Primary Lymphoedema

PRIMER
Primary lymphoedema
Pascal Brouillard1, Marlys H. Witte 2, Robert P. Erickson3, Robert J. Damstra4,
Corinne Becker5, Isabelle Quéré 6 and Miikka Vikkula 1,7,8 ✉
Abstract | Lymphoedema is the swelling of one or several parts of the body owing to lymph
accumulation in the extracellular space. It is often chronic, worsens if untreated, predisposes
to infections and causes an important reduction in quality of life. Primary lymphoedema (PLE) is
thought to result from abnormal development and/or functioning of the lymphatic system, can
present in isolation or as part of a syndrome, and can be present at birth or develop later in life.
Mutations in numerous genes involved in the initial formation of lymphatic vessels (including
valves) as well as in the growth and expansion of the lymphatic system and associated pathways
have been identified in syndromic and non-syndromic forms of PLE. Thus, the current hypothesis
is that most cases of PLE have a genetic origin, although a causative mutation is identified in only
about one-third of affected individuals. Diagnosis relies on clinical presentation, imaging of the
structure and functionality of the lymphatics, and in genetic analyses. Management aims at
reducing or preventing swelling by compression therapy (with manual drainage, exercise
and compressive garments) and, in carefully selected cases, by various surgical techniques.
Individuals with PLE often have a reduced quality of life owing to the psychosocial and lifelong
management burden associated with their chronic condition. Improved understanding of
the underlying genetic origins of PLE will translate into more accurate diagnosis and prognosis
and personalized treatment.
Oedema is swelling due to the accumulation of fluid in Secondary lymphoedema is the most frequent subtype of
the interstitium and can involve all parts of the body. lymphoedema, with around 20% of women undergoing
Oedema is chronic when it lasts >3 months. The patho- breast cancer therapy that includes removal of lymph
physiological basis for oedema lies upon the forces nodes developing it4,9. A clinical approach directed
defined by the Starling law1 and includes filtration pres- towards (chronic) oedema should consider all (patho)
sure and a colloid osmotic pressure difference between physiological, environmental and personal factors
the interstitial fluid and capillary fluids. Oedema devel- influencing both lymphatic drainage and microvascular
ops under abnormal Starling forces, increased endothe- filtration10. A dedicated article on cancer-associated sec-
lial permeability (for example, due to inflammation) or ondary lymphoedema was recently published in Nature
impaired lymphatic drainage2. Recurrent comorbidities Reviews Disease Primers11.
include venous insufficiency, ulcers, infections (such as The focus of this Primer is on PLE, an umbrella term
cellulitis, a bacterial infection of the skin) and diabetes that covers all developmental lymphatic anomalies lead-
mellitus3,4. Risk factors include age, obesity and heart ing to a failure of the lymphatic system and swelling of
failure4. The careful diagnosis and understanding of the any part of the body (Fig. 1). PLE can be congenital or
cause of chronic oedema are important for the imple- develop later in life (at puberty or even beyond 50 years
mentation of a dedicated management protocol and of age). Diagnosis of PLE can be difficult and many indi-
treatment. Today, the term chronic oedema, which was viduals remain undiagnosed. There are no good inci-
first used for epidemiological purposes5, is used as an dence or prevalence estimates and even less so regarding
umbrella term for the broader understanding of the term geographical regions and ethnicities. LIMPRINT, an
lymphoedema and to cover complex cases of swelling6–8. international consortium, is trying to establish such
Historically, the term ‘primary lymphoedema’ (PLE) data12. In the USA, 165,000 lymphoedema-related admis-
was recognized in cases of anatomical or functional sions were recorded between 2012 and 2017 (ref.13). The
✉e-mail: miikka.vikkula@ developmental disorders of the lymphatic system, classification of PLE has long been based on the age of
uclouvain.be whereas ‘secondary lymphoedema’ occurs after the onset (congenital, early onset or late onset); however,
https://doi.org/10.1038/ destruction of initially normal lymphatics, for exam- with the discovery of underlying genetic causes, a gene
s41572-021-00309-7 ple, by infections (such as filariasis) or invasive surgery. and symptom-based classification has been proposed
NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:77 1
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Author addresses reported, variants in genes associated with NIHF may

also be associated with PLE, increasing further locus
1
Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium. heterogeneity behind PLE.
2
Department of Surgery, Neurosurgery, and Pediatrics, University of Arizona College of The prevalence of PLE has been estimated at 1.5 per
Medicine, Tucson, AZ, USA. 100,000 individuals in older studies26. However, this
3
Department of Pediatrics, University of Arizona College of Medicine, Tucson, AZ, USA.
figure was based on a retrospective study using the data-
4
VASCERN PPL European Reference Centre; Department of Dermatology, Phlebology
and Lymphology, Nij Smellinghe Hospital, Drachten, Netherlands. base of recorded diagnoses extrapolated to the popu
5
Lymphoedema Center, Clinique Jouvenet, Paris, France. lation and it most likely underestimates the prevalence of
6
Department of Vascular Medicine, Centre de référence des Maladies Lymphatiques et PLE. Recent large-scale estimates of the prevalence
Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, of chronic oedema (including PLE and secondary lym-
France. phoedema) in the South West London community vary
7
VASCERN VASCA European Reference Centre; Center for Vascular Anomalies, Division from a general prevalence of 1.33 per 1,000 people in
of Plastic Surgery, University Clinics Saint-Luc, University of Louvain, Brussels, Belgium. the population of the catchment area, increasing to
8
Walloon Excellence in Lifesciences and Biotechnology (WELBIO), de Duve Institute, 5.4 per 1,000 individuals aged >65 years and 10.3 per
University of Louvain, Brussels, Belgium. 1,000 individuals aged >85 years5. One study evaluated
a database of 9,477 patients with lymphoedema between
by the International Society of the Study of Vascular 1999 and 2010, of whom 138 had an age of onset of
Anomalies (ISSVA). We follow this classification, which <21 years (2.6% of the lymphoedema population)27.
is based on clinical and genetic findings. The newly Others described PLE as a predominantly paediatric dis-
suggested dyadic nomenclature associating gene name order affecting 1.2 per 100,000 people aged <20 years26.
with a phenotypic descriptor could provide a more pre- Clearly, better definitions and more accurate numbers
cise nomenclature (for example, VEGFR3 (encoded by are still missing.
FLT4)-related lymphoedema)14. An algorithm that helps One reason for the lack of precise epidemiology is
with diagnostic workup has also emerged (see Diagnosis, also the important heterogeneity in clinical presentation
screening and prevention)15. PLE often occurs isolated of lymphoedema (Tables 1,2). Moreover, each phenotype
but it can also be associated with a variety of additional is a rare disease, meaning that the prevalence is below
clinical features. As of December 2020, an OMIM query the threshold of 5 in 10,000. In addition, penetrance in
with the term “lymphedema” retrieved 94 entries, under- familial cases can be low, as is the case, for example, for
scoring the strong genetic influence. Current treatments mutations in VEGFC (encoding vascular endothelial
of PLE are often limited to alleviating symptoms or sur- growth factor C (VEGFC)) in Milroy-like disease, in
gery. Thus, there is an important need for improved which up to 50% of individuals carrying a mutation do
patient care. This need calls for a better understanding of not develop clinically detectable lymphoedema28.
the underlying causes of PLE to enable the development Some studies suggest that PLE is more frequent in
of novel treatments. women, for example, in families with a CELSR1 muta-
tion29. This observation suggests that hormonal differ-
Epidemiology ences may have a role. However, there might be other
Lymphoedema has been known since the middle of the biases, such as the often-referred fact that women
nineteenth century. Hereditary forms were first reported tend to be more prone to consulting clinicians than
by Nonne16 and Milroy17; these forms were congeni- men (owing to stronger societal pressure on physical
tal PLE. In 1898, Meige reported an inherited form of appearance) and/or that PLE is more severe in females
puberty-onset PLE. PLE associated with yellowing of the than in males. Imaging of the lymphatic system in rela
nails was reported in 1964 (ref.18). The cause of Meige tives in the same families who carry PLE mutations
disease and yellow nail syndrome still remain unknown19. sometimes unravels abnormal lymphatic vasculature
The first inherited mutations causing PLE were discov- also in mutation-carrier individuals who have not (yet)
ered for the so-called Nonne–Milroy disease in 2000 in developed lymphoedema30.
the FLT4 gene, encoding vascular endothelial growth Our current knowledge on the genetic variability
factor receptor 3 (VEGFR3), followed by the discovery among PLE remains limited. For about 70% of patients,
of many other mutations20,21. Altogether, 31 genes or loci an underlying genetic defect has not yet been discovered
have been reported to cause postnatal PLE with or with- but is probably present in many22,23 and most of the genes
out preceding non-immune hydrops fetalis (NIHF; with Mendelian mutations concern a limited number of
severe prenatal oedema) (Table 1) and 18 await further patients and families (only one or two patients or fami-
confirmation (Table 2). These genes or loci explain about lies have been reported for some genes, such as PTPN14
27% of PLE cases in one well-studied cohort22,23. Whether (ref.31), RELN32 or GJA1 (refs33,34)). Several of the genes
there are differences between ethnicities is unknown. have also been identified only recently, limiting epi
In some phenotypes, peripheral PLE is associated with demiological data. Moreover, in some conditions, such
central lymphatic defects otherwise called complicated as microcephaly with or without chorioretinopathy, lym-
lymphatic anomalies (CLAs)24. In addition to genes phoedema or mental retardation syndrome due to muta-
mutated in PLE, an increasing number of genes is asso- tions in KIF11, lymphoedema is not always present35.
ciated with NIHF25. NIHF is often recessive and can be This finding renders it difficult to have a representative
lethal. It can be observed in association with lysosomal and comprehensive overview of the current state of the
storage diseases, skeletal dysplasias, cardiac anoma- epidemiology of PLE as a whole and even more so for
lies and disorders of glycosylation. Although not yet each of the subtypes.
2 | Article citation ID: (2021) 7:77 www.nature.com/nrdp
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a b c d e for South African clinicians40. In Europe, expert refer-

