Primary lymphedema is an umbrella term encompassing all developmental lymphatic anomalies that result in lymphedematous swelling. Primary lymphedema is highly heterogenous in its presentation, affecting patients of any age, with lymphedema anywhere in the body ranging from mild to severe enlargement. Lymphedematous swelling may occur in isolation or in association with other syndromic features. As such, diagnosis is challenging and often missed. Unlike secondary lymphedema, the natural history of primary lymphedema is unpredictable, with some patients achieving complete spontaneous regression soon after symptomatic onset and others developing progressive disease. Indications for surgical management are, therefore, poorly defined. Treatment algorithms are largely based on practice patterns for secondary lymphedema, with very few studies providing evidence in this distinct patient population.

The true incidence and prevalence of primary lymphedema are largely unknown due to under-reporting and under-recognition. In adults, primary lymphedema is significantly less common than secondary, comprising less than one percent of all cases of lymphedema (Goss 2019). Within the pediatric population, however, primary lymphedema is significantly more common, encompassing over 90% of cases [1,2]^[1][2]. Among children, symptoms of primary lymphedema appear during infancy (49.2%), childhood (9.5%) or adolescence (41%) ^[3]. The reported prevalence of primary lymphedema is 1.15/100,000 among individuals aged less than twenty ^[4], with an overall population prevalence in the United States of 1.33/1000; however, these numbers are believed to be an underestimation ^[5]. Epidemiological details, such as geographic regions or ethnicities of higher incidence, are lacking ^[6].

Primary lymphedema is more common amongst females, with a 3.5:1 ratio ^[4]; however, gender discrepancies differ based on age of presentation. Development of primary lymphedema during adolescence is more common among girls (approximately 2:1 ratio), whereas in infancy, boys are more commonly affected than girls (approximately 2:1 ratio) ^[1]. The significantly earlier age of onset in boys, when compared to girls, is hypothesized to be attributable to epigenetic factors that are hormonally mediated, allowing differing expressivity over the lifespan ^[1]. OurThe understanding of the relationship between sex hormone expression and lymphedema is in its infancy and is theorized based on observations of worsening lymphedema during puberty, menses, and pregnancy. Estradiol is proposed to influence the expression of VEGF-C, a growth factor implicated in lymphatic endothelial repair with a known role in lymphedema. The full extent of this relationship, and the role of sex in the development of primary lymphedema, remains to be fully elucidated and may represent an exciting area for therapeutic intervention ^[7].

Historically, primary lymphedema was classified into three categories based on the age of onset: lymphedema congenita (birth to approximately 2 years), lymphedema praecox (approximately 2–35 years), and lymphedema tarda (>35 years) ^[8]. Though widely used, inconsistent age ranges are reported, and the classification does not necessarily correlate with developmental age ^[9]. Further, this system provides no insight into pathogenesis, phenotype, or management ^[10]. To this end, several classification pathways have been described in which diagnosis is made based on features such as (i) syndromic associations, (ii) systemic involvement, (iii) involvement of the cutaneous and vascular systems, (iv) age of onset, (vi) other associated phenotypic findings, (vii) family history, and (viii) genetic mutations [6,11,12,13]^{[6][11][12][13]}. These pathways provide information on the natural history and clinical presentations of the many forms of primary lymphedema.

A relationship between primary lymphedema and vascular anomalies has been proposed; nearly one-quarter of patients with primary lymphedema have concomitant vascular malformation. Unlike primary lymphedema, which is not associated with a vascular malformation in which lymphatic hypoplasia is the most common, lymphatic hyperplasia is the most frequently identified malformation amongst patients with a vascular malformation [14,15]^[14][15]. As such, the International Society for the Study of Vascular Anomalies (ISSVA) in 2018 included primary lymphedema in their classification system for vascular anomalies in the category of “lymphatic malformation”, in conjunction with macro- and micro-cystic lymphatic malformation ^[16]. Congenital lymphedema malformation lesions can be divided into truncular (lesions that develop later in development, during the formation of the lymphatic trunks, vessels, and lymph nodes) or extratruncular (lesions secondary to abnormalities in the embryonic tissues). Systemic primary lymphedema is reported as a type of truncal lymphatic thought to result from a defect of the lymphatic system that occurs late in lymphangiogenesis, whereas lymphatic malformations are attributable to defects early during development. Hereditary primary lymphedema, such as Milroy’s disease or distichiasis-lymphedema, however, is not the result of truncular defects and as such, their classification as a ‘congenital’ lymphedema has been called into question ^[17].

