Primary Lymphedema in a Pediatric Patient

AFFILIATIONS:
¹Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
²Clinical Professor of Pediatrics, the University of Calgary
³Pediatric Consultant, the Alberta Children’s Hospital, Calgary, Alberta, Canada
⁴Pediatric Dermatologist, the Pediatric Institute, Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia
⁵Associate Clinical Professor of Pediatrics, Dermatology and Skin Sciences, the University of British Columbia, Vancouver, British Columbia, Canada

CITATION:
Lim C, Leung AKC, Leong KF, Lam JM. Pediatric primary lymphedema. Consultant. 2023;63(2):e6. doi:10.25270/con.2022.11.000005

Received September 9, 2021. Accepted September 23, 2021. Published online November 29, 2022.

DISCLAIMER:
Dr Leung is the Photo Essay series editor. He was not involved with the handling of this paper, which was sent out for external peer review. The authors report no relevant financial relationships.

CORRESPONDENCE:
Catherine Lim, BKin, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3 (catherine.lim@alumni.ubc.ca)

Introduction

Primary lymphedema may present as isolated lymphedema or part of a syndrome, such as Turner syndrome or Noonan syndrome. This case report details isolated lymphedema and highlights features on history, physical examination, and imaging that clinicians may look for when considering if the lymphedema is primary, secondary and isolated, or part of a syndrome.

Case Presentation
A 3-year-old boy presented to an outpatient clinic with a history of painless edema involving both lower extremities since birth.

The patient was born at 38 weeks’ gestation via spontaneous vaginal delivery after an uneventful pregnancy. At birth, his weight was 2.9 kg (17th percentile), length was 47 cm (6th percentile), and head circumference was 35 cm (66th percentile). He had achieved all developmental milestones for his age. Mental and physical development were within normal limits. The swelling initially affected his feet at 18 months of age and progressed to involve both calves and shins symmetrically. Two episodes of cellulitis were documented at ages 18 and 24 months.

The patient was an only child, and his parents were nonconsanguineous parents. His father had similar symptoms since birth (Figure 1). There was no other family history of skin or genetic diseases.

Figure 1. Bilateral lymphedema of the lower limbs of the patient (right) and his father (left).

Review of systems was negative for other symptoms, apart from lower leg swelling. There was no history of weight loss, fever, or other constitutional symptoms. He was not taking any medications. The patient appeared his stated age with no microcephaly and no syndromic features. Distichiasis was not present.

Physical examination revealed swelling in the lower legs bilaterally with symmetric nonpitting pedal edema up to his mid-calves (Figures 1 and 2). No other body parts, including genitalia, were swollen. His abdomen was soft and nontender with no evidence of ascites, abdominal organ enlargement, or lymph node enlargement. His legs were nontender and capable of full active range of motion in the knee, ankle, and metatarsal and interphalangeal joints. No prominent vein distension was found. Kaposi-Stemmer sign was positive as the examiner was unable to pinch the skin at the base of the dorsal second toe. Upslanting toenails were noted bilaterally (Figure 2). The authors report that informed patient consent was obtained for publication of the images used herein.

Figure 2. Bilateral lymphedema of the patient's feet along with upslanting toenails.

He weighed 14 kg (42nd percentile) and measured 93 cm (31st percentile). He was afebrile with a heart rate of 99 beats/min, blood pressure of 90/62 mm Hg, and respiratory rate of 16 breaths/min. Lung and cardiovascular examinations were normal. Motor and sensory examinations and gait were within normal limits. Full active range of motion was achieved in both lower legs and feet bilaterally.

Radiologic examination of both lower extremities did not reveal any skeletal defects. Ultrasound and doppler study showed thickening of skin and subcutaneous tissue with normal patency of major arteries and veins. No cystic structure was seen. Ultrasound suggested subcutaneous edema without underlying arterial or venous malformation. Lymphoscintigraphy, leg biopsy, and genetic analyses were not performed.

Ultrasound did not show evidence for an arteriovenous malformation or chronic venous disease. Lipedema was excluded based on involvement of the feet and a positive Kaposi-Stemmer sign. Obesity and drug-induced swelling were excluded based on history and physical examination findings. A diagnosis of secondary lymphedema was excluded based on a lack of evidence of other disease processes or history of trauma or immobility to the lower legs.

Ultimately, a clinical diagnosis of primary lymphedema was made based on bilateral swelling beginning in the feet at birth and later extending to the calf, a positive Kaposi-Stemmer sign, and a positive family history. He was treated conservatively with compression bandages.

Discussion
The lymphatic system is a unidirectional circuit that drains lymph fluid to the lymph nodes and systemic venous circulation.¹ Circulation of this lymph fluid depends on compressive forces and contraction of muscles.¹ Lymphedema presents as chronic, progressive swelling of subcutaneous tissue that is caused by excessive retention of lymphatic fluid in the interstitial space due to defective lymphatic drainage or vessels.^2,3 This is opposed to edema, which presents as an increase in interstitial fluid volume.¹ The etiology of lymphedema can categorized as either primary or secondary. Primary lymphedema is rare and caused by an inherent defect of lymphatic vessels.^1,2 In contrast, secondary lymphedema is a consequence of underlying venous insufficiency, malignancy, infection (eg, filariasis, tuberculosis), radiation therapy, or trauma (lymphadenectomy).^2,4

