Hereditary lymphedema is a group of genetic pathologies that manifest as a violation of lymph outflow from various parts of the body (most often the lower extremities) with the development of pronounced edema. Symptoms of this condition are swelling of the affected limbs, developing at different ages (depending on the form of the disease), aggravated by physical exertion and under the influence of other factors. Diagnosis of hereditary lymphedema is based on the data of the patient’s hereditary history and physical examination. Molecular genetic methods of determination have been developed for some types of pathology. There is no specific treatment, various techniques of lymphatic drainage massage and special diets are used to reduce the severity of symptoms. In some cases, surgical correction is performed.
Q82.0 Hereditary lymphedema
Hereditary lymphedema (primary lymphedema, elephantiasis) is a group of congenital disorders of lymph circulation, which may be caused by dysplasia of lymphatic vessels, abnormalities in the process of resorption of tissue fluid or destruction of valves. This disease has been known since ancient times, but its detailed study began only in the XIX century – for example, in 1891 W. Milroy described a family form of hereditary lymphedema, (a year earlier, a similar pathology was described by Nonne, but could not prove its innate nature). In the following years, many forms of this condition were discovered with varying degrees of severity of symptoms. Both isolated types, manifested only by edema, and variants of pathology combined with other disorders were described.
Hereditary lymphedema occurs quite often relative to other hereditary pathologies, but its exact prevalence has not been determined, it has only been established that for some forms these figures are about 1:10000. Women predominate among the patients, according to experts, their share in the total number of patients with edema of a genetic nature is about 80%. Most often, hereditary lymphedema manifests itself in childhood and adolescence, so most patients are young people under 18 years old, but some forms of pathology are characterized by later development.
Hereditary lymphedema of any type occurs due to impaired functioning of the lymphatic system – it can be dysplasia of lymphatic vessels, destruction of their valves or violation of the processes of reabsorption of tissue fluid. Most forms of this condition are autosomal dominant hereditary diseases, in some cases incomplete penetration of the defective gene is observed, especially in heterozygotes. The prevailing number of women in the sexual distribution of hereditary lymphedema is due to physiological and endocrine features – the presence of an increased level of estrogen reduces the pressure of tissue fluid, which facilitates its accumulation. Mutations of various genes can lead to this condition, which also affects the phenotypic picture of the disease.
The following are the most common forms of hereditary lymphedema:
- Nonne-Milroy syndrome or hereditary lymphedema type 1A – regarding the causes of this disease with an autosomal dominant type of inheritance, geneticists have not yet come to an unambiguous conclusion. It was found out that the defective gene is located on the 5th chromosome, presumably it is VEGF3 – it encodes one of the growth factors of lymphatic vessels and is massively synthesized during embryonic development, and in adults it is found in the lymphatic endothelium. A defect in this protein leads to hereditary lymphedema due to dysplasia and underdevelopment of small-caliber lymphatic vessels.
- Hereditary lymphedema type 1B is the least studied form of the disease, which is associated with mutations of genes located at some loci of the 6th chromosome.
- Hereditary lymphedema type 1C is the most common variant of this pathology, according to some data, it causes more than 90-94% of all cases of this edematous condition. The cause of development is mutations of the GJC2 gene localized on the 1st chromosome. The product of its expression is the protein connectin-47, a representative of a wide family of proteins that form slit contacts between cells of various tissues. Connectin-47 performs this role in the endothelium of lymphatic vessels, therefore, with defects in the GJC2 gene, its permeability changes, and the normal outflow of tissue fluid becomes difficult, which leads to hereditary lymphedema. According to some reports, with the mutation of the above gene, hypoplasia of lymphatic vessels occurs, but experts believe that this is a secondary phenomenon. Like many other forms of this disease, hereditary lymphedema type 1C is transmitted by an autosomal dominant mechanism with incomplete penetrance.
- Major’s syndrome or hereditary lymphedema type 2 is a fairly rare form of the disease characterized by a late onset, sometimes there are children’s variants. This gives some researchers a reason to divide the Major syndrome into two subtypes – with early and late development. The etiology of this variant of hereditary lymphedema has not been thoroughly studied, a mutation of the F0XC2 gene, which is one of the transcription factors of other genes, is assumed. As a result, the functioning of the valves of lymphatic vessels is disrupted, which delays the transport of fluid and creates conditions for its accumulation in tissues.
In addition, specialists often distinguish into separate types of hereditary lymphedema edema of a lymphatic nature accompanying some other genetic pathologies. The most well-known variant of this condition is lymphedema in Shereshevsky-Turner disease. In addition, lymphatic edema can accompany diseases such as yellow nail syndrome and Hennekam’s disease.