ral centres have been nominated by health ministries
in different EU countries and networked under 24
European Reference Networks to gather the best exper-
tise and provide accessible cross-border health care. The
European Reference Network of Rare Vascular Diseases
(VASCERN) covers the working groups on primary
and paediatric lymphoedema (PPL-WG) and on vas-
cular anomalies (VASCA-WG). These working groups
define recommendations for diagnostics, prevention,
and treatment41 and can also endorse published national
guidelines42. An important patient/professional organi-
zation supporting the field is the Lymphatic Education
& Research Network, in addition to the longstanding
f g involvement and programmes of the International
h
Society of Lymphology (ISL), founded in 1966, and the
National Lymphedema Network, founded in 1987.
Mechanisms/pathophysiology
Lymphatic vessel malfunction
Normal lymphatic physiology. The lymphatic system is
a unidirectional vascular system that transports surplus
tissue fluid back to the blood circulation. The system is
composed of vascular conduits and lymphoid organs,
including the lymph nodes and cellular elements such
i j as lymphocytes and dendritic cells circulating in liquid
lymph. Lymph also contains ‘absorbents’ such as water
and chylomicra, which are lipoproteins formed in the
small intestine that transport dietary fats.
For lymphatic vessels to function effectively, lymph
— formed from blood capillary filtrate, cell products and
trafficking cells — must be absorbed from the interstit-
ium, carried through non-leaky, valveless initial lym-
phatics and pre-collectors, and propelled through patent,
intrinsically contractile, valved peripheral collecting
channels and interposed lymph nodes to finally reach
Fig. 1 | Examples of primary lymphoedema. Technetium (99mTc) albumin-aggregated the cisterna chyli (a dilated collecting structure) that
lymphoscintigraphy (LSG) of hands (top) and feet (bottom) of a healthy person as a
drains visceral lymph, including milky chylous intestinal
control (part a). Bilateral primary lymphoedema (PLE) in an individual carrying a VEGFR3
mutation, with visible large saphenous vein on top of the fascia (part b) and LSG showing lymph in the abdomen (Fig. 2). From there, lymph from
no uptake (part c). Familial hyperplastic refluxing PLE on lower extremities in an individual the lower part of the body finally arrives at the main
carrying a FOXC2 mutation (lymphoedema–distichiasis) (part d), with LSG showing thoracic duct. In addition, although with considerable
associated genital lymphoedema and irregular poorly transporting lymphatic collector variability in the topographical anatomy of these cen-
channels on the left, with extensive dermal and genital tracer reflux after bilateral tral lymph-collecting structures, a right lymphatic duct
foot injections (part e). Congenital PLE with lymphatic hyperplasia involving the also drains the lungs, heart and upper right quadrant
left lower extremity (part f), with LSG showing lymph stasis visible on left abnormal of the body. These collectors are joined by the bilateral
lymphatic nodes (blue arrows) and enlarged trunks (red arrows) as compared with cervical lymphatics draining lymph from the head and
normal right nodes and trunks (yellow arrows) (part g). Lympho-MRI showing central neck. Cervical lymphatics also drain lymph from the
conducting lymphatic anomalies with enlargement of the Cysterna chyli (green arrow)
specialized meningeal lymphatic system (which collects
and thoracic duct (red arrows), and large lymphatic anomalies on both sides of the upper
mediastinum and upper thorax (blue arrows) (part h) similar to those in part g. Examples interstitial, cerebrospinal and perivascular fluid from
of superficial lymphatic hyperplasia visualized by lympho-MRI (part i) and visualization of the brain) and the glymphatic drainage in the brain43,44.
superficial lymphatic network on the arm by injection of indocyanine green (part j). This central lymph then passes through bilateral valved
entries (lymphovenous valves) into the central venous
system to complete the ‘blood–lymph loop’ of the extra-
The European Commission stated that “rare diseases cellular fluid circulation45. Of note, the lymphatic chan-
are life-threatening or chronically debilitating diseases nel pathways are much more variable inter-individually
that are of such low prevalence that special combined than those of arteries or veins46–48.
efforts are needed to address them”36. The International The process of lymph formation (termed the lym-
Lymphoedema Framework considers lymphoedema as a phatic load) is governed by two gradients: the gradient
neglected health problem and has set up the LIMPRINT of hydrostatic pressure from fluid within the blood cap-
study12. Although predominantly studied in Caucasians, illaries, which forces fluid outward to the lower pres-
PLE has been reported in Asians37 and Africans38,39. sure of the interstitial fluid, and the inward gradient of
Guidelines for PLE care have also been established oncotic pressure due to plasma proteins and other large
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Table 1 | Confirmed lymphoedema genes and loci

Genea Locus Disease or syndrome Major associated signs OMIM Inheritance Protein functionb Refs
number
(Prader–Willi) 15q11.2 Prader–Willi Obesity, developmental 176270 AD NA 233
delay, short stature

(Aagenaes) 15q26.1 Cholestasis–lymphoedema Cholestasis 214900 AR NA 121
(TBX1?) 22q11.2 del 22q11 deletion Dysmorphism, 611867 De novo NA 120
cardiovascular anomalies
(Phelan– 22q13 del Phelan–McDermid Developmental delay, 606232 AD NA 168
McDermid) hypotonia
(Turner) Xp11.4/ Turner Cardiac anomalies, webbed NA De novo NA 114,133
Yp11.2 del neck, dysmorphism, slowed

growth
ABCC9 12p12.1 Cantu Hypertrichosis, osteochon- NA AR Anion transporter 234
drodysplasia, cardiomegaly
ADAMTS3 4q13.3 Hennekam lymphangiectasia– Dysmorphism, 618154 AR Extracellular 93,235
lymphoedema syndrome 3 protein-losing enteropathy enzyme

ANGPT2 8q23.1 Lymphoedema NA NA AD Ligand 23
CCBE1 18q21.32 Hennekam lymphangiectasia– Dysmorphism, 235510 AR Adaptor protein 236
lymphoedema syndrome 1 protein-losing enteropathy

CELSR1 22q13.31 Lymphoedema NA NA AD Transmembrane 104
EPHB4 7q22.1 Hydrops fetalis, central Hydrops fetalis 617300 AD Transmembrane 109,237
conducting lymphatic receptor

anomaly (HFASD)
FAT4 4q28.1 Hennekam lymphangiectasia– Dysmorphism, 616006 AR Transmembrane 238
lymphoedema syndrome 2 protein-losing enteropathy protein

FLT4 (VEGFR3) 5q35.3 Nonne–Milroy lymphoedema Hydrops fetalis 153100 AD, AR, Transmembrane 20,21
de novo receptor
FOXC2 16q24.1 Lymphoedema–distichiasis Distichiasis, ptosis, varicose 602402 AD, de novo Transcription factor 73
veins
GATA2 3q21.3 Emberger Myelodysplasia 614038 AD Transcription factor 171
GJC2 (Cx47) 1q42.13 Lymphoedema NA 613480 AD Connexin 108
IKBKG (NEMO) Xq28 Osteopetrosis with Dental anomalies, 300291 X-linked Intracellular 239,240
lymphoedema ectodermal dysplasia, signalling molecule

immunodeficiency
KIF11 10q23.33 Microcephaly with or Microcephaly with or 152950 AD, de novo Intracellular 241
without chorioretinopathy, without chorioretinopathy, signalling molecule

lymphoedema or mental mental retardation
retardation
KRAS 12p12.1 Noonan syndrome 3, Short stature, dysmorphism, 609942 AD, de novo Intracellular 242,243
Gorham–Stout disease cardiac anomaly, signalling molecule

developmental delay
NSD1 5q35.3 Sotos syndrome 1 Macrocephaly, rapid 117550 De novo Histone 244,245
growth, cardiac anomaly methyltransferase

PIEZO1 16q24.3 Hydrops fetalis, generalized Hydrops fetalis, short 616843 AR Ion channel 246,247
lymphatic dysplasia stature, facial dysmorphism

PTPN11 (SHP2) 12q24.13 Noonan syndrome 1, hydrops Short stature, dysmorphism, 163950 AD Intracellular 248
cardiac anomaly, signalling molecule

developmental delay
RAF1 3qp25.2 Noonan syndrome 5 Short stature, dysmorphism, 611553 AD Intracellular 249,250

developmental delay
RASA1 5q14.3 Parkes–Weber (CM-AVM1), Capillary and arteriovenous 139150 AD Intracellular 251,252,253
chylothorax malformations signalling molecule

RIT1 1q22 Noonan syndrome 8 Short stature, dysmorphism, 615355 AD Intracellular 254–257

developmental delay
SOS1 2p22.1 Noonan syndrome 4 Short stature, dysmorphism, 610733 AD Intracellular 258,259

developmental delay
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Table 1 (cont.) | Confirmed lymphoedema genes and loci

number
SOS2 14q31.1 Noonan syndrome 9 Short stature, dysmorphism, 616559 AD Intracellular 260–262

developmental delay
SOX18 20q13.33 Hypotrichosis–lymphoedema– Hypotrichosis, 607823, AD, AR, Transcription 228,263
telangiectasia–(renal defect) telangiectasia, ileal atresia, 137940 de novo factor

syndrome aortic dilation
THSD1 13q14.3 Hydrops, severe oedema Hydrops fetalis, cardiac NA AR Transmembrane 264,265
anomaly protein
TSC2 16p13.3 Tuberous sclerosis 2 Hamartomas, 191092 AD Intracellular 266,267
developmental delay signalling molecule

VEGFC 4q34.3 Nonne–Milroy-like NA 615907 AD Ligand 28,134,
lymphoedema 268–270
OMIM numbers are only provided if the description mentions a lymphatic defect. When a maximum of five publications exists for primary lymphoedema-causing
mutations in one gene, we listed them all; otherwise, if more than five, we listed only the original ones. AD, autosomal dominant; AR, autosomal recessive; CM-AVM1,
capillary malformation-arteriovenous malformation 1; NA, not applicable. aMutated genes and loci associated with postnatal primary lymphoedema with or without
non-immune hydrops fetalis with more than three index patients reported or, if only two index patients, supported by functional validation or linkage; in alphabetical
order. bSee signalling in Fig. 3.
molecules that cannot pass freely through the capillary lymphatic capillaries include alterations in initial inter-
barrier, which drives fluids towards the blood vessels and endothelial open ‘buttons’ (loosely apposed perme-
is therefore opposed by the hydrostatic pressure gradient. able junctions) and continuing closed impermeable
These so-called Starling forces and the lymphatic load ‘zipper’ junctions56 and related gap junction proteins,
are further modified by a filtration coefficient reflecting anchoring filaments45,49,50, tissue pressure mechanosen-
capillary surface area and permeability. Normally, in an sors (for example, Piezo-type mechanosensitive ion chan-
oedema-free state, the volume of the lymphatic load is nel component 1 (PIEZO1))57, and the newly described
matched by the lymphatic capacity (the rate of lymph hyaluronan bulbs58 (structures composed of a large matrix
adsorption) to return lymph to the bloodstream (nor- of glycosaminoglycan and integrins, which are involved
mal thoracic duct lymph flow is approximately 1 ml per in cellular migration into the lymphatics dependent
minute)45,49–52. There are regional variations in the abso- on lymphatic vessel endothelial hyaluranon receptor 1,
lute numerical value of the Starling forces and filtration Lyve1)59 (Fig. 2). Disturbances in lymphatic vessel growth
coefficient (for example, the tight relatively impermeable (either reduced growth (aplasia or hypoplasia), increased
blood–brain barrier in contrast to the low-hydrostatic size or number of the vessels (megalymphatics and
pressure, highly permeable liver sinusoids) under nor- hyperplasia, respectively), or growth in the wrong place,
mal physiological conditions, which may be greatly termed collectively as ‘lymphangiodysplasias’) could
exaggerated in disease states53,54. lead to or reflect anatomical or functional lymphatic
obstruction (peripheral and/or central). These abnor-
Pathophysiology of PLE. Congenital lymphatic mal- malities can be imaged dynamically most easily in PLE
formation or malfunction anywhere along these con- by whole-body lymphoscintigraphy (particularly when
tinuous pathways can be fatal during prenatal life or combined with resolution-enhanced and 3D-localized
delayed or even silent after birth, until it leads to an single-photon emission computed tomography (SPECT))
imbalance between the processes of lymph formation but also by other modalities such as MRI with or with-
(lymphatic load) and lymph absorption (lymphatic out contrast and indocyanine green (ICG) fluorescent
capacity)45,49–51 (Fig. 2). At that point, tissue swelling lymphangiography45,47–50,55,60–66. Lymphangiodysplasias
becomes manifest, presenting as PLE involving the can also be caused or exacerbated by maldeveloped,
limbs, chylous (chylomicra-containing intestinal lymph) hypoplastic or fibrotic regional lymph nodes67. Defective
or non-chylous lymph accumulations and/or effusions lymphatic valves45,48–50,55,60,68 can lead to valve incompe-
in the body cavities, as lymphostatic encephalopathy tence, lymphangiectatic dilatations and lymph reflux
from brain oedema33, or even as external leaks (in which into superficial valveless collaterals, tissues or body cav-
lymph exudates from the skin). Stasis of lymph (a high ities or as external leakage from the skin. Heightened
protein, hyaluronan-rich fluid-altering extracellular permeability can allow leakage from initial or collect-
matrix (ECM)) reflects diminished lymphatic capa ing lymphatics and impaired contractility45,48–50,55 would
city and sets into motion a localized tissue response. delay lymph transport. Specific transgenic mouse models
This response is characterized in varying degrees by closely mimic these contrasting clinical and lymphatic
inflammation, fibrosis, adipose deposition, immune imaging phenotypes (for example, lymphatic aplasia
dysregulation, susceptibility to infection, and both lym or hypoplasia in the angiopoietin 2 (Angpt2) knockout
phang iogenesis and haemangiogenesis as part of a mouse69 and refluxing lymphatic hyperplasia in the Foxc2
progressive ‘overgrowth’ phenomenon45,49–51,55. haploinsufficient mouse70).
At the absorptive level, aberrations that could inter- These pathogenetic mechanisms may stay latent and
fere with the relatively free passage of fluid and macro not manifest as tissue fluid accumulation and, moreover,
molecular and cellular lymph components into the they might affect other cardiovascular or general systemic
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Table 2 | Suggested lymphoedema genes

number
ARAF Xp11.3 Central conducting NA NA De novo Intracellular signalling 190
lymphatic anomaly molecule