Primary lymphedema may present as isolated lymphedema without an inciting factor or part of a syndrome associated with congenital pathologic development of lymphatic vessels. Primary lymphedema has been reported in conditions such as Turner syndrome and Noonan syndrome.^2,4,5 In 1985, Leung⁶ reported a dominantly inherited syndrome of microcephaly and congenital lymphedema, a finding that other researchers have since confirmed.⁷

Primary lymphedema usually presents as a de novo mutation or with an autosomal dominant inheritance with incomplete penetrance and variable expressivity.² It is familial and congenital.² More than 20 genes have been linked to lymphatic developmental anomalies, but only 30% of patients have identifiable genetic mutations, most notably in the signaling pathway for vascular endothelial growth factor C.² For example, Milroy disease (hereditary lymphedema type IA) has mutations in the VEGFR3 gene.² Other germline mutations implicated in primary lymphedema include FOXC2, SOX18, and CCBE1.³

Primary lymphedema occurs equally in women and men. However, men are more likely to present in infancy, whereas women tend to present in adolescence.⁴ Classification can be further divided by age of onset. Congenital lymphedema occurs at birth or shortly thereafter and is associated with aplastic lymphatics and bilateral leg edema.^1,2 Lymphedema praecox typically arises during puberty or less commonly, during pregnancy.^1,2 The condition usually presents as unilateral foot or calf swelling.^1,2 Lymphedema tarda, a less common condition, is characterized as primary lymphedema presenting after aged 35 years.^1,2 Hereditary lymphedema type IA (Milroy disease) presents with lymphedema from birth to aged 2 years, whereas hereditary lymphedema type II (Meige disease) presents from puberty to aged 35 years.²

Primary lymphedema typically begins as painless, firm swelling in one foot that travels proximally.^1,3 The extremities are most often affected, followed by the genitalia.⁴ Initially, the swelling is pitting but over time becomes nonpitting edema.¹ Chronic lymphedema is characterized by hyperkeratotic, hyperpigmented, and verrucous skin.¹ Patients may complain of discomfort, heaviness, or decreased range of motion in the affected limb.¹ The Kaposi-Stemmer sign is positive when the examiner is unable to pinch a fold of skin at the base of the second toe on the dorsal aspect of the foot.¹ This is indicative of lymphedema and is not seen in similar conditions, such as lipedema or venous insufficiency.

Differential Diagnosis
Lymphedema can be confused with many other disease processes.³ The differential of lymphedema includes lipedema, other vascular anomalies and tumors (ie, hemangioma, kaposiform hemangioendothelioma, microcystic/macrocystic lymphatic malformation), chronic venous insufficiency, syndromes with limb size discrepancies due to hypertrophy of the soft tissue and bones (ie, Klippel-Trénaunay syndrome, CLOVES syndrome, Parkes Weber syndrome, Proteus syndrome), myxedema, drug-induced swelling, obesity, and non-specific edema.² Lipedema, a syndrome of bilateral adipose deposition, occurs almost exclusively in women and affects the buttocks and lower extremities but not the feet.^1,2 Lipedema has a negative Kaposi-Stemmer sign, and the swelling is nonpitting, tender, and soft.^1,2 Deep vein thrombosis is also in the differential and should be excluded with ultrasound.¹ Diagnosis is clinical and can be confirmed with lymphoscintigraphy (92% sensitive; 100% specific).^1,3 Magnetic resonance imaging may show the characteristic honeycomb pattern of lymphedema, representing the dilated subcutaneous channels between dermis and fascia, and can also rule out other vascular pathologies.^1,3 Biopsy may be conducted if malignancy is suspected.⁴

Treatment and Management
Management is focused on restoring function and cosmesis of the affected limb and preventing progression and complications of the disease.¹ Treatment encompasses compression garments, exercise, regular moisturizing and cleansing, patient education, and psychological support.¹ Currently, there is no role for pharmacologic therapy.⁴ Compression garments or devices are first-line therapies, including combinations of custom compression stockings, multilayer compression bandages, and 2 hours of pneumatic compression per day.^1,4 Massage or manual lymph drainage is effective when combined with compression and exercise.⁴ Rarely, reconstructive or debulking surgery may be considered for moderate to severe disease, including staged skin/subcutaneous excision or suction-assisted lipectomy.^1,4 Severe genital disease may be treated with skin/subcutaneous resection.⁴

Complications include recurrent skin infections (eg, cellulitis, erysipelas, tinea pedis, and lymphangitis), cutaneous malignancies (eg, squamous cell carcinoma, basal cell carcinoma, cutaneous lymphomas, melanoma, Kaposi sarcoma, or cutaneous angiosarcoma), elephantiasis verrucosa nostras, and lymphatic papillomatosis.^1,2 Recurrent cellulitis (more than 3 episodes per year) may be treated with prophylactic antibiotics (penicillin V daily or cephalexin).^1,4 Infection can be prevented with regular cleansing, keratolytic agents (eg, salicylic acid), moisturizing, and wearing protective clothing.⁴

Conclusion
Primary lymphedema in children is not common; this case report reviewed key features in the differential diagnosis of primary lymphedema. Lipedema, obesity or drug induced swelling, and aterial or venous malformations were excluded based on history, physical examination, and imaging. Further work up with lymphoscintigraphy, leg biopsy, or genetic analyses could have been considered if there were suspicion for a syndromic condition.