Primary Lymphedema

It has been proposed that all cases of primary lymphedema are due to an inherited abnormality of the lymphatic system, sometimes termed congenital lymphatic dysplasia. However, it is possible that many sporadic cases of primary lymphedema occur in the presence of a (near) normal lymphatic system and are actually examples of secondary lymphedema for which the triggering events have gone unrecognized. These might include seemingly trivial (but repeated) bacterial or fungal infections, insect bites, barefoot walking (silica), DVT, or episodes of superficial thrombophlebitis. In animal models, simple excision of lymph nodes or trunks leads to acute lymphedema that resolves within a few weeks, presumably due to collater-alization. In animals, the human condition can only be mimicked by inducing extensive lymphatic obliteration and fibrosis. Even then, there may be considerable delay between the injury and the onset of edema. Primary lymphedema is much commoner in the legs than the arms. This may be due to gravity and a bipedal posture, the fact that the lymphatic system of the leg is less well developed, or the increased susceptibility of the leg to trauma or infection. Furthermore, loss of the venoarteriolar reflex (VAR), which protects lower limb capillaries from excessive hydrostatic forces in the erect posture, with age and disease (CVI, diabetes) may be important.

Primary lymphedema is often classified on the basis of apparent genetic susceptibility, age of onset, or lymphangiographic findings (Table 10.5). None of these is ideal, and the various classification systems in existence can appear confusing and conflicting as various terms and eponyms are used loosely and interchangeably. This problem has hampered research and efforts to gain a better understanding of underlying mechanisms, the effectiveness of therapy, and prognosis. Primary lymphedema, where there appears to be a genetic susceptibility or element to the disease, may be further divided into those cases that are familial (hereditary), where typically the only abnormality is lym-

CHRONIC VENOUS INSUFFICIENCY,VARICOSE VEINS, LYMPHEDEMA, AND ARTERIOVENOUS FISTULAS Table 10.5. Lymphangiographie classification of primary lymphedema


Age of onset


Puberty (praecox)

Any age

Sex distribution

Male > female

Female > male

Male = female


Whole leg

Ankle, calf

Whole leg, thigh only


Uni = bilateral

Often bilateral

Usually unilateral

Family history

Often positive

Often positive






Response to compression






Lymphatics are increased

Absent or reduced distal

There is obstruction at the

in number, although

superficial lymphatics;

level of the aortoiliac or

functionally defective;

also termed aplasia or

inguinal nodes; if associated

there is usually an


with distal dilatation, the

increased number of

patient may benefit from

lymph nodes; may have

lymphatic bypass

chylous ascites,

operation; other patients

chylothorax, and

have distal obliteration as




phedema and there is a family history, and those cases that are syndromic, where the lymphedema is only one of several congenital abnormalities and is either inherited or sporadic. Syndromic lymphedema may be sporadic and chromosomal [Turner's (XO karyotype), Klinefelter's (XXY), Down (trisomy 21) syndrome], or clearly inherited and related to an identified or presumed single gene defect [lymphedema-distichiasis (autosomal dominant)], or of uncertain genetic etiology (yellow-nail and Klippel-Trenaunay-Weber syndromes). Familial (hereditary) lymphedema can be difficult to distinguish from nonfamilial lym-phedema because a reliable family history may be unobtainable, the nature of the genetic predisposition is unknown, and the genetic susceptibility may translate into clinical disease only in the presence of certain environmental factors. Although the distinction may not directly affect treatment, the patients are often concerned lest they be passing on the disease to their children. Two main forms of familial (hereditary) lymphedema are recognized: Noone-Milroy (type I) and Letessier-Meige (type II). It is likely that both eponymous diseases overlap and represent more than a single disease entity and genetic abnormality. Milroy's disease is estimated to be present in 1 in 6000 live births and is probably inherited in an autosomal-dominant manner with incomplete (about 50%) penetrance. In some families, the condition may be related to abnormalities in the gene coding for a vascular endothelial growth factor (VEGF) on chromosome 5. The disease is characterized by brawny lymphedema of both legs (and sometimes the genitalia, arms, and face) that develops from birth or before puberty. The disease has been associated with a wide range of lymphatic abnormalities on lymphan-giography. Meige's disease is similar to Milroy's disease except the lymphedema generally develops between puberty and middle age (50 years). It usually affects one or both legs but may involve the arms. Some, but not all, cases appear to be inherited in an autosomal-dominant manner. Lymphangiography generally shows aplasia or hypoplasia.

Lymphedema congenita (onset at or within 2 years of birth) is commoner in males, more likely to be bilateral and to involve the whole leg. Lymphedema praecox (onset from 2 to 35 years) is three times commoner in females, has a peak incidence shortly after menarche, is three times more likely to be unilateral than bilateral, and usually only extends to the knee. Lymphedema tarda develops, by definition, after the age of 35 years and is often associated with obesity, with lymph nodes being replaced by fibrofatty tissue. The cause is unknown. Lymphedema develop


ing for the first time after 50 years should prompt a thorough search for underlying (pelvic, genitalia) malignancy. It is worth noting that, in such patients, lymphedema often commences proximally in the thigh rather than distally.

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