B3GAT3 11q12.3 Linkeropathies Short stature, skeletal NA AR Extracellular enzyme 271
dysplasia, dysmorphism,
cardiac anomaly,
developmental delay
BRAF 7q34 Noonan syndrome 7 and Short stature, dysmorphism, 613706 AD Intracellular signalling 272,273
cardiofaciocutaneous cardiac anomaly, molecule

syndrome developmental delay
CBL 11q23.3 Noonan syndrome-like Short stature, dysmorphism, 613563 AD Intracellular signalling 274
disorder with or without cardiac anomaly, molecule

leukaemia developmental delay
FBXL7 5p15.1 Hennekam Dysmorphism, NA AR Ubiquitin protein ligase 275
protein-losing enteropathy complex subunit

GJA1 (CX43) 6q22.31 Oculodentodigital Microcephaly, hearing loss, 164202 AD Connexin 33,34
dysplasia dysmorphism
HGF 7q21.11 Lymphoedema NA NA AD Ligand 96,276
KLHL40 3p22 Hydrops fetalis Myopathy 615348 AR E3-ubiquitin ligase 277,278
MET 7q31 Lymphoedema NA NA AD Transmembrane receptor 96,276
NF1 17q11.2 Neurofibromatosis type 1 Cafe-au-lait spots 162200 AD Intracellular signalling 279
molecule
NRP1 10p11.22 Lymphoedema NA NA AD Transmembrane co-receptor 280
NRP2 2q33.3 Lymphoedema NA NA AD Transmembrane co-receptor 280
PTPN14 1q32.3–41 Choanal atresia and Choanal atresia 613611 AR Intracellular signalling 31
lymphoedema molecule
RELN 7q22.1 Lissencephaly 2 Lissencephaly 257320 AR Extracellular matrix protein 32
SEMA3A 7q21.1 Lymphoedema NA NA AD? Extracellular matrix protein 281
SHOC2 10q25.2 Noonan syndrome-like Short stature, dysmorphism, 607721 AD Intracellular signalling 282,283
disorder with loose cardiac anomaly, molecule

anagen hair 1 developmental delay
TIE1 1p34.2 Lymphoedema NA NA AD Transmembrane receptor 284
TSC1 9q34.13 Tuberous sclerosis 1 Hamartomas, 191100 AD Intracellular signalling 285,286
developmental delay molecule

OMIM numbers are only provided if the description mentions a lymphatic defect. When a maximum of five publications exists for primary lymphoedema
(PLE)-causing mutations in one gene, we listed them all; otherwise, if more than five, we listed only the original ones. AD, autosomal dominant; AR, autosomal
recessive; NA, not applicable. aGenes suggested on the basis of only one or two patients: rare cases of known syndrome with PLE or associations on the basis
of a limited number of suggestive variants. Some could have PLE by coincidence and/or another cause. These await confirmation by identification of additional
cases and/or functional validation; in alphabetical order. bSee signalling in Fig. 3.
developmental events, resulting in multiorgan syndromes and impact of specific functional abnormalities in the
or, in select instances, contributing to lymph over integrated lymphatic system of vessels, fluid, nodes and
production (overload), for example, by venous pressure trafficking of immune cells (lymphatic ‘systemomics’)71
elevation, further overwhelming the diminished lym- is particularly crucial to fill in the gaps in our under-
phatic capacity. Indeed, specific initiating mechanisms standing of uncomplicated PLE and of the pleiomor-
controlling lymphatic growth, specialized lymphatic phic manifestations in associated syndromes55,72 and to
structures, and cell migration and adhesion (at an anato translating the findings of experimental models into
mical, physiological or molecular level) have been pin- the management of the human condition.
pointed in some forms of PLE (see Genetic basis below).
These mechanisms have been observed in patients and/or Genetic basis
mouse models and further elucidated in vitro. However, Single genes. Our evolving knowledge of genes in which
exactly how lymph transport is affected and compensated mutations cause lymphoedema has depended on syner
for (at the peripheral, visceral and central lymphatic gistic findings in both human and mice. Zebrafish
system level) and what accounts for the variability in have more recently been studied and it is clear that the
manifesting lymphoedema (site, severity, age of onset) relative importance of the many shared essential gene
remains elusive. Current techniques for non-invasive products can differ between the three species. The
in vivo multimodal lymphatic imaging and histological first major discoveries were based on classical human
study of diseased lymphatics are limited in assessing lym- genetic approaches using linkage studies in large fam-
phodynamics. Yet, determining the sequence, interaction ilies to locate and clone genes involved in lymphatic
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development and function. Germline mutations in FLT4 endothelial cells, which are derived from embryonic
in Nonne–Milroy disease and FOXC2 in lymphoedema– veins, and assemble to form lymphatic capillaries77.
distichiasis (development of extra eyelashes) syndrome An alternative theory suggested that lymph sacs are
are early examples20,21,73 (Table 1). The finding of lym- derived from lymphangioblasts, that is, mesenchymal
phatic abnormalities in mice with mutations in Prox1, precursor cells independent of veins, in a process sim-
Angpt1 and Angpt2 led to the discovery of genes involved ilar to vasculogenesis78,79. In fact, lymphangiogenesis
in the early stages of lymphatic development. The many seems to be a combination of both. According to the
genes involved and their mechanisms of action have been second theory, lymphangioblasts, the first lymphatic
recently reviewed74–76. Overall, three patterns of inher- endothelial precursors, likely differentiate in part from
itance are observed in PLE, including autosomal domi- a subset of endothelial cells located in lateral regions
nant (including de novo mutations), autosomal recessive of the anterior cardinal vein and/or at least in part
and X-linked (Tables 1,2). PLE mutations affect proteins from undifferentiated mesenchymal cells in periph-
with various types of cellular function; most mutations eral tissues80. Lymphangioblasts sprout, migrate and
are loss-of-function, although some, such as in the genes proliferate to form lymph sacs. Centrifugal sprouting
associated with Noonan syndrome, are gain-of-function. from these sacs forms distinct lymphatic capillary
networks, which later merge to develop the primitive
Initiation of lymphatics. The first theory on lym- lymphatic capillary plexus81. The paraxial mesoderm
phangiogenesis proposed that primitive lymph sacs was also demonstrated as a major source of lymphatic
(primordial lymphatic vascular structures) arise from endothelium82.
Normal Hypoplasia Hyperplasia
R lymph
duct Thoracic Reduced
duct lymph
transport
Lymph
transport
Cisterna
chyli
Retrograde
Regional reflux
lymph Abnormal or
nodes absent valves,
Dermal
Lymph reflux and increased
transport diffusion contractility (?)
Reduced Reduced
number of lymph
Lymph valves and absorption
absorption contractility
Lymphatic nodes Lymph vessels Lymph Chylomicron
Fig. 2 | Schematic of the spectrum of pathological findings in PLEs. ligands or receptors (for example, mutations in the gene encoding VEGFR3),
Primary lymphoedema (PLE) can be classified into hypoplastic and which impair the growth of lymphatic channels and associated lymph nodes
hyperplastic forms on the basis of various lymphatic imaging modalities and and manifest as hypoplasia. The second type interferes with lymphatic valve
operative findings. On the left side of the hypoplastic and hyperplastic formation or function (for example, mutations in the gene encoding FOXC2)
examples are mild segmental forms and, on the right, more generalized and is associated with hyperplasia of lymphatic channels and nodes and
(systemic) forms. Individual patients may exhibit a single feature or retrograde lymph flow. Over time, as lymphoedema persists, additional
combinations of these findings. In general, pathogenetic gene variants, non-specific changes occur such as lymphatic and lymph node fibrosis or
exemplified by the two most common hereditary lymphoedemas, fall into obliteration, pericyte investment of lymphatic capillaries, and exuberant
two categories. The first involves deficiencies of lymphatic growth factor lymphangiogenesis.
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Valves Valves Proteoglycans, Valves

B3GAT3
extracellular
ADAMTS3 matrix
RELN
CCBE1 THSD1
SEMA3A
HGF ANGPT2 VEGFC
CX43
TIE2 TIE1 VEGFR3
EPHB4 MET FAT4 Extracellular
NRP2 NRP1
Intracellular
CBL CBL
CX47
RASA1 PTPN11 KIF11 PTPN14
PIEZO1
PI3K FBXL7
SOS1 SOS2 ABCC9 CELSR1
PTEN
KLHL40
NF1 RIT1 KRAS NRAS AKT proteins
Ubiquitination
SHOC2
Chromosomal loci associated with PLE