Accurate diagnosis of primary lymphedema can be challenging given the numerous other conditions that can present with limb enlargement. In a review of children referred to a lymphedema clinic, 38.7% had been misdiagnosed with primary lymphedema [18,19]^[18][19]. As such, the delay to accurate diagnosis of primary lymphedema is often significant, reported at more than ten years between symptomatic onset and clinical diagnosis ^[2].

The differential diagnosis for an enlarged, swollen extremity in the absence of obvious injury is wide and may include systemic causes (including cardiac, hepatic, nephrotic, thyroid diseases, hypoproteinemia), venous insufficiency or thrombosis, drug-related (rapamycin inhibitors, antipsychotics, antidepressants, anti-Parkinsonian medications, bisphosphonates), or lipedema [20,21]^[20][21]. Other congenital considerations include vascular anomalies (micro- or macro-cystic lymphatic malformations, capillary or venous malformations, infantile hemangiomas, and Kaposiform hemangioendothelioma), or hypertrophic syndromes (Klippel–Trénaunay, Parkes Weber, and CLOVES) [18,22]^[18][22].

4. Pathophysiology

Unlike secondary lymphedema, which is most commonly attributable to disease or injury to the lymphatic system, primary lymphedema arises due to intrinsic abnormalities of the lymphatics. Reduced lymphatic growth (hypoplasia, aplasia), increased lymphatic size (megalymphatic), increased number of vessels (hyperplasia), growth in the incorrect location (lymphangiodysplasia), valvular dysfunction (resulting in lymphangiectactic dilatation, lymphatic reflux, lymphorrhea), and/or functionally inadequate drainage with impaired contractility may arise secondary to genetic mutations that may be familial or arise de novo [6,8]^[6][8]. Results from lymphoscintigraphy findings suggest that the majority (56%) of patients have hypoplastic lymphatics (56%) or aplasia (14%) [14,15]^[14][15]. Furthermore, disruption in mechanisms, including initiation of lymphangiogenesis, differentiation of lymphatic structures, and mediation of cell migration and adhesion, have all been implicated in primary lymphedema ^[6]. Primary lymphedema may be fatal in the prenatal period or remain silent until any time in life when an imbalance between lymph production and lymph transport results in edema, chylous or non-chylous lymph accumulations and/or effusions ^[6]. The natural history of primary lymphedema differs significantly from secondary lymphedema. Whereas secondary lymphedema is thought to always progress, outcomes for patients with primary lymphedema are unpredictable, with progressive, stagnant, and recessive disease patterns all described. Some authors report that the age of lymphedema onset does not influence the progression and morbidity conferred by the lymphedema [18^[18][19],19], whereas others suggest that patients with later onset are less likely to spontaneously improve when compared to those who developed lymphedema within the first year of life ^[23]. Among patients with a progressive course, there is considerable variability in the rapidity of lymphedema progression and development of lymphatic sclerosis and soft tissue fibrosis ^[24]. The pathophysiology of adult-onset primary lymphedema is not well understood. No specific germline or somatic mutations have been identified, nor has familial transmission been described. It is suggested the delayed presentation is likely attributable to less severe developmental anomalies of the lymphatic system that do not become clinically apparent until the lymphatic function fails later in life [14,15]^[14][15]. Lymphangiography has demonstrated that adult-onset primary lymphedema is associated with less severe aplasia or hypoplasia compared to early-onset disease; on lymphoscintigraphy, patients with adult-onset primary lymphedema have significantly more dermal backflow (73%) compared to children (31%) [14,15]^[14][15]. With aging, contraction frequency decreases, impairing pumping activity and slowing the velocity of lymphatic flow. In both animal models and human lymphoscintigraphy, lymphatic drainage is shown to slow with age ^[20].

