Primary lymphedema can present during: (1) infancy, (2) childhood, (3) adolescence, or (4) adulthood. Although patients with primary lymphedema have malformed lymphatics at birth, individuals often develop swelling after infancy. Similar to adults with secondary lymphedema following lymph node removal and/or radiation, an interval exists between the onset of malfunctioning lymphatics and swelling. Fluid leaking out of the venous circulation is unable to be returned by the lymphatic vasculature. The high-protein interstitial fluid causes inflammation and further injures functioning lymphatics until edema is noticed clinically. Other factors, such as hormones, may influence the onset of lymphedema. For example, females most commonly present with the disease in adolescence.

Primary lymphedema traditionally has been divided according to the age of the patient when the swelling develops: “congenital,” “praecox,” or “tarda” [1]. This classification system is neither standardized nor precise, and the terms have been applied inconsistently (Table 7.3) [3, 11]. For example, “congenital” lymphedema is used if swelling was noted at birth, “shortly after birth,” birth to 3 months, birth to 1 year, or birth to 2 years. Thus, some authors would consider a 6-month-old infant presenting with lymphedema to be “congenital,” whereas others would label it “praecox.” A “congenital” anomaly may not present at birth (a child or adolescent who develops primary lymphedema was born with malformed lymphatics). “Praecox” is synonymous with “early” and relative to another time point; it does not identify an age range. A 1-day-old child with “congenital” lymphedema is “praecox” to a 1 month-old infant with lymphedema (although both would be labeled “congenital”). Similarly, “tarda” is used to describe “late” onset lymphedema, but a 1-month-old child is “tarda” to a 1-day-old neonate with congenital swelling. Developmental terminology should be used to define the onset of primary lymphedema: infancy, childhood, adolescence, or adulthood [3, 11]. These periods are defined and their use will facilitate communication and research.

In the pediatric population onset occurs in infancy (49.2 %), childhood (9.5 %), or adolescence (41.3 %) (Fig. 7.1) [3]. Primary lymphedema develops during adulthood in 19 % of patients (Fig. 7.2) [9]. Males are more likely to present in infancy (68 %), while females most commonly develop the disease during adolescence (55 %) [3]. The lower extremities are affected in 91.7 % of patients; 50 % have unilateral lymphedema and 50 % have bilateral disease [3]. Eighteen percent have genital lymphedema, which is usually associated with lower extremity lymphedema. Four percent of patients with primary lymphedema have isolated genital involvement. Sixteen percent of children with idiopathic lymphedema have upper extremity disease [3]. Rarely, a child can have lymphedema affecting the legs, genitalia, and/or arms (Fig. 7.3). Bilateral lower extremity lymphedema is more common in patients presenting in infancy (63 %), compared to adolescence (30 %) [3].

Eleven percent of patients with primary lymphedema have a familial/syndromic association (e.g., Turner syndrome, Noonan syndrome, Milroy disease) (Fig. 7.4) [3]. Children with onset in infancy and a familial history are referred to as having Milroy disease. This eponym often is erroneously applied to patients with any type of primary lymphedema. The term Milroy disease should be restricted to an infant with lower extremity lymphedema (unilateral/bilateral) present at birth with either: (1) a family history of the condition or (2) no family history of lymphedema, but a documented mutation in vascular endothelial growth factor receptor-3 (VEGFR3) [12]. Patients also should not be labeled as “Milroy disease” if they have either: (1) lymphedema appearing after infancy; (2) lymphedema/lymphatic anomalies outside of the extremities; or (3) associated anomalies (e.g., dysmorphic face, epicanthal folds, cardiac anomalies, or biliary atresia) [12]. A mutation in VEGFR3 is present in 75 % of children with familial lower extremity lymphedema, compared to 68 % of children without a family history of lymphedema [12]. Therefore, a positive family history of autosomal transmission is not essential for a diagnosis of Milroy disease. There can be de novo mutations in VEGFR3 and recessive transmission also can occur. Meige disease refers to familial lymphedema of the lower extremity that manifests during adolescence. “Meige disease” should not be used for patients with adolescent onset of lymphedema without a family history of the disorder [13].

Patients with a FOXC2 mutation causing lymphedema–distichiasis have an extra row of eyelashes and may exhibit eyelid ptosis and/or yellow nails. Hypotrichosis–lymphedema–telangiectasia (SOX18 mutation) causes sparse hair, and cutaneous telangiectasias. Hennekam syndrome (CCBE1 mutation) is characterized by generalized lymphedema with visceral involvement, developmental delay, flat faces, hypertelorism, and a broad nasal bridge [8]. Patients with Turner syndrome have a 57 % percent risk of lymphedema; 76 % have onset in infancy and 19 % develop swelling during childhood or adolescence [14]. Noonan syndrome may manifest with generalized lymphedema, intestinal lymphangiectasis and/or fetal hydrops. Patients with Noonan syndrome have a 3 % risk of lymphedema [15]. Hennekam syndrome is characterized by unusual facies, seizures, lymphedema of the lower limbs, genitalia and face, intestinal lymphangiectasis, and mental retardation. Overall, a genetic cause of primary lymphedema is present in 36 % of patients’ familial disease, and in 8 % of individuals without a family history of the condition [16]. Most of the known mutations for lymphedema involve proteins involved in the VEGFR3 pathway (e.g., FLT4, GJC2, FOXC2, SOX 18, GATA2, CCBE1, PTPN14) [16].

Primary lymphedema is a progressive condition and there is no cure. Generally, patients with primary lymphedema have less morbidity (e.g., enlarged limb size, infections, reduced function) compared to adults with secondary lymphedema (Table 7.4). One explanation may be that patients with primary lymphedema have compensated for the lack of lymphatic function because the defect occurred during embryogenesis. Lymphedema generally is not painful; significant discomfort is inconsistent with the disease. However, as the circumferential overgrowth of the extremity worsens and the limb becomes heavier, underlying musculoskeletal symptoms can occur.