TSC1 IKBKG 15q11.2 — Prader–Willi
ARAF RAF1 BRAF
TSC2 15q26.1 — Aagenaes
22q11.2 del — TBX1?
MEK proteins 22q13 del — Phelan–McDermid
RHEB NF-κB proteins Xp11.4/Yp11.2 del — Turner
MAPK1 MAPK3
mTOR
Proliferation Survival
Nucleus GATA FOXC2 FOXC2 LEC and valves
NSD1
ETS proteins NF-κB proteins GATA2 FOXC2 SOX18 PROX1 PROX1 FLT4
Histone
Confirmed CLAs only Needs further confirmation Not mutated but links elements
Fig. 3 | Loci, genes and proteins associated with PLE. The core of the lymphatic pathway is constituted by the VEGFC–
VEGFR3 axis, but additional ligand–receptor signalling pathways emerge, including ANGPT2–TIE1 or ANGPT2–TIE2 and
HGF–MET. Phenotypes with a mutation in one of the proteins of the RAS pathway constitute the RASopathies. Genes and
proteins in orange have been confirmed to be associated with primary lymphoedema (PLE), whereas those in green need
to be confirmed in additional patients or by functional validation of the variants. Genes associated with complicated
lymphatic anomalies (CLAs) are in yellow; most variations in these are somatic or mosaic but KRAS mutations are also
germline in PLE (Noonan) and a germline PTEN mutation was reported once in Gorham–Stout disease. Accessory proteins
not known to be mutated in PLE but part of the pathways are in grey. Dashed lines indicate protein transfer or secretion or
indirect inhibition. LEC, lymphatic endothelial cell.
There are multiple genes involved in the early devel- encoding the corresponding human proteins cause
opment of the lymphatics, mainly studied in mice and lymphoedema-associated syndromes in patients;
zebrafish, and some of these genes have been found to Table 2 ), receptors, cell cycle regulators, and adhe-
be implicated in human lymphatic disease; not surpris- sion factors (their complex interactions will be further
ingly, some of them are also involved in vasculogene- described and are illustrated in Fig. 3)89. The ECM com-
sis. The first human lymphatic-specific markers were position also has an important role and can regulate
VEGFR3 (ref.83), LYVE1 (ref.84) and podoplanin85. The transcription factor activity90.
discovery of prospero homeobox protein 1 (PROX1)86 Besides signalling molecules, membranous receptors
provided the earliest expressed marker for early lym- and transcription factors, other bioactive molecules,
phatic development. Its absence prevented lymphatic such as retinol for lymphatic maturation, are essential91.
endothelial cell (LEC) development, which instead ECM components, such as SVEP1 (also known as poly-
became blood endothelium and resulted in only a dom), also have a role92. Hennekam lymphangiectasia
blood vascular phenotype. Its continuous expression is (abnormal dilation of lymphatic vessels)–lymphoedema
required to maintain the LEC phenotype87. The upregu syndrome is caused by mutations in multiple genes, such
lation of Prox1 (reviewed in ref.88) induced many LEC as those encoding the ECM-binding protein CCBE1,
markers such as podoplanin and VEGFR3, many tran- ADAMTS3 (an enzyme that cooperates with CCBE1
scription factors (especially FOXC2 but also IKBKG, to cleave and activate VEGFC) and FAT4 (a membrane
GATA2, SOX18 and KIF11; mutations in the genes protein likely to be involved in cell polarity)93,94.
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Rare mutations in VEGFC, the major stimulator of Cx43 and Cx47 (refs105–107). Knockouts of Cx37 and
lymphatic growth and development, also cause lym- Cx43 disrupt lymphatic valve development and result in
phoedema28. Its receptor, VEGFR3, is a tyrosine kinase embryonic lymphoedema and chylothorax with mark-
receptor initiating PI3K–AKT signalling and the inter- edly reduced postnatal survival105. Two GJC2 mutations
acting RAS–MAPK cascade. Inactivating mutations in were initially reported in two families with dominantly
VEGFR3 are a cause of Nonne–Milroy disease (familial inherited lymphoedema108, followed by other families
congenital bilateral lower-limb lymphoedema, the most and one family with a mutation in GJA1 (encoding
frequently found genetic cause of lymphoedema)20,21 Cx43)33. In addition, mutations in EPHB4, encoding a
(Fig. 3; Table 2). Mutations in the genes encoding many member of the ephrin family of RTK receptors, which
components of these intracellular signalling pathways are interact with connexins, have been found in cases of fatal
associated with phenotypes exhibiting lymphoedema, NIHF109 (Fig. 3).
including Noonan syndrome, cardiofaciocutaneous
syndrome, lymphoedema–choanal atresia syndrome Expansion and proliferation of lymphatics. After the
and rare cases of chylothorax (thoracic duct damage initiation of lymphangiogenesis, laminar fluid flow
with chyle leakage surrounding the lungs) (see Signalling and interstitial pressure trigger lymphatic expansion and
pathways below; Fig. 3; Tables 1,2). Mutations in some of proliferation, at least in vitro. LECs exposed to laminar
these genes can serve as modifying genes; for example, fluid flow stimulate a pore subunit of the s-activated
mutations in GJC2 (encoding connexin 47) may inter- calcium channel (ORAI1), which induces the upreg-
act with non-genetic factors to cause post-breast surgery ulation of Kruppel-like factor 2 (KLF2) and KLF4 and
lymphoedema95 or be causative in PLE96. induces the expression of VEGFA, VEGFC, fibroblast
growth factor receptor 3 (FGFR3), and p57 (also known
Lymphatic valve formation. In general, mutations in as cyclin-dependent kinase inhibitor 1C)110. As with most
genes related to defective valve formation tend to pro- of the genes mentioned in initiating the development of
duce lymphatic hyperplasia or lymphangiectasia and lymphatics (excluding VEGFC and VEGFR3), mutations
lymph reflux. By contrast, genes involved in the initia- in these genes causing human lymphoedema have not yet
tion (above) or maintenance and proliferation (below) been found. However, recessive mutations in PIEZO1 are
of lymphatics produce PLE with lymphatic hypoplasia associated with human lymphoedema98. In addition, in a
or aplasia in the periphery and even centrally. The large multigeneration family with highly penetrant lym-
left-sided lymphovenous valve (and the frequent second phoedema, digenic inheritance has been documented
right-sided lymphovenous valve) connecting the tho- with both FOXC2 and biallelic PIEZO1 mutations111.
racic duct (which is the central lymphatic collector) Gap junction (connexin) proteins are not only
to the central vein is the only place (other than the involved in valve formation (Cx37 and Cx47) but are
much smaller right lymphatic duct valved entry) where important for the function of lymphatics (Cx26) as they
the post nodal lymph fluid and blood normally come control the flow of fluid containing small and larger
into contact. This may be the first ‘lymphatic’ valve to molecules between cells, which may be their role in valve
develop. The mechanotransducer PIEZO1 senses the formation. It is the leaked fluid from the blood vascular
laminar flow of lymphatic fluid and this detection is a system that the lymphatics return to the blood circula-
major stimulus to valve formation97. Recessive mutations tion112. Gap junctions are also important in coordinating
in PIEZO1 are associated with human lymphoedema98. smooth muscle-mediated contractility, which propels
The precursor cells also require transcription factor lymphatic fluid centripetally105,106,113.
SOX18, NRF2, Coup transcription factor 2 and PROX1.
These lymphovenous valves continue to develop with Chromosomal loci associated with PLE. Several chro-
FOXC2 as the major activator99 for valve development, mosomal disorders are associated with lymphoedema
with planar cell polarity gene products and connexins in (Table 1). Turner syndrome (45,XO) frequently has infan-
their maturation100–102. tile generalized lymphoedema (before the chromosomal
Planar cell polarity refers to the coordinated orienta- cause was discovered, it was considered a separate syn-
tion of cells in epithelia in the direction perpendicular drome, known as Bonnevie–Ullrich) and can re-occur
to the apical-basal orientation and is essential for cell in children and adults. Although an X-chromosomal
orientation. In mice, two chemically induced, nonsense p11.4 location shared with Yp11.2 has been identified,
mutations in Celsr1 were found to affect planar cell a specific gene has not been pinpointed114,115. Moreover,
polarity (spin cycle and crash mouse mutants). These trisomy 21 (and the rarer trisomies 13 and 18) is fre-
two mutants and a conditional deletion of Celsr1, using a quently associated with increased nuchal folds detected
Prox1 promoter to specifically delete Celsr1 in endothe- in utero by ultrasonography (posterior lateral neck swell-
lial cells of developing lymphatics, allowed study of the ings thought to be related to enlargement of the cervical
role of CELSR1 in later development103; it was shown, lymphatic sacs)116. Old case reports based on classical
with VANGL2, to have a crucial role in lymphatic valve karyotyping associated mosaic trisomies or intersti-
formation103. Families with lymphoedema due to muta- tial deletions and duplications to nuchal translucency
tions in the planar polarity gene CELSR1 have been or PLE117–119. The cause of these phenotypes could be
described29,104. a mutation in one of the now known genes) localized
Gap junction molecules (connexins) are also impor- in these regions (Tables 1,2). The frequently diagnosed
tant for lymphatic development and three have been Prader–Willi syndrome, which involves abnormal
found to be expressed in most lymphatic vessels: Cx37, imprinting of a portion of chromosome 15 caused by
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gene or chromosomal mutations, often presents with Recently, loss-of-function or dominant-negative

lymphoedema along with other syndromic features55. mutations were identified in ANGPT2 in PLE23.
Additional loci include the locus of the Phelan– Mutations in many genes of the RAF–MEK–ERK
McDermid syndrome (22q13), the 22q11.2 deletion — MAPK cascade cause lymphoedema-associated syn-
syndrome locus120 and the locus for the Aagenaes syndromes. In mice, another pathway dependent on MAPK
drome (15q26.1)121. As the incidence of lymphoedema that is associated with lymphatic problems is the ternary
in various syndromes is unknown and case reports are complex factors pathway, which regulates immediate early
scarce, epidemiological studies are needed. genes through serum response elements. The knockout
of the gene encoding one of these factors, Net, results in
Signalling pathways lymphovascular defects, including chylothorax128, but
Lymphangiogenesis. In addition to the proteins and PLE-causing mutations in the corresponding human gene
signalling pathways implicated in human disease dis- are not known. Finally, hepatocyte growth factor (HGF)
cussed above, there are many other signalling pathways and its tyrosine kinase-activating receptor MET promote
involved in lymphatic development and function122. lymphatic vessel formation and function129 (Fig. 3).
These pathways control cell growth and proliferation,
apoptosis, cell migration and differentiation, and cell Overgrowth syndromes involving the lymphatics. A
adhesion. As mentioned, VEGFC is essential for the limited number of overgrowth syndromes involve the
initial development and maintenance of lymphatics, lymphatics. These syndromes can be quite disfigur-
whereas VEGFD, which stimulates adult lymphangio ing and, because germline mutations would be lethal,
genesis by binding to VEGFR3, is not essential123, at are due to somatic mutations. The famous case of the
least in mice. The levels of VEGFR3 are strongly con- ‘Elephant Man’ involved an individual who was long
trolled by Notch signalling124. VEGFC stimulation thought to have neurofibromatosis type 1, whereas
results in receptor phosphorylation and downstream almost certainly he had Proteus syndrome, which is
activation of multiple signalling pathways, which stim- due to somatic, gain-of-function mutations in AKT1.
ulate LEC proliferation and migration. Ephrin B2 sig- The protein product of this gene, RAC-α serine/
nalling at its tyrosine kinase-activating receptor, ephrin threonine-protein kinase (AKT1), is involved in a sig-
type B receptor 4 (EPHB4), is also essential for lym- nalling pathway involving several genes implicated in
phatic development (Fig. 3). This signalling pathway is lymphatic malformations. PIK3CA produces phos-
unusual in that it involves ‘reverse signalling’, in which phatidylinositol 4,5-bisphosphate 3-kinase catalytic
the ligand (ephrin) also functions as a receptor in the subunit-α isoform, which can be dephosphorylated by
cell expressing it. This dual ligand–receptor function of PTEN. This dephosphorylation decreases PI3K con-
the membrane protein mediates bi-directional signals centrations and prevents it from translocating AKT1 to
between neighbouring cells; thus, intracellular signal- the cell membrane, where AKT1 is phosphorylated and
ling is induced in both cells (forward (in the neigh- activated by upstream kinases. PTEN loss-of-function
bouring cell) and reverse (in the ligand-expressing mutations cause PTEN hamartoma tumour syndrome,
cell)). The reverse signalling is essential for lymphatic whereas somatic gain-of-function mutations in PIK3CA
remodelling and valve formation125. The ephrin signal- are found in CLOVES syndrome, characterized by
ling pathway as well as VEGFC and VEGFD signalling congenital lymphatic overgrowth, vascular malforma-
through neuropilins provide a connection between tions, epidermal nevi and skeletal abnormalities, and in
lymphatic network patterning and that of neurons. Klippel–Trenaunay–Weber syndrome of bone and angio
Vascular growth factors are secreted by neurons and lymphatic overgrowth as well as in isolated lymphatic
neurotropins are secreted by developing vessels, ena- malformations55,76,130. Other PIK3CA-related overgrowth
bling co-tracking of the development of both systems. syndromes that may be associated with lymphatic
Other signalling molecules, including semaphorins and anomalies also exist130.
Slits as well as their receptors plexin and roundabout In conclusion, our understanding of the pathophys-
homologue (Robo), also connect the two guidance iological mechanisms underlying PLE is incomplete.
pathways126. Their full role is beyond this Review but Nonetheless, molecular discoveries over the past two
well covered in ref.126. decades have identified multiple genes, proteins and
Another signalling pathway important for lymphatic signalling pathways involved in lymphatic growth
development is that of the ANGPT1 and ANGPT2 and development, with these findings providing funda
ligands and the tyrosine-protein kinase receptors TIE1 mental insights into PLE (Fig. 3). Further lymphatic
and TIE2. The two tyrosine kinase receptors are differ- imaging, particularly dynamic studies since the 1970s
entially activated by the two angiopoietins. ANGPT1 documenting the various peripheral and central lym-
activates TIE2, whereas ANGPT2 activates TIE2 only phatic system disturbances in PLE, has served to con-
on LECs and blocks the activation of TIE2 on angiogenic nect the proposed molecular events with physiological
blood endothelial cells because an inhibiting vascular evidence of lymphatic maldevelopment and dysfunc-
endothelial protein tyrosine phosphatase (VEPTP) is tion manifested in the clinical appearance and compli-
expressed in blood endothelial cells but not LECs127. cations of PLE. Opposite pathophysiological pathways
Knockout mouse models demonstrate that ANGPT2 are reflected in the hypoplastic form (inadequate peri
is required for haemangiogenesis and lymphangio- pheral lymphatic growth) and hyperplastic refluxing
genesis, with the lymphatic defects being corrected by form (defective lymphatic valve formation and central
the expression of ANGPT1 instead of ANGPT2 (ref.69). lymphatic malformation) of PLE depicted in Fig. 2.
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Diagnosis, screening and prevention than the lymphoedema. These conditions are rare and
Diagnosis require a dedicated multidisciplinary workup. The
PLE is often diagnosed on the basis of a clinical exami- European Reference Networks are established to provide
nation. When swelling of the limbs and external genitals cross-border health care for all EU citizens regarding
are found congenitally, in children or adolescents, with rare and complex disease conditions.
or without a syndrome, an anomalous lymphatic devel- Patients with PLE are reported all over the world.
opmental disorder or syndrome should be considered In tropical countries, where filariasis and podoconiosis
(Fig. 4; Table 1). Signs and symptoms in different organs (which is caused by chronic exposure to volcanic red
give clues to the diagnosis. Lymphoedema swelling can clay soil) are the major causes of lymphoedema, PLE is
be mild to severe; worsen, fluctuate or improve with probably often diagnosed as secondary lymphoedema.
time; affect different parts of the body (limbs, arms, In developed countries, diagnosing PLE is becoming
hands, head and neck, abdomen, etc.); be unilateral less ambiguous, allowing preliminary statistics of inci-
or bilateral; and present at different ages of onset even dence and prevalence. Swelling of a limb in children is
in adults. Lymphoedema leads to tissue changes such rare and requires specialized diagnosis. In one study,
as an increase in fat or fibrosis over time. This obser- among 170 individuals aged <20 years referred under
vation explains why the pitting oedema clinical test the diagnosis of lymphoedema, 25% had other diagnoses
(indentation from pressure applied with the thumb on such as lymphovascular malformation, lipofibromatosis
a small area of the skin that persists after release of the or lipoedema131.
pressure), which indicates the presence of interstitial
oedema if positive, can be negative. The International Testing functionality of the lymphatics
Society of Lymphology has defined four clinical stages Isotopic lymphoscintigraphy has been used for >50 years
for lymphoedema60 (Box 1). and follows the migration of an isotopic tracer along the
Multiple PLE phenotypes are possible, related to the lymphatic vasculature after an interstitial injection132.
organs affected by the failure of the lymphatic system Abnormal findings include delayed transit time of the
such as lung effusions, intestinal lymphangiectasias radiolabelled colloid to the regional lymph nodes, der-
(overt proliferation of lymphatic vessels) with chylous mal backflow (accumulation of tracer in cutaneous
ascites and numerous embryonic oedemas under the lymphatics), asymmetrical node uptake, formation
term NIHF. It can be part of a complex syndrome, in of collateral lymphatic channels, and tracer uptake in
which other signs concern the patient and family more deep lymph nodes in the elbow or knee region, which is
Ophthalmic Psychological and neurological