4.1. Genetics

Primary lymphedema is most commonly idiopathic, as approximately 70% of patients with primary lymphedema have no identifiable underlying genetic defect; however, it is likely the genetic basis of disease in these patients simply has not yet been discovered ^[6]. Genetic predisposition to primary lymphedema is most commonly attributable to an inherited autosomal dominant mutation with variable penetrance ^[21]. Even within a single family, significant differences in lymphedema phenotype are common. Over thirty genes and loci have been identified and implicated in lymphangiodysplasia or lymphangiogenesis [6,24,25]^[6][24][25]. Identified genes implicated in primary lymphedema include FLT-4, VEGFC, FOXC2, GJA1, PTPN14, SOX18, HGF, GJC2, GATA2, FAT4, CCBE1, ADAMTS3, and NEMO ^[1]. Specific molecular pathways implicated in the disease process include the PI3K/AKT, VEGF-C/VEGFR, RAS/MAPK, and HGF/MET pathways. The details of these mutations, their molecular pathways, and their clinical manifestations have been thoroughly described [6,26]^[6][26]. A full review of genetic mutations associated with syndromic lymphedema is reviewed by Pateva and Brouillard and is beyond the scope of this researticlech [6,21]^[6][21]. Genetic testing is indicated when patient history and physical exams are suggestive of an underlying syndrome. Current methods of genetic testing using blood or saliva are reported to have low efficacy in accurately diagnosing primary lymphedema ^[26]. These limitations are attributable to insufficient knowledge of the genetic basis of lymphedema resulting in a paucity of targets to specifically test. In tWhis context, whoole exome sequencing, when available, is becoming an increasingly popular option. In addition to its diagnostic functions, routine genetic analysis academically provides greater insight into genotypic variability and genotype-phenotype correlations ^[6]. Lymphedema is one of the multiple clinical features characteristic of numerous genetic syndromes, including Hennekam’s, Aagenaes’, microcephaly-chorioretinopathy-lymphedema, Mucke’s, Noonan syndrome, Turner’s, Prader–Willi, CHARGE, Irons–Bianchi, Emberger, oculo-dento-digital, Phelan–McDermid, and yellow nail syndrome [11,27]^[11][27]. We herein include a discussion on the most common genetic syndromes associated with lymphedema.

4.2. Milroy Disease

Milroy’s disease was first described by Dr. Milroy in 1892 as an inherited, congenital, nonprogressive lymphedema of the lower extremity [27,28]^[27][28]. Milroy’s disease is the most common hereditary form of primary lymphedema ^[29]. This syndrome is attributable to an autosomal dominant mutation of gene FLT4 on gene 5q35.3 which encodes for vascular endothelial growth factor receptor-3 protein (VEGFR-3). Penetrance is relatively low; approximately 50% of patients with the mutation do not have clinically detectable lymphedema ^[6]. This mutation disrupts the tyrosine kinase domain of VEGFR, which in rodents is reported to disrupt the growth and development of the lymphatic endothelial cells [29,30]^[29][30]. Vegfr3 heterozygous knockout mice develop a lymphedema phenotype secondary to aplastic lymphedema ^[31]. By contrast, in humans, Milroy’s disease is not associated with lymphatic aplasia but rather a functional failure: significant impairment of initial lymphatic absorption hypothesized to be attributable to poor endothelial junction flap valves and poor lymph transport associated with vessel hypoplasia [27,31]^[27][31]. These patients additionally have large superficial veins that have a propensity for reflux and valve failure ^[27]. Patients with Milroy disease present perinatally with bilateral lower extremity lymphedema, often associated with “woody” overlying skin and prominent veins. Lymphedema is typically confined to the feet and ankles, with slanting ‘ski-jump’ toenails due to the disease of the nail bed ^[11]. Diagnosis can be suspected as early as 12 weeks of gestation with ultrasound identification of pedal edema ^[27]. The term “Milroy disease” has erroneously been used as a ‘catch-all’ phrase to encompass all infants presenting with lymphedema present at birth or within the first year of life. The correct terminology refers to a familial form of primary lymphedema characterized by edemlower extremity edemasent at birth. Historically, patients required both a consistent phenotype and a positive family history to be diagnosed with Milroy’s; however, de novo mutations can occur in patients with no family history. Therefore, diagnostic criteria of Milroy’s disease now include infants diagnosed with lower extremity lymphedema with either a positive family history and/or documented FLT4 mutation [18,19,27]^[18][19][27]. Disease phenotypically consistent with Milroy’s but without a positive family history of FLT4 mutation should be termed “Milroy-like lymphedema” ^[11]. Based on these criteria, patients with involvement extending beyond the lower extremity, a delayed presentation, or a negative for a VEGFR-3 mutation should not be included in this diagnosis. Of note, not all patients presenting with a phenotype consistent with Milroy’s disease have a VEGFR3 disruption; one study identified that among these patients, the mutation was present in 72% with a positive family history and 64% without ^[27].

