Dermatology Online Journal

Lymphedema praecox
Carina Rizzo MD, Lisa M Gruson MD, Brent D Wainwright MD
Dermatology Online Journal 15 (8): 7

Department of Dermatology, New York University

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Abstract

A 57-year-old man presented with the post-pubertal onset of asymptomatic swelling of the left arm and legs that had been complicated by recurrent bouts of cellulitis. The presentation and disease course are consistent with lymphedema praecox, which is a subtype of primary lymphedema with onset at puberty and a slowly progressive course. The subtypes of lymphedema, pathogenesis, and treatment are reviewed.

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Figure 1

History

In May, 2008, the Dermatology Service at the Veterans' Affairs New York Harbor Healthcare System consulted on the case of a 57-year-old man with recurrent cellulitis of the left upper extremity. The insidious onset of painless, mild swelling of the left upper extremity and lower extremities began in late adolescence. Worsening of left upper extremity swelling occurred in 1971 while he was serving in the military, without preceding trauma or infection. Evaluation for filariasis, venous thrombosis, a malignant condition, as well as liver, renal, cardiac, or thyroid diseases was negative at that time. Cellulitis first occurred in the left upper extremity four years later after minor trauma and then recurred approximately two to four times yearly for the following 25 years. Venous thrombosis developed in the left lower extremity during a hospitalization for recurrent left upper extremity cellulitis in 1976, but no underlying thrombophilia was detected. Slowly progressive swelling of the affected extremities continued. Past treatments have included skin care, elevation of the affected extremities, compression with elastic hose, the use of a pneumatic compression pump, and administration of furosemide. Medical history includes eczema, seborrheic dermatitis, prostate cancer that was diagnosed in 1985 and treated with radical prostatectomy, a 60-pack-year smoking history, chronic obstructive pulmonary disease, and myocardial infarct in 2006. There is no family history of lymphedema or other congenital defects.

Physical Examination

Non-pitting edema of the lower extremities and of the distal aspect of the upper extremity was present. There was slight warmth in all affected extremities but no erythema or tenderness. The right arm was unaffected. The eyelashes and hair were normal.

Laboratory data

A complete blood count, metabolic profile, and thyroid function tests were normal.

Histopathology

None.

Comment

Lymphedema may result from primary or secondary causes. Secondary causes include filariasis, which is the most common cause worldwide, and malignant conditions with associated radiation therapy and surgery, which is the most common cause in industrialized countries. Trauma, thyroid disease, obesity, and chronic venous insufficiency also may lead to secondary lymphedema [1].

Primary lymphedema results from a congenital defect in the lymphatic circulation and is categorized according to the age of onset as congenital (Milroy disease), praecox (Meige disease), or tarda. Congenital lymphedema is typically present at birth or develops prior to the first year of life. It affects the lower extremities although the upper extremities and even the trunk or face may be involved. Cases may be sporadic or familial, and inheritance is classically autosomal dominant although recessive inheritance has been described [4]. Milroy disease has been linked to dominant mutations in the FLT4 gene that result in impaired tyrosine kinase activity of the vascular endothelial growth factor receptor 3 (VEGFR-3), which disrupts lymphangiogenesis [1, 5, 6]. The expressivity and penetrance are variable, which suggests that additional environmental or genetic factors may contribute.

Lymphedema praecox is the most common form of primary lymphedema. It develops prior to the age of 35 at or after puberty [7]. The classic presentation is of unilateral involvement of a lower extremity although involvement of both lower extremities and of the upper extremities is not uncommon [8]. It is thought that the delayed onset may be accounted for by an underlying defect in the lymphatic circulation, which must be unmasked by a secondary insult, such as infection or trauma. However, only a minority of patients recognize such an event. A female preponderance and onset during puberty or pregnancy suggest a possible hormonal factor [1].

The underlying gene defect or defects have not yet been defined. An association with mutations in the forkhead box C2 (FOXC2) gene was initially suggested, but this association has been refuted [9]. Mutations in FOXC2 impair venous and lymphatic development and underlie the lymphedema-distichiasis syndrome, which is an autosomal dominant disorder that is characterized by lymphedema, double rows of eyelashes, and associated congenital defects, such as cleft palate and cardiac abnormalities [10]. Initial reports of FOXC2 mutations in Meige disease were subsequently found to represent subtle cases of lymphedema-distichiasis syndrome. A large candidate gene analysis in primary lymphedema found mutations in four biologically plausible genes, fatty acid binding protein 4 (FABP4), vascular endothelial growth factor receptor-2 (NRP2), sry-related HMG-box gene 17 (SOX17), and vascular cell adhesion molecule 1 (VCAM1) that segregated with lymphedema; however, a causal relationship could not be proved [11]. In another study, an association with mutations in the hepatocyte growth factor (HGF) and receptor (MET) pathway was noted [12]. It is possible that Meige disease represents a common phenotypic presentation that arises from any number of congenital lymphatic defects, and further investigation will be needed to define the pathogenesis.

Lymphedema tarda does not become evident until after the age of 35. This form of lymphedema often presents with involvement of the lower extremities and may be related to valvular defects although the underlying etiology has not yet been delineated.

Hypotrichosis-lymphedema-telangiectasia syndrome represents an additional very rare form of congenital lymphedema that is caused by mutation in the transcription factor gene SOX18, with both autosomal dominant and recessive inheritance described [13, 14].

Lymphedema is a clinical diagnosis, and diagnostic tests are typically not required. Lymphangiography has been replaced by lymphoscintigraphy as the modality of choice for evaluating lymphatic function preoperatively or if the diagnosis is in question [1, 8].

Primary lymphedema has a benign course with a favorable prognosis [8]. Recurrent cellulitis is the most common complication, and the development of lymphangiosarcoma rarely has been described in chronic cases [2]. Treatment is primarily supportive and includes elevation of the extremity, the use of elastic support hose, and massage or pneumatic compression devices. Meticulous skin care and avoidance of trauma is vital to prevent infections, which may further damage the lymphatic circulation [1, 2]. The use of diuretics to decrease capillary filtration and thus minimize the lymphatic burden has been attempted with limited success [1, 15]. Benzopyrones, which decrease capillary permeability and have been suggested to prevent lymphatic fibrosis by decreasing macrophage activity, have been applied to the treatment of lymphedema, but no clear benefit has been shown [16]. Surgical intervention is reserved for rare cases of medical failure or when mobility has become compromised.

References

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12. Finegold DN, et al. HGF and MET mutations in primary and secondary lymphedema. Lymphat Res Biol 2008;6:65 [PubMed]

13. Irrthum A, et al. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 2003;72:1470 [PubMed]

14. Irrthum A, et al. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 2000;67:295 [PubMed]

15. Rockson SG, et al. American Cancer Society Lymphedema Workshop. Workgroup III: Diagnosis and management of lymphedema. Cancer 1998;83:2882 [PubMed]

16. Badger C, et al. Benzo-pyrones for reducing and controlling lymphoedema of the limbs. Cochrane Database Syst Rev 2004:CD003140 [PubMed]

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