• Distichiasis • Lymphostatic encephalopathy
• Ptosis • Microcephaly or macrocephaly
• Chorioretinopathy • Intellectual disability
Cardiovacular
Head and neck • Chylopericardium
• Dysmorphism • Congenital heart disease
• Hypertelorism • Venous valvular insufficiency
• Webbed neck
Chest
• Hydrops fetalis
Cutaneous • Chylothorax
• Café-au-lait lesions • Non-chylous effusions
• Hypertrichosis or hypotrichosis • Respiratory failure
• Vascular lesions • Chyloptysis
Limbs
Abdominal and gastrointestinal • Elephantiasis
• Chylous acites • Varicose veins
• Protein-losing enteropathy
• Malnutrition Haematological
• Obesity • Immunodeficiency
• Myelodysplastic syndrome
• Stomatocytosis
Musculoskeletal
• Skeletal deformities Genitourinary
• Short stature • Chyluria
• Limb overgrowth • Hydrocele
• Myopathy • Chyloscrotum
• Hypotonia • Genital lymphorrhoea
Fig. 4 | Recurrent manifestations associated with rare syndromic PLEs. The most frequently associated signs and
symptoms of primary lymphoedema (PLE) are regrouped by organs and anatomical localization. See text for details
and Tables 1 and 2 as well as ref.72.
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pathological. The spatial resolution of scintigraphy is Genetic analyses

poor and has been improved using simultaneous ana- Genetic testing is being used as part of the clinical
tomical localization by SPECT–CT. The isotopic lym- workup in highly specialized centres managing patients
phoscintigraphy patterns of gene-related PLE vary, with lymphatic anomalies, especially for familial cases. In
from no intake in VEGFR3-related PLE to intake into genetic centres, most often, next-generation sequencing
large and numerous collateral lymphatics with dermal techniques are used to screen blood-derived DNA using
backflow in FOXC2-related PLE33,65,109,133–135. ICG fluor gene panels. However, with a growing number of known
escence lymphography is used to evaluate the real-time genes related to PLE to be tested, whole-exome sequenc-
transport of a fluorescent tracer in the lymphatic vessels ing is becoming the best option. Chromosome analysis
in the upper dermal space up to a maximum depth of can be performed in detecting some syndromic PLEs.
3–5 mm (ref.136). Tissue culture from affected tissue and next-generation
sequencing can be helpful in finding somatic mutations
Imaging the lymphatics but, so far, in most of the patients with PLE in whom a
Nowadays, non-contrast magnetic resonance lym- causative mutation has been identified, the mutations
phangiography (MRL; also known as lympho-MRI)25 is were germline (inherited or de novo). Yet, many patients
a non-invasive technique that enables visualization of remain undiagnosed and untested as they do not consult
slow-moving non-bloody fluids such as those in large a specialized centre. Genetic testing increases our knowl-
lymphatic vessels. It is based on heavily T2 weighted fast edge on phenotypic variability and genotype–phenotype
spin-echo sequences and maximum intensity projection correlations, enabling more specific genetic counselling
reconstruction (Fig. 1). MRL has enabled the classifica- as well as better stratification into subphenotypes and
tion of the lymphatic system abnormalities in primary patient information.
lymphoedema, considering lymph nodes and lymphatic
vessel involvement137. Dynamic contrast-enhanced MRL Classification of lymphatic anomalies
enables static and dynamic visualization of the central A diagnostic algorithm based on detailed phenotyping,
lymphatic system by injecting gadolinium contrast agent family history, age at onset, localization of the affected
in the groin lymph nodes in patients with PLE and/or lymphatics, presence of visceral involvement, diag-
CLA138 or intrahepatic lymphatic anomalies139. This nosis of concomitant syndromes and genotyping has
technique enables understanding of the lymphatic flow been established15. We propose here a revised classifi-
disorders before planning interventional procedures140; cation of lymphatic anomalies (Fig. 5). This classifica-
however, it is not widely available. tion, although not complete as the field evolves rapidly,
Pedal lymphangiography imaging using oil-based allows stratification of patients into main subcategories
iodinated agents injected into the lymphatic vessels, and considers the evolution of phenotypes in time (more
which were dissected and cannulated, was developed for signs become apparent with age). It also clearly links
surgical purposes and used for the anatomical classifica- CLAs and lymphatic malformations to the diagnostic
tion of PLE141 but has been abandoned because of its vis- workup. Eventually, this approach can have therapeu-
cosity and side effects. Lymphangiography based on the tic consequences and can prevent unnecessary (inva-
puncture of lymph nodes in the groin is now preferred sive) diagnostic measures143. Genetic data allow further
to injection in the feet for the visualization of the central refinement of this algorithm.
lymphatic conducting vessels in adults and children142.
Screening
Box 1 | The four clinical stages for lymphoedema as defined by the Screening for patients who are at risk of developing
International Society of Lymphology PLE is difficult in terms of selection. Three groups
are at risk: relatives of a patient known to have PLE,
A limb may exhibit more than one stage, which may reflect alterations in different patients with one of the syndromes associated with
lymphatic territories.
PLE but without clinical signs or symptoms of PLE,
Stage 0 (or Ia) and patients who develop erysipelas (an infection of
Latent or sub-clinical condition in which swelling is not yet evident despite impaired the superficial layers of the skin) without any preceding
lymph transport, subtle alterations in tissue fluid and/or composition, and changes signs of chronic oedema, chronic venous insufficiency,
in subjective symptoms. It may exist months or years before overt oedema occurs.
lymphoedema, diabetes mellitus, overweight or previ-
This assessment requires imaging techniques.
ous bouts of erysipelas144. There are no guidelines on
Stage I pre-symptomatic screening and we lack estimations for
Early accumulation of fluid relatively high in protein content (for example, compared the risk of developing PLE.
with venous oedema) that subsides with limb elevation. Pitting may occur. An increase
When a patient is diagnosed with a gene defect caus-
in various types of proliferating cells may also be observed.
ing lymphoedema, the possibility for family screening can
Stage II be offered. Full information for the patient and consider
Limb elevation alone rarely reduces the tissue swelling and pitting is manifest. Later in ation of the advantages and disadvantages are needed
stage II, the limb may not pit, as excess subcutaneous fat and fibrosis develop. for shared decision-making. Owing to variable pene-
Stage III trance, the lymphoedema can be mild or even absent,
Comprises lymphostatic elephantiasis (enlargement of the limbs) in which pitting can which influences the relevance of screening for relatives.
be absent and trophic skin changes, such as acanthosis (overgrowth of the keratinocyte Despite all developments in the field of genetics and
layer of the skin), alterations in skin character and thickness, further deposition of fat sophisticated techniques to visualize the anatomy
and fibrosis, and warty overgrowths, have developed.
and function of lymphatics, the role of clinicians within an
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Lymphatic anomaly
Lymphoedema Lymphatic malformation
Lymphatic or vascular anomalies
With associated signs or With visceral involvement With associated