4.3. Meige Disease

First described in 1898, Meige disease was initially identified as familial lymphedema presenting in the lower extremity with onset during adolescence ^[32]. Over a century later, no genetic etiology underlying Meige disease has been identified; therefore, current recommendations suggest that a positive family history is necessary for this diagnosis [18,19]^[18][19]. The lymphatic system in these patients is reported to function at approximately 10% normal capacity ^[5]. Lymphedema is typically limited to below the knee, and Meige disease has no other associated features ^[11].

4.4. Distichiasis-Lymphedema

Distichiasis-lymphedema syndrome is a single-gene disorder with high penetrance and variable expressivity ^[27]. Over thirty FOXC2 mutations have been described as affiliated with distichiasis-lymphedema syndrome, and phenotypic expressivity is more common amongst female mutation carriers than males ^[33]. Mutation of the FOXC2 gene is associated with lymphedema in combination with distichiasis, defined as the presence of a second row of eyelashes emerging from the Meibomian glands. The lymphatic abnormality associated with this autosomal-dominant syndrome is typically hyperplasia ^[33] though others suggest this syndrome is more likely attributable to lymphatic and venous valve failure, a theory corroborated by lymphoscintigraphy and venous duplex ultrasound analysis ^[27]. Lymphedema presents in the bilateral lower limbs typically in adolescence, though manifestation at birth or in the fifth decade of life has also been described ^[10]. Distichiasis-lymphedema may be associated with congenital heart disease, pterygium, lid ptosis, cleft lip/palates, and/or venous malformations ^[33].

4.5. Turner Syndrome

Over 40% of children with Turner’s will have lymphedema at birth, most commonly affecting all four limbs distally ^[22]. Cervical lymphedema can contribute to a webbed neck and a low posterior hairline. Lymphedema in this patient population typically disappears by 2–3 years of age, although some patients see a recurrence in at least one limb at some point in their lives [23,34]^[23][34]. The lymphatic abnormality in Turner Syndrome is proposed to be due to a failure of lymphatic absorption at the distal level ^[34].

4.6. Noonan Syndrome

Noonan syndrome is an autosomal dominant genetic disorder commonly associated with the mutation of PTPN11. The syndrome is characterized by multiple congenital anomalies, including short stature, webbed neck, facial abnormalities, intellectual disabilities, and heart defects ^[33]. The development of lymphedema in association with Noonan syndrome is inconsistent ^[23]. Lymphangiectasia of the gastrointestinal tract and chylothorax has been described ^[5].

4.7. Hennekam Syndrome

Hennekam syndrome is due to mutation of CCBE1 (collagen and calcium binding EGF-domain 1) resulting in systemic marked lymphatic dysplasia. ^[5]. This syndrome is characterized by lower limb lymphedema and lymphangiectasia, facial anomalies (flat face, broad nasal bridge, and hypertelorism), and varying severities of mental retardation [11,33]^[11][33]. Lymphangiectasia may develop in the gastrointestinal tract, lungs, pleura, pericardium, thyroid, or kidneys ^[5]. Associated features may include hypothyroidism, glaucoma, seizures, hearing loss, and renal anomalies ^[11]. Patients typically have symptomatic improvements in their first year of life; then, the disease gradually progresses over time ^[5].