistent swelling, which can cause discomfort, skin changes, and an increased risk of skin infections (cellulitis). In some cases, other parts of the body, such as the arms or face, may also be affected.
Distichiasis involves the growth of extra eyelashes, often emerging from the oil glands (Meibomian glands) along the eyelid margin [PMID:20301323]. These extra eyelashes can be fine and soft, causing no issues, or they can be stiff, irritating the eye's surface (cornea), leading to symptoms like redness, pain, light sensitivity, and recurrent infections. Other less common features that have been reported include structural heart defects, cleft palate, and spinal abnormalities, though these are not seen in everyone with the condition.
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Affected organs
The most significantly affected organ system in lymphoedema-distichiasis is the lymphatic system, which can be malformed or function poorly, leading to fluid retention and swelling. The eyes are also directly affected by the growth of extra eyelashes, which can cause irritation to the cornea and conjunctiva. The skin overlying affected areas can become thickened and prone to infection. While less common, the condition can sometimes be associated with abnormalities affecting the heart, the roof of the mouth (palate), and the spine.
Risks & severity
The severity of lymphoedema-distichiasis varies widely. Lymphoedema can range from mild, intermittent swelling to severe, disabling swelling that significantly impacts mobility and quality of life. The risk of developing lymphoedema is very high in individuals with this condition, with estimates suggesting that more than 80% will experience it at some point [PMID:20301323]. It typically starts during puberty but can develop at any age.
The extra eyelashes (distichiasis) also have a variable impact. Some individuals experience no symptoms from them, while others suffer from chronic eye irritation, pain, and corneal damage that can affect vision. There is also an increased risk of cellulitis (skin infection) in areas affected by lymphoedema.
Genetic causes
Lymphoedema-distichiasis is caused by changes (pathogenic variants) in the FOXC2 gene. The FOXC2 gene provides instructions for making a protein known as a transcription factor. Transcription factors are crucial for controlling the activity of other genes. The FOXC2 protein plays a vital role in the development of many tissues and organs before birth, particularly in the formation and proper function of the lymphatic system.
When a pathogenic variant occurs in the FOXC2 gene, it disrupts the normal function of the FOXC2 protein. This disruption leads to problems with how the lymphatic system develops and functions, resulting in lymphoedema. It also affects the development of the eyelids, causing the growth of extra eyelashes (distichiasis).
- FOXC2 forkhead box C2The FOXC2 gene provides instructions for a protein critical in the formation of various organs and tissues during development, particularly impacting lymphatic and vascular systems.
Inheritance pattern
Lymphoedema-distichiasis follows an autosomal dominant inheritance pattern. This means that only one altered copy of the FOXC2 gene, out of the two copies present in each cell, is sufficient to cause the condition. If a parent has lymphoedema-distichiasis, there is a 50% chance that each of their children will inherit the pathogenic variant and develop the condition. The condition affects males and females equally. It is possible for a new pathogenic variant to occur spontaneously in an individual, meaning neither parent carries the altered gene; this is known as a de novo variant.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of lymphoedema-distichiasis is often suspected based on the characteristic clinical features of lymphoedema and distichiasis. A definitive diagnosis is typically confirmed through genetic testing, which identifies pathogenic variants in the FOXC2 gene. Genetic testing for this condition is available within the NHS Genomic Medicine Service, often initiated through a clinical genetics referral.
Healthcare professionals, such as ophthalmologists for eye symptoms or lymphoedema specialists for swelling, may also be involved in the diagnostic process. Referral for genetic testing would usually be made via a Clinical Genetics service. The relevant R-code for testing for inherited lymphoedema conditions is R309, which includes analysis of the FOXC2 gene.
Management & lifestyle
Management for lymphoedema-distichiasis focuses on addressing the specific symptoms experienced by each individual. For lymphoedema, management typically involves conservative measures such as compression garments, manual lymphatic drainage, regular exercise, and meticulous skin care to prevent infections. These treatments aim to reduce swelling and improve comfort. Regular monitoring by a lymphoedema specialist is often recommended.
For distichiasis, treatment depends on whether the extra eyelashes are causing irritation. If symptoms are mild, lubricants may be sufficient. For more troublesome eyelashes, various treatments can be considered, including epilation (removal), cryotherapy, or laser ablation to destroy the hair follicles. Referral to an ophthalmologist is important for appropriate assessment and management. Individuals with this condition are typically managed by multidisciplinary teams within the NHS, including genetic counsellors who can provide information and support regarding the genetic aspects.
UK care pathway
In the UK, individuals suspected of having a rare genetic condition like lymphoedema-distichiasis would typically be referred to a Clinical Genetics service. These services provide expert assessment, genetic counselling, and access to genomic testing through the NHS Genomic Medicine Service. Genetic counsellors can offer crucial information about the condition, its inheritance pattern, and implications for family members. Testing for inherited causes of lymphoedema, including FOXC2, is covered under NHS R-code R309. The ENIGMA and ClinGen frameworks contribute to the understanding and classification of gene variants.
Frequently asked questions
What is the difference between lymphoedema and distichiasis?
Lymphoedema is chronic swelling caused by a problem with the lymphatic system, often seen in the legs. Distichiasis is the growth of an extra row of eyelashes, usually along the eyelid margin. Both are key features of lymphoedema-distichiasis.
Is lymphoedema-distichiasis always inherited?
Lymphoedema-distichiasis is typically inherited in an autosomal dominant pattern. This means if one parent has the condition, each child has a 50% chance of inheriting it. However, in some cases, the genetic change can happen spontaneously for the first time in an individual (a 'de novo' variant).
Can the extra eyelashes cause problems?
Yes, while some people have no issues, stiff extra eyelashes can rub against the eye, causing irritation, redness, pain, and potentially damaging the clear front surface of the eye (cornea). An ophthalmologist can advise on management options.
How is lymphoedema managed in this condition?
Management of lymphoedema usually involves treatments such as compression garments, specialist massage (manual lymphatic drainage), regular exercise, and good skin care to help reduce swelling and prevent infections. These are typically overseen by a lymphoedema specialist.
Will my children also have lymphoedema-distichiasis?
If you have lymphoedema-distichiasis due to a pathogenic variant in the FOXC2 gene, each of your children has a 50% chance of inheriting the same genetic variant and therefore developing the condition. Genetic counselling can provide more personalised information and support.
References
- Marques NS, Miranda A, Barros S. Lymphoedema-distichiasis syndrome. BMJ case reports. 2016. PMID: 26759405
- Yasuda D, Sato N, Yanagida K. Lysophosphatidic acid-mediated NF-κB activation promotes FOXC2 expression essential for lymphatic valve development. The Journal of clinical investigation. 2026. PMID: 41528806
- Erickson RP, Dagenais SL, Caulder MS. Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations. Journal of medical genetics. 2001. PMID: 11694548
- Bell R, Brice G, Child AH. Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene. Human genetics. 2001. PMID: 11499682
- Sholto-Douglas-Vernon C, Bell R, Brice G. Lymphoedema-distichiasis and FOXC2: unreported mutations, de novo mutation estimate, families without coding mutations. Human genetics. 2005. PMID: 15906099
- Rezaie T, Ghoroghchian R, Bell R. Primary non-syndromic lymphoedema (Meige disease) is not caused by mutations in FOXC2. European journal of human genetics : EJHG. 2008. PMID: 18197197
- Connell F, Brice G, Jeffery S. A new classification system for primary lymphatic dysplasias based on phenotype. Clinical genetics. 2010. PMID: 20447153
- Brice G, Mansour S, Bell R. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. Journal of medical genetics. 2002. PMID: 12114478