symptoms in other organs signs or symptoms
in other organs
Over Over
Isolated primary time Syndromic time Complex or complicated Isolated or combined with Syndromic
lymphoedema lymphoedema lymphatic anomaly vascular malformations
• Primary lymphoedema
and distichiasis • Central conducting lymphatic • Lymphatic malformation
• Hennekam syndrome anomaly • Lymphatic–venous
• Hydrops fetalis • HLTS • Generalized lymphatic dysplasia malformation
• Congenital • MCLMR • Intestinal lymphangiectasia • Capillary–lymphatic–venous • CLOVES
• Early onset • Noonan syndrome • Generalized lymphatic anomaly malformation • Klippel–Trenaunay
• Puberty onset • Parkes–Weber • Gorham–Stout disease • Capillary–lymphatic syndrome
• Late onset • Others • Kaposiform lymphangiomatosis malformation • PROS
Fig. 5 | Proposed classification of lymphatic anomaly phenotypes. This effusions and intestinal lymphangiectasias (see Box 2 for genes). Lymphatic
practical algorithm allows the stratification of patients into main lesions that are more localized are defined as lymphatic malformations
subcategories and considers the evolution of phenotypes in time (more and, in these conditions, lymphoedema is rarely present. As phenotypes
signs become apparent with age). It also clearly links complicated evolve postnatally, a diagnosis may move from isolated PLE or complex or
lymphatic anomalies and lymphatic malformations to the diagnostic complicated lymphatic anomalies towards syndromic lymphoedema.
workup. Isolated primary lymphoedema (PLE) can have different time Diagnostic terms are those used by ISSVA (International Society for the
points of symptom onset; in isolated PLE, only peripheral lymphoedema Study of Vascular Anomalies). CLOVES, congenital lipomatous overgrowth
(with or without varicose veins) is present. If signs or symptoms occur in with vascular malformation, epidermal nevi and scoliosis syndrome; HLTS,
other organs, diagnosis is more likely to be a lymphoedema-related hypotrichosis–lymphoedema–telangiectasia syndrome; MCLMR,
syndrome (see Table 1 for genes). Complex or complicated lymphatic microcephaly with or without chorioretinopathy, lymphoedema or mental
anomalies include phenotypes in which lymph and/or chyle accumulate retardation; PROS, PIK3CA-related overgrowth syndrome. Adapted from
centrally in the trunk, including, for example, chylous ascites, pleural ref.15, CC BY 4.0.
interdisciplinary expert team is crucial for meticulous to minimize the negative impact of the disease, improve
phenotyping, selection of diagnostic tools and use of function and prevent complications. No study has been
genetic techniques145. performed for PLE only.
Patients experiencing one episode of erysipelas of the The interventional parts of secondary and tertiary
leg, which presented without warning signs and without prevention have many elements in common, including
signs of previous lymphoedema, frequently (79%) show staying active and maintaining a healthy lifestyle with
lymphatic impairment of both legs by scintigraphy30,146. enough physical exercise147–149, preventing obesity at all
In daily practice, bilateral scintigraphy can be useful to ages150,151 and preventing erysipelas3. In secondary pre-
confirm lymphatic impairment. vention, clinimetrics (indexes, rating scales and other
expressions used to describe or measure symptoms,
Prevention physical signs and other clinical phenomena) for lifestyle
Preventive medicine is often used in chronic conditions (for example, pedometer, weight control) are performed
in which an overall cure is not possible. Three catego- by the patients themselves and there is no concomitant
ries are recognized: primary prevention, focusing on treatment related to lymphatic vascular diseases. In ter-
preventing the disease in the general population; sec- tiary prevention, intervention is part of the treatment
ondary prevention, intended for those with risk factors protocol for PLE and is monitored with clinimetrics
but clinical signs or symptoms not yet observed; and ter- in the International Classification of Functioning,
tiary prevention, which is part of the treatment of active Disability and Health (ICF) domains131,152.
disease. The interventions used for these three types of
prevention differ. Management
For relatives of patients with PLE who carry the gene Non-invasive medical and conservative management
defect but are asymptomatic, secondary prevention can Long-term management in all patients aims to min-
be relevant to prevent lymphoedema. Genetic testing imize the negative impact of the disease, improve
can give a decisive answer about the risk in such cases. function, and prevent short-term and long-term com-
When symptoms of PLE are present, tertiary prevention plications. Considering that PLE is a rare and chronic
is important to support treatment regimens and to try condition, attention is also paid to holistic management
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and long-term patient self-management. From a thera- As an example, swelling of the VEGFR3-associated
peutic perspective, much research has focused on breast Nonne–Milroy disease remains localized under the
cancer-related secondary lymphoedema. These recom- knees, mainly involving the forefoot, toes, ankles and
mendations include wearing garments, skincare, and pre- the leg under the knee. Care focuses on distal bandages,
venting personal factors that may mistakenly consider skin moisturization, and prevention of ingrowing nails
lymphoedema as weight gain or obesity153–155 or due to and related infections. The end of uncertainty about the
the lack of physical activity149,150. Although not studied for future for these patients positively affects their quality
PLE, these factors can be extrapolated to be relevant of life.
for PLE. To further increase our knowledge, management In other cases, venous insufficiency due to incompe-
of PLE should also include the identification of associated tent venous valves, such as in lymphoedema–distichiasis161
genetic mutations. Selected patients might benefit from or oedema secondary to hypoalbuminaemia42, may
gene-targeted drug therapies, especially within the group hamper swelling control. Specific approaches are used
of CLAs (Box 2). In tropical countries with low resources, in patients with PLE of the genitals as effective com-
the WHO recommends daily hygiene practices, such as pression is difficult and debulking surgery usually takes
washing and drying the skin to avoid infection, as the place early162,163.
central component of long-term self-care for the manage Data related to compression use in children with lym-
ment of filariasis-related lymphoedema, with limited phoedema are rare164–166. There is a soft agreement on
benefit on swelling. Compression, a key component to avoiding applying bandages or hosiery systematically
reduce and prevent worsening of swelling, is commonly on babies’ limbs as long as function and mobility are not
not available because of limited health-care resources. impaired as stated on the VASCERN guideline adapted
Similar considerations are expected to apply to PLE. from the French national guideline42.
Control of swelling. PLE swelling occurs in any part Treatment of lymphatic-related organ failure and
of the body, although it affects the lower limbs more associated syndromic comorbidities. Intestinal lym-
frequently131,156. The prevention of worsening of swelling phangiectasia results in an exudative enteropathy with
and tissue changes is mainly achieved through the appli- hypoalbuminaemia and subsequent worsening of swell-
cation of compression, prevention of skin infections and ing and γ-globulin deficiency. The cornerstone of man-
controlling weight (Fig. 6a–d; Supplementary Fig. 1a–g). agement relies on a specific low-fat diet excluding the
Complex decongestive therapy aims at reducing swelling long-chain triglycerides that are absorbed by intestinal
within a few weeks using multilayer compression band- lymphatics and associated with drugs that reduce chyle
aging, manual lymphatic drainage, skincare, deconges- flux and loss of albumin167. Infusion of γ-globulin and
tive exercises under compression and rehabilitation. albumin is required in severe cases. Pulmonary lym-
Maintenance therapy aims to maintain the reduction of phangiectasia or reflux result in restrictive respiratory
swelling long term after intensive complex decongestive failure. Prevention of infections and oxygen supply are the
therapy or can be the only therapy when swelling is mild, only effective treatments. Syndromic comorbidities, such
based on a randomized study in patients with cancer157 as learning difficulties in Phelan–McDermid syndrome168
involving long-term wearing of compression hosiery, or sensory-neural deficiencies in Emberger syndrome169,
either regular or tailor-made, skincare, and exercise. can make the application of compression therapy difficult.
There are few clinical practice guidelines158 (of which only Growth hormone use in children with Noonan syndrome
two are international, by the International Lymphedema has no effect on lymphoedema itself170. Diseases such as
Framework and the American Venous Forum159,160) Emberger syndrome are also associated with a specific
or international consensus statements55,60 and none risk of leukaemia or cancers; patients should be moni-
specifically focuses on the management of PLE. tored through cancer surveillance programmes171,172 and
Conservative therapy can now be tailored according benefit from haematopoietic stem cell transplants early in
to natural history of PLE when the genotype is known. life172–176. In the case of CLAs (Box 2), lymphatic organ fail-
ure associated with pulmonary and intestinal lymphangi-
Box 2 | CLAs or lymphangiectasias ectasia, pleural or pericardial leakage or ascites, and bone
destruction requires specific interventions.
Complicated lymphatic anomalies (CLAs) are characterized by localized lymphatic
malformations affecting bones and other tissues with chylothorax, chylopericardium
Infections. Complications such as cellulitis starting
and/or chylous ascites. Primary lymphoedema is present in some cases. Examples
include the following.
early in life3, sometimes even before lymphoedema
manifests146, require treatment with antibiotics (usu-
• Generalized lymphatic anomaly, caused by a mosaic gain-of-function mutation
in PIK3CA185
ally penicillin). Long-term prophylaxis of recurrences
or early self-initiated antibiotic treatment are proposed,
• Gorham–Stout disease, caused by a mosaic gain-of-function mutation in KRAS,
along with careful skincare and treatment of fungal
possibly by a germline loss-of-function mutation in PTEN187,243,287
infections144. Warts are described in children177, are fre-
• Kaposiform lymphangiomatosis, caused by a mosaic gain-of-function mutation
quent in specific PLEs such as GATA2 deficiencies178–180,
in NRAS183,184
and may require specific treatment181,182.
• Generalized lymphatic dysplasia, caused by recessive mutations in ADAMTS3, CCBE1,
FAT4, FBXL7, PIEZO1 (refs93,235,236,238,246,247,275)
Repurposing cancer drugs for CLAs. In a few patients
CLAs that can be associated with primary lymphoedema include central conducting lymphatic with a CLA, a somatic gain-of-function mutation
anomalies, for example, RASopathies and Hennekam syndromes188,189,237,288.
that activates an intracellular signalling pathway also
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a b c d
e f g h i j
Fig. 6 | Non-surgical and surgical treatments of PLE. Patient with primary lymphoedema (PLE) since adolescence.
Situation 9 years after partial debulking surgery without follow-up compression (part a); after 2 months of intensive
decongestive treatment with multilayer bandages (part b); and after 10 months (part c) and 27 months (part d) of
self-management. Lateral and back views in Supplementary Fig. 1. Patient with PLE since birth (part e) was operated
by lymph node transfer in the inguinal area and, 1 year later, in the knee region; results after 4 years (part f). Liposuction
was performed on the thigh. Compression garments were still needed. Patient with PLE since birth, associated with
chylothorax in childhood (part g); result 1 year after lymphovenous anastomosis (part h). Lympho-MRI before (part i)
and after lymphovenous anastomosis (part j).
implicated in cancers has been identified183–187. Central effects191. However, the trial was stopped because besta-
conducting lymphatic anomalies (CCLAs) are also tin demonstrated no improvement over placebo in the
not infrequently observed in various RASopathies, primary endpoint of skin thickness and secondary
such as Noonan syndrome, owing to activation of the endpoints of limb volume and bioimpedance.
RAS–MAPK signalling pathway. Thus, repurposing of
small-molecule inhibitors developed for oncology to tar- Interventional procedures
get these pathways has emerged as a novel possibility to Surgery. Two kinds of surgical procedures are used in
test for the treatment of selected patients with CLAs188,189. patients with PLE: those aiming to remove excess tis-
One of two patients with CCLA and a gain-of- sue and those aiming to restore lymph flow. Radical
function ARAF mutation was treated with the MEK excision of skin and subcutaneous tissue to the level of
inhibitor trametinib off-label. Improvement of lym- the deep fascia followed by skin grafting is no longer
phoedema and pulmonary function was observed190. used on legs owing to poor aesthetic and functional
Similarly, a patient with Kaposiform lymphangiomato- outcomes. Nowadays, the main indication for excision
sis with a somatic CBL variant seems to have benefited surgery is to treat primary scrotal lymphoedema, for
from treatment with a MEK inhibitor186. Increased sur- which compression often fails with severe psychological
vival and reduced lymphatic backflow was observed in impact27.
a mouse model of Gorham–Stout disease treated with Liposuction removes excess fat tissue, which is part of
trametinib. The model was generated on the basis of an the swelling of primary lymphoedema192,193. It has been
activating KRAS mutation identified in Gorham–Stout proposed as an alternative to the removal of tissue in
disease187. paediatric patients27. It is a second-line option in patients
Aside from these cancer drugs, the development of with psychosocial distress because of the appearance of
drugs targeting inflammation, such as bestatin, an inhib- the affected area, recurrent infections and substantial
itor of leukotriene A4 hydrolase (LTA4H), was inves- impairment of function194. The level of evidence for posi-
tigated in patients with either secondary or primary tive outcomes is increasing193,195,196. Lifelong high levels of
non-congenital lymphoedema suggesting some positive compression are required around the clock to maintain
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the benefit. Liposuction is not indicated in patients seek- circulation, known as the Fontan circulation207,208. The
ing an alternative to compression or not complying with resulting elevated central venous pressure and high
lifelong compression. Bariatric surgery improves limb lymphatic flow lead to protein-losing enteropathy and
volumes in patients with obesity with PLE197. plastic bronchitis (characterized by expectoration of
Lymphatic reconstructions aim to restore lymphatic branching bronchial casts) in some patients with addi-
flow and are proposed earlier during lymphoedema. tional lymphatic anomalies209. Interventional techniques,
Microsurgical procedures create lympho-lymphatic for example, catheterization of the thoracic duct and
and lymphovenous anastomosis. These techniques have embolization, are increasingly used in the management
been proposed for >30 years, mostly in carefully selected of central conducting lymphatic anomalies associated
groups of patients with local segmental obstruction of with lymph and chyle reflux, such as chyluria210, genital
proximal lymphatics (for example, following cancer leakage211, protein-losing enteropathy and ascites212, and
treatment) when peripheral lymph vessels were patent pulmonary lymphatic anomalies46.
and with preserved contractility198. Supramicrosurgical
reconstruction enables the creation of fine connec- Quality of life
tions (0.3–0.8 mm in diameter) between distal lym- PLE is a chronic condition and its diagnosis is only one
phatics and subdermal venules (lymphaticovenular aspect of patient assessment. The large psychological
anastomosis). These techniques present good results burden of PLE and chronic oedemas has been evidenced
if the lymphatic vessels are of good quality (autono- using generic or specific health-related quality-of-life
mous contraction and valves are still present) (Fig. 6g–j). tools12,213 and is worse in patients in hospital than in
Guidance with lymphoscintigraphy patterns and ICG those treated at the community level214, underscoring
fluorescence lymphangiography are being investigated the necessity to include these aspects in the diagnosis
to screen proper candidates and choose the dynamic and health profile assessment215,216. In 2001, the WHO
vessels199–201. Only a few observational non-randomized introduced the ICF217. This bio-psycho-social ICF model
studies include patients with PLE of lower limbs or includes five domains of functioning of a patient: bio-
genitals despite optimized compression decongestive medical aspects, activities of daily living, participation in
management200,202,203. These approaches might not be society, personal factors and environmental factors; the
useful in FOXC2-associated PLE or PLE associated latter two influence the first three functional aspects and
with mutations in connexin genes as the venous system need to be considered. Validated clinimetrics218 can be
presents reflux or there is absence of contractility of established by a consensus group or during the creation
functional capillaries100. of guidelines152 to design a treatment protocol and the
Free lymph node transfer (LNT) is based upon measurement of its effects in all domains.
the transfer of a group of nodes and their own vessels Most studies utilizing ICF health profiles219 and ded-
from an unaffected extremity to a new location. It is a icated ICF quality-of-life questionnaires (such as lymph
fascio(cutaneous) flap with arteries and veins that is ICF-lower limb220 and the Lymphedema Quality of Life
transferred and revascularized by microsurgical anasto- Inventory (LYQLI)221) are based on secondary lymphoe-
mosis, like finger transplantation. In hypoplasia cases, dema. A comparison of the validity of five different out-
the addition of nodes in a free fatty flap (autologous come measurement tools was performed in patients
lymph node transplantation from patients themselves, with lower-limb lymphoedema and suggested specific
avoiding graft rejection) enables neogenesis of lymphatic use according to the aim of the outcome measurement222.
vessels owing to the presence of growth factors (VEGFs Thus, it is not clear whether extrapolation of the
and cytokines). LNT and autologous lymph node trans- validity of quality-of-life tools used for secondary lym-
plantation are reconstructive techniques that have been phoedema to PLE is acceptable. Because PLE is a rare
developed mainly as prevention or treatment of second- disease, it is associated with delayed diagnosis, feelings of
ary lymphoedema after breast cancer treatment. The insecurity and mistrust of professionals, aspects that do
available case reports testify complete normalization in not exist in secondary lymphoedema223. Growing with
20% of patients204 (Fig. 6e–f; Supplementary Fig. 1h–i). a different body shape also has different effects from
LNT has been associated with lymphoedema occurring secondary lymphoedema. Moreover, specific question-
on asymptomatic limbs in patients with PLE205. The naires are being developed for children and young adults
combination of LNT with lymphovenous anastomosis (NCT01922635).