Different variants of the disease are characterized by different age of onset of symptoms, their severity and concomitant manifestations. For example, Nonne-Milroy’s disease is accompanied by a slight swelling of the legs, which can be detected already at the birth of the patient. In the future, this condition progresses, leading to a characteristic clinical picture of the disease.
Hereditary lymphedema types 1B and 1C are very similar to each other and begin to develop in childhood or adolescence. In some cases, swelling of the legs (less often – hands) can occur in these forms and in adults. This is due to the fact that the insufficiency of lymph outflow can be partially compensated without attracting attention for many years and manifested only by minor or moderate swelling of tissues after physical exertion. Pregnancy, obesity and poor nutrition can lead to decompensation of these forms of hereditary lymphedema. Major’s syndrome most often occurs at the age of 30-50 years, sometimes earlier – this is due to the gradual destruction of the valves of lymphatic vessels.
With the further course of hereditary lymphedema, a vicious circle is formed – violations of lymph outflow lead to edema, which further complicates the work of lymphatic vessels. At first, the limbs swell greatly, when pressing on the tissue, a trace of a finger remains. Then, on the surface of the skin of the legs or hands, a so–called “lemon crust” is formed – a sign of stagnation of lymph in the dermis. Gradually, edema and skin disorders progress. The affected limbs noticeably increase in volume, sometimes reaching significant sizes (elephantiasis), areas of hyperkeratosis form on the skin.
Lymph stagnation in hereditary lymphedema complicates microcirculation and tissue nutrition, therefore trophic disorders (ulcers, erosions) occur on the legs or arms, which are often complicated by secondary infection. Infectious agents can infect still functioning lymphatic vessels (lymphangitis), which further complicates the outflow of lymph and leads to rapid progression of the disease. In severe cases and in the absence of treatment, hereditary lymphedema disfigures the appearance of the limbs, can lead to sepsis and cardiovascular insufficiency.
The definition of lymphedema in general as an edematous syndrome, as a rule, is not particularly difficult – a simple examination of the patient’s skin and palpation of the affected limbs is enough for this. At the same time, pronounced edema is determined, when pressing on the tissue, traces remain in the form of pits that do not straighten out for a long time. When questioning a patient with hereditary lymphedema, it turns out that swelling increases with prolonged walking, standing and physical exertion. In some cases, a neonatologist may suspect this condition when examining a newborn – for example, with Nonne-Milroy’s disease. To prove the lymphatic nature of edema, such a study as lymphangiography (contrast X–ray examination of lymphatic vessels) can be performed – in this condition, their hypo- or aplasia will be detected.
The presence in the patient’s hereditary history of such edema and syndromes in close relatives indicates the genetic nature of this condition. The final diagnosis can be confirmed by molecular genetic studies – currently, hereditary lymphedema caused by mutations of the GJC2 and VEGF3 genes is being determined in laboratories. At the same time, direct sequencing of the sequence of the above genes is performed, which makes it possible to detect a genetic defect. In some cases, it makes sense to check for other hereditary pathologies, which, among other things, can manifest as edematous syndrome.
Therapy of hereditary lymphedema boils down to several principles – improving lymph outflow, reducing tissue fluid retention and eliminating secondary disorders caused by edematous syndrome. To improve the outflow, a variety of lymphatic drainage massages (both manual and hardware) and special compression knitwear are used, sometimes local medicines are used. For some forms of hereditary lymphedema, surgical techniques can be effective, creating more complete ways of evacuation of tissue fluid into the lymphatic or circulatory systems. To reduce the retention of lymph in the tissues, special diets with a reduced content of proteins and salts are prescribed – these nutrients can significantly aggravate the course of lymphatic edema.
In advanced forms of hereditary lymphedema with pronounced secondary disorders (elephantiasis, trophic ulcers, infection), complications are treated. Antibiotics are prescribed to fight infection, trophic disorders are treated with vitamin therapy, regenerative agents and biogenic stimulants. With pronounced elephantiasis, surgical removal of excess tissue volume (resection surgery) is sometimes performed, which leads to an improvement in both the appearance and condition of the patient with hereditary lymphedema.
Prognosis and prevention
The prognosis of hereditary lymphedema depends on the severity of the symptoms of the disease, the timeliness of the start and nature of treatment, as well as a number of other factors. Under optimal conditions, regular lymphatic drainage massages, proper diet, restriction of fluid intake and physical activity, the prognosis is quite favorable – patients can only worry about leg swelling at the end of the day. In the case of a more severe course of hereditary lymphedema, violation of the treatment plan or lack of therapy, this condition can lead to disability of the patient due to elephantiasis and even to a fatal outcome due to secondary infection and trophic disorders. Therefore, when detecting the disease, patients should carefully adhere to all doctor’s prescriptions, do not eat salty or high-protein foods, monitor the drinking regime and avoid prolonged stress on the limbs, especially static.