is proposed in the management of complicated PLE in
adults and children206. Long-term management of PLE issues
Decongestive lymphoedema therapy is the first line of
Embolization of the lymphatics. The improvement management of PLE to improve quality of life. However,
of static and dynamic lymphangiography techniques compression maintenance therapy of lymphoedema is a
enables the diagnosis of lymphatic flow anomalies and lifelong process and remains the main treatment even
the guiding of lymphatic interventional procedures. after interventional procedures. It requires that the
Embolization of reflux from the thoracic duct into the patient wears compression garments daily, exercises,
pulmonary parenchyma and of leakages into the mesen- performs skincare, and sometimes repetitively conduct
teric lymphatics was first developed as a palliative option self-massage and bandaging. The burden of long-term
in selected patients with single ventricle heart malforma- management is obvious and requires a commitment to
tion in whom heart transplantation could not be per- self-management and a self-efficacy belief as shown in
formed following failure of the surgical cavo-pulmonary children and parents224. Compression is not mandatory
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Box 3 | Patient perspective (part 1) is identified could be as high as 70% of patients accord-
ing to our estimates (P.B. and M.V., unpublished work).
E. is a 24-year-old young woman born with a generalized lymphatic anomaly. These are Yet, most likely, the majority of variants of unknown sig-
her words about what it means to live with primary lymphoedema, recorded on nificance do not have an effect on protein function and
December 2020 as a webinar. represent rare polymorphisms. Thus, novel genes asso-
The journey for a diagnosis ciated with PLE need to be looked for as many pieces are
I was 8 weeks old, my mum noticed that my left arm was bigger than my right arm, and still missing to reconstitute the full puzzle and finding
they had no idea what was going on. There started a very long journey to diagnose it. additional pieces would lay down the basis for under-
We went to the general practitioner, who then referred diagnosis to a specialist standing the multiple reasons for the development
paediatrician in the area. I was diagnosed with hemihypertrophy syndrome. At that
of PLE.
time, 24 years ago, there was very little understanding of what was going on and my
parents would feel a lot of confusion. It was only a few years later that they started to
Additional challenges in identifying the genetic basis
notice that it was my left arm and leg, but also that my lungs were involved. This led of PLE are based on the fact that the available techniques
to being able to see a specialist team, who diagnosed pulmonary lymphangiectasia and to identify causative intronic and intergenic variants
determined that I was having a sort of underlying generalized lymphatic anomaly. are less developed than those for exonic variants. As
I could talk for ages about how long this journey took. The essence of what I am saying the effect of disease-causing variants should present
is that growing with this, having lymphoedema, was not really understood at all at that at protein level and therefore also at the mRNA level,
time. My parents talk about the challenges and difficulties they had to be able to access RNA-based studies might be helpful. This approach
the care I needed and just to be able to understand what was going on. This uncertainty could provide insights on deep intronic mutations,
went on for many years, until we were able to get the right diagnosis many years after. exonic splice-altering mutations that are not identified
Being able to access specialized centres with doctors and professionals who know what
as pathogenetic as they are synonymous changes, pro-
is going on makes a huge difference. That is so life-changing.
moter mutations, methylation disturbances, and other
Growing up with lymphoedema changes that would regulate gene expression level. After
Ultimately, it is about understanding the needs of children and young people. They an exhausting search for intragenic mutations, we could
are quite different. Following the medical recommendations, you feel it is quite a big
look for alterations in the rest of the genome: mutations
commitment. One of the hardest things for me was managing all of these different
appointments, having to travel to a lot of different places and seeing many different
in non-coding parts of the DNA, microRNAs, long
doctors. At the same time, working at school and getting my degree was so important non-coding RNAs or DNA alterations that result from
to me. I struggled a lot with not being at school because of lymphoedema. viral infection for viruses that integrate their genetic
Being now 24 years old, my advice would be to rely on a support network and get material into the genome. Occasionally, patients with
plans in place with school, colleges and universities. Being open to the reality of the unilateral PLE could carry a somatic mutation only
challenges, and this is not easy to do. It is not easy to stand in front of people and talk detectable in the affected tissue. Moreover, PLE could
about your challenges in life. In the end, it is about understanding that people can help also develop as a result of gene-to-gene interactions
you if they understand how they can help you. For example, [finding] shoes, clothes, and therefore validated algorithms to study oligogenic
garments, that is a daily struggle, and I still find that so challenging. One day hopefully diseases are needed.
I will get a pair of red high heel shoes; that is one of my aspirations in life, still a way to go.
Many of the mutations in genes causing Mendelian
forms of PLE have incomplete penetrance. Sex-specific
in toddlers and even children might not cope with penetrance is also starting to emerge and could help
aggressive decongestive therapy or wear prescription provide a more accurate prognosis when taken into
garments. Professionals need to adapt compression to consideration. Hormones seem to have an important
the patient’s life and not vice versa and take the time role in PLE development yet their influence is poorly
needed for patients to accept their condition and tailor understood and needs focused studies.
the therapy. Education can be delivered in camps or dur- Another intriguing question is the overlap of
ing social and networking activities; it helps young peo- PLE-causing genes with secondary lymphoedema as
ple not to feel alone with their rare condition and is also the same genes may be involved. Two studies have sug-
useful for professionals to share their experience225,226 gested such a link95,227. An association was found with
(Boxes 3,4). LCP2 (encoding lymphocyte cytosolic protein 2), NRP2
(encoding neuropilin 2), SYK (encoding spleen tyros-
Outlook ine kinase, also known as tyrosine-protein kinase SYK),
Lymphoedema is a global problem (Box 5). The man- VCAM1 (encoding vascular cell adhesion protein 1),
agement of PLE is still in its infancy, although the dis- FOXC2 and VEGFC. However, other studies are needed
ease has been recognized for years. One of the reasons to confirm the significance of these associations.
is the wide variety of presentations, from isolated forms When developing therapeutic approaches, it is
to combinations with other features in syndromes. A important to visualize the interplay between the different
second major reason is the lack of understanding of genes that have already been identified for PLE. In 2014,
the pathogenetic events leading to the disease and the 20 of them were grouped in a hypothetical LEC and
underlying genetic causes. many of the gene products were geared around a central
VEGFC–VEGFR3 signalling pathway74. This model has
Genetic variability now become more complex, with the inclusion of other
In large-scale genetic screens, numerous variants of ligand–receptor complexes (ANGPT2–TIE1/TIE2 and
unknown significance are detected. If these were to be HGF–MET) and the effect of RAS–MAPK and PI3K–
considered as disease-causing mutations (assuming that AKT signalling, which point to more severe syndromic
they would be validated as such by functional tests), the forms (Fig. 3). Moreover, along the lymphatic vasculature,
proportion of individuals in whom a causative mutation the impact of the gene mutations and mutated proteins
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Box 4 | Patient perspective (part 2) moving towards whole-exome sequencing, for which the
analysis can be re-processed for individuals in whom a
Fears causative mutation has not been identified when new
Fear and anxiety around cellulitis are very real. They can come on very quickly, they genes are reported. With evolving copy number detec-
can be severe and you can feel very unwell. It is a constant in the back of your mind.
tion algorithms, whole-exome sequencing data can also
You have to be aware of it, that it is dangerous. But you still have to live and enjoy your
identify partial and whole-gene deletions, although
life. It is a balance. Now, I learned my warning signs, and that is important and takes
time. It is also about getting help from the network you have built around you, including there are still limitations. Overall, increased germline
professionals and clinicians. genetic testing of patients will enable more precise
(molecular) diagnostics and genetic counselling, which
Covering the information with the general practitioner and self-management
in turn allows at-risk family members to be informed
As a patient, you can have so much control on your lymphoedema. I was the one sharing
the knowledge with the general practitioner, using leaflets I was given by the support
and establishment of preventive measures. Importantly,
group. But with that comes a lot of responsibilities. You can in the end feel overwhelmed. such data help to better stratify patients for clinical
research studies.
Psychological aspects
Detailed clinical analysis of all patients, including
I would not cope with people seeing my leg for years. It took a lot of time to wear
a dress when I wanted to wear a dress. We have to be in a place of self-acceptance.
re-evaluation after established genetic diagnosis, will
Lymphoedema is for life, and it takes time to understand and live with it. enable calculation of the risks for additional signs and
I was not good at taking my medication and putting my compression on. Well, to be symptoms in each PLE subtype. For example, in hypo-
honest, we all get good and bad days. So it is also important that young people know trichosis–lymphoedema–telangiectasia syndrome (char-
that it is OK not to always feel OK with lymphoedema. acterized by sparse hair, lymphoedema and small dilated
Sharing with peers cutaneous vessels), additional features are reported in
When you see other patients as a young person, there is no better feeling. You do feel almost every new case for this pleiotropic disease228.
alone with a rare disease, and it can be hard. It has been hard to establish my identity as Such stratified epidemiological data will be paramount
‘E.’ and not only ‘E. with a bigger leg’. for the clinical diagnostics, genetic counselling, manage-
ment and follow-up of patients. Such data will also help
in the development of diagnostic algorithms15 (Fig. 5).
may differ. Some mutations affect LEC proliferation or Stratification will also enable the more precise study of
survival more globally, whereas others affect the devel- response to conventional and surgical treatments and,
opment or stability of lymphatic valves or lymphovenous eventually, to predict outcomes, which could have an
valves (such as EPHB4 mutations). Thus, we will need important impact on patient care.
in vivo models to gather more detailed data for the var- Imaging technologies are also developing rapidly,
ious pathways involved and unravel eventual ways to promising a more detailed evaluation of PLE. MRL is
develop novel therapies and preventive measures. now increasingly used, also in combination with periph-
eral ICG fluorescence lymphangiography. Combining
Diagnosis and treatment these two techniques can help to reclassify the cause
The diversity of genes associated with PLE, both known of PLE to peripheral, central or combined deficiency.
(10 of them were identified during the past 5 years) Whole-body lymphangioscintigraphy associated with
and still to be unravelled, combined with technolog- 3D localization by SPECT–CT can provide functional
ical advancements, can lead to the rapid evolution of imaging of peripheral and central lymphatic flow60.
diagnostic genetic testing of PLE. Gene panels have Such multimodal approaches can be particularly useful
given the most reliable results but they rapidly become in cases of PLE associated with CCLA and can guide
outdated. The recommended diagnostic approach is the planning of interventional management. The Society
of Interventional Radiology (SIR) and the Journal of
Vascular Interventional Radiology selected lymphatic
Box 5 | Lymphoedema — the global picture imaging as their focus topic of the year for 2020 (ref.46).
Lymphoedema is globally a Neglected Public Health issue6. In upper-middle-income Photoacoustic imaging is another emerging imaging
and high-income countries, where cancer is one of the top 10 leading causes of death, technique that provides unique scalability of optical res-
lymphoedema is recognized as a sequala of cancer, associated with a solid reputation olution and acoustic depth of penetration. When associ-
of being an untreatable adverse effect of the treatment of cancer11. Its incidence is ated with the use of light-absorbing biomolecules, such
increasing with ageing, immobility and obesity, which are leading risk factors for as oxy-haemoglobin and deoxyhaemoglobin and lipids,
lymphoedema and related cellulitis in these countries289,290. The WHO recognizes specific vascular structures can be targeted. Moreover,
lymphatic filariasis as one of the five preventable neglected tropical diseases indocyanine green, which is taken up by lymphatic ves-
threatening 859 million people in 50, mostly low-income, countries. The Global
sels, allows the use of photoacoustic imaging for lym-
Programme to Eliminate Lymphatic Filariasis (GPELF) is aiming at providing anti-filarial
medicines and a minimum package of care in all areas with known patients and
phangiography, which has a higher spatial resolution
progression of lymphoedema291. This package focuses on hygiene and misses the point than other imaging modalities229–231.
of compression. PLE is hardly recognized in these countries292 but has been recently The outlook for future personalized management of
recognized in Europe as a rare disease (prevalence <1 per 2,000 individuals36) and PLE is multifaceted. Diagnostics and interventional pro-
benefits from programmes dedicated to Rare Disease Networks such as VASCERN. cedures should benefit from the further development of
Yet, unequal access to diagnosis and treatment is the reality all patients face owing to sensitive imaging methods for lymphatic dysfunctions.
the underdiagnosis of lymphoedema, lack of efficient management and the inadequacy Combined with large-scale genetic analyses and other
of the reimbursement policies for medical devices even in Europe293. Dedicated omics-type approaches in research, it should gather data
research programmes are required as stated in the USA by the Lymphatic Education to decipher the underpinnings of PLE development.
& Research Network.
Understanding PLE pathophysiology is the foundation
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for the development of innovative PLE-specific thera results were inconclusive. The eventual benefit of this
peutics such as modulators of lymphangiogenesis technique, aiming to induce lymphangiogenesis locally,
and/or gene therapy approaches, stem cell-based treat- remains unknown in PLE. Targeted therapies have
ment, and the development of artificial lymphatics by already emerged for other vascular anomalies caused
tissue engineering. In addition to bestatin, VEGFC has by somatic mutations that increase signalling via the
been used in a clinical trial. It was combined with LNT PI3K–AKT–mTOR pathway or the RAS–RAF–MAPK
to induce lymph vessel growth and connectivity to the pathway, including CLAs188. Thus, the future is full of
transferred lymph nodes in patients with secondary hope also for patients with PLE.
lymphoedema after breast cancer232. However, the com-
Published online xx xx xxxx
pany (Herantis Pharma) recently announced that the
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of nonimmune hydrops fetalis, congenital cardiac 279. Ponti, G. et al. Giant elephantiasis neuromatosa in de la Recherche Scientifique – FNRS Grants T.0026.14 and
defects, and haemangiomas in four patients from a the setting of neurofibromatosis type 1: a case report. T.0247.19, the Fund Generet managed by the King Baudouin
consanguineous family. Am. J. Med. Genet. A 176, Oncol. Lett. 11, 3709–3714 (2016). Foundation (Grant 2018-J1810250-211305), and by la Région
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subependymal giant cell astrocytomas treated with 281. Ricci, M. et al. Review of the function of SEMA3A in and the Lymphatic Malformation Institute, USA. M.H.W. has
Mammalian target of rapamycin inhibitors. J. Child. lymphatic vessel maturation and its potential as a received research support from the University of Arizona Health
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267. Geffrey, A. L., Shinnick, J. E., Staley, B. A., Boronat, S. families with rare causative variants. Lymphology 53, (TIPPS) Award and National Institutes of Health NHLBI
& Thiele, E. A. Lymphedema in tuberous sclerosis 63–75 (2020). R25HL108837 for diverse undergraduate research trainees
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(2014). newborn heterozygous for the c.4A>G SHOC2 Secretary-General, International Society of Lymphology, Tucson,
268. Gordon, K. et al. Mutation in vascular endothelial mutation. Am. J. Med. Genet. A 164A, 1015–1020 AZ, USA, and Zurich, Switzerland. The authors are grateful to
growth factor-C, a ligand for vascular endothelial growth (2014). Grace Wagner and Juan Ruiz for programmatic assistance and
factor receptor-3, is associated with autosomal 283. Takenouchi, T. et al. Severe craniosynostosis with to Liliana Niculescu for expert secretarial assistance.
dominant Milroy-like primary lymphedema. Circ. Res. Noonan syndrome phenotype associated with SHOC2
112, 956–960 (2013). mutation: clinical evidence of crosslink between FGFR Author contributions
269. Balboa-Beltran, E. et al. A novel stop mutation in the and RAS signaling pathways. Am. J. Med. Genet. A Introduction (M.V., P.B., M.H.W. and R.P.E.); Epidemiology
vascular endothelial growth factor-C gene (VEGFC) 164A, 2869–2872 (2014). (M.V., P.B., M.H.W., R.P.E. and I.Q.); Mechanisms/pathophys-
results in Milroy-like disease. J. Med. Genet. 51, 284. Michelini, S. et al. TIE1 as a candidate gene for iology (M.V., P.B., M.H.W., R.P.E. and I.Q.); Diagnosis, screen-
475–478 (2014). lymphatic malformations with or without lymphedema. ing and prevention (M.V., P.B., M.H.W., R.P.E., R.J.D., C.B.
270. Mukenge, S. et al. Investigation on the role of biallelic Int. J. Mol. Sci. 21, 6780 (2020). and I.Q.); Management (M.V., P.B., M.H.W., R.P.E., C.B. and
variants in VEGF-C found in a patient affected by 285. Lucas, M. & Andrade, Y. Congenital lymphedema with I.Q.); Quality of life (M.V., P.B., M.H.W., R.P.E., R.J.D.
Milroy-like lymphedema. Mol. Genet. Genomic Med. tuberous sclerosis and clinical Hirschsprung disease. and I.Q.); Outlook (M.V., P.B., M.H.W., R.P.E. and I.Q.);
8, e1389 (2020). Pediatr. Dermatol. 28, 194–195 (2011). Overview of Primer (M.V.).
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PRIMER

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:77 1

Author addresses reported, variants in genes associated with NIHF may

2 | Article citation ID: (2021) 7:77 www.nature.com/nrdp

a b c d e for South African clinicians40. In Europe, expert refer-

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:77 3

Table 1 | Confirmed lymphoedema genes and loci

delay, short stature

(TBX1?) 22q11.2 del 22q11 deletion Dysmorphism, 611867 De novo NA 120

Yp11.2 del neck, dysmorphism, slowed

lymphoedema syndrome 3 protein-losing enteropathy enzyme

CCBE1 18q21.32 Hennekam lymphangiectasia– Dysmorphism, 235510 AR Adaptor protein 236

lymphoedema syndrome 1 protein-losing enteropathy

conducting lymphatic receptor

lymphoedema syndrome 2 protein-losing enteropathy protein

GJC2 (Cx47) 1q42.13 Lymphoedema NA 613480 AD Connexin 108

lymphoedema ectodermal dysplasia, signalling molecule

without chorioretinopathy, without chorioretinopathy, signalling molecule

Gorham–Stout disease cardiac anomaly, signalling molecule

growth, cardiac anomaly methyltransferase

lymphatic dysplasia stature, facial dysmorphism

cardiac anomaly, signalling molecule

cardiac anomaly, signalling molecule

chylothorax malformations signalling molecule

cardiac anomaly, signalling molecule

cardiac anomaly, signalling molecule

4 | Article citation ID: (2021) 7:77 www.nature.com/nrdp

Table 1 (cont.) | Confirmed lymphoedema genes and loci

cardiac anomaly, signalling molecule

telangiectasia–(renal defect) telangiectasia, ileal atresia, 137940 de novo factor

developmental delay signalling molecule

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:77 5

Table 2 | Suggested lymphoedema genes

lymphatic anomaly molecule

cardiofaciocutaneous cardiac anomaly, molecule

disorder with or without cardiac anomaly, molecule

protein-losing enteropathy complex subunit

KLHL40 3p22 Hydrops fetalis Myopathy 615348 AR E3-ubiquitin ligase 277,278

MET 7q31 Lymphoedema NA NA AD Transmembrane receptor 96,276

NRP2 2q33.3 Lymphoedema NA NA AD Transmembrane co-receptor 280

SEMA3A 7q21.1 Lymphoedema NA NA AD? Extracellular matrix protein 281

disorder with loose cardiac anomaly, molecule

TSC1 9q34.13 Tuberous sclerosis 1 Hamartomas, 191100 AD Intracellular signalling 285,286

developmental delay molecule

6 | Article citation ID: (2021) 7:77 www.nature.com/nrdp

Normal Hypoplasia Hyperplasia

Lymphatic nodes Lymph vessels Lymph Chylomicron

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:77 7

Valves Valves Proteoglycans, Valves

RASA1 PTPN11 KIF11 PTPN14

Chromosomal loci associated with PLE

Nucleus GATA FOXC2 FOXC2 LEC and valves

8 | Article citation ID: (2021) 7:77 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:77 9

gene or chromosomal mutations, often presents with Recently, loss-of-function or dominant-negative

10 | Article citation ID: (2021) 7:77 www.nature.com/nrdp

Ophthalmic Psychological and neurological

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:77 11

pathological. The spatial resolution of scintigraphy is Genetic analyses

12 | Article citation ID: (2021) 7:77 www.nature.com/nrdp