Hereditary Primary Lymphoedemas (Milroy Disease and Class)

Milroy disease (FLT4/VEGFR3), lymphoedema-distichiasis, Meige disease, lymphoedemas of the OMIM LMPHM1–14 series, Hennekam syndromes, PIEZO1-related generalised lymphatic dysplasia, hypotrichosis-lymphoedema-telangiectasia and the remaining monogenic lymphoedemas, organised according to the 2020 St George's classification

Literature and regulatory information update: 26 October 2026.

0. Initial Reference Table

0.1. Summary of the class and of the entry entity (Milroy disease)

0.2. Table of all types in the class

Related entities: GATA2 deficiency; FLT4 allelic disease; MCLMR; RASopathies; Turner syndrome; hydrops; PROS; dehydrated stomatocytosis; incontinentia pigmenti.

1. Introduction

1.1. Definitions

Lymphoedema is the accumulation of protein-rich interstitial fluid resulting from low-output failure of the lymphatic system, that is, from a reduced lymphatic transport capacity in the face of a normal lymphatic load; it is distinguished from the high-output oedema of cirrhosis, nephrotic syndrome, right heart failure and venous insufficiency, in which the lymphatic load exceeds intact transport [16]. The 2023 consensus of the International Society of Lymphology (ISL) estimates that about 85% of lymphoedema worldwide is secondary to acquired obliteration of the lymphatics; the remainder corresponds to primary lymphoedema, caused by a developmental lymphatic dysplasia [16]. The 2020 St George's classification uses three terms with precise meanings: «primary lymphatic anomaly» designates all lymphatic anomalies due to a developmental defect; «primary lymphoedema» designates oedema of an extremity caused by a developmental, presumably genetic, defect of the structure or function of the lymphatic pathways; and «lymphatic malformation» designates evident structural defects, truncal (interfering with drainage and causing lymphoedema) or non-truncal (isolated, without lymphoedema) [3]. The glossary of the same document defines systemic involvement as chylothorax, chylopericardium, chylous ascites, intestinal or pulmonary lymphangiectasia or non-immune hydrops fetalis, and generalised lymphatic dysplasia (GLD, «generalized lymphatic dysplasia») as a generalised structural or functional anomaly of lymphatic development [3].

1.2. Founding descriptions

In 1891, Max Nonne described four cases of «hereditary congenital elephantiasis» of the lower limbs, and in 1892 William Forsyth Milroy published in the New York Medical Journal the pedigree of a family with 97 members, 26 of whom had had leg oedema since birth, painless, non-progressive and confined to the lower limbs; the Nonne-Milroy eponym derives from these two descriptions [1, 50]. According to OMIM, Milroy's family, from Omaha (Nebraska), spanned 6 generations; in 1898, Henry Meige described familial lymphoedema of pubertal onset, and in 1965 Esterly gathered 22 published pedigrees and one of his own, with 152 affected individuals [2]. Clinical tradition divided the primary lymphoedemas into congenital, «praecox» (pubertal onset) and «tarda» (later onset), and called the familial form of pubertal onset without other features Meige disease [1, 51]. The initial classification by age at onset (Milroy type I, early; Meige type II, post-pubertal) was abandoned by OMIM when it was found that early and late onset coexisted in the same family, and the lymphoedemas came to be classified by molecular defect and mode of inheritance [2]. The association between lower limb lymphoedema and a supernumerary row of eyelashes was described by Falls and Kertesz in 1964, as webbed neck with eyelid and lymphatic anomalies, and characterised as a hereditary syndrome by Robinow, Johnson and Verhagen in 1970; the «lymphoedema and ptosis» form, previously treated as a separate entity, was later recognised as the same syndrome [11, 52]. In 1989, Raoul Hennekam and colleagues described four relatives, children of consanguineous parents, with intestinal lymphangiectasia, severe lymphoedema of the limbs, genitalia and face, a flat face with a broad nasal bridge and hypertelorism, dental and ear anomalies, seizures and moderate intellectual disability, and proposed a new autosomal recessive syndrome [53].

1.3. Milestones of molecular discovery

Milroy disease was mapped to 5q34-q35 and, in 2000, two groups identified FLT4 missense variants that inactivate the VEGFR-3 kinase: Irrthum and colleagues described a histidine→arginine substitution in the catalytic loop that inhibits autophosphorylation, and Karkkainen and colleagues showed that all mutant alleles from several families had an inactive kinase and prevented activation of downstream pathways [54, 55]. In the same year, starting from a t(Y;16)(q12;q24.3) translocation in a patient with neonatal lymphoedema similar to that of Turner syndrome and from linkage to 16q24.3, Fang and colleagues identified truncating FOXC2 variants as the cause of lymphoedema-distichiasis, the second hereditary lymphoedema gene [56]. There followed SOX18 in hypotrichosis-lymphoedema-telangiectasia (2003), CCBE1 in Hennekam syndrome (2009), GJC2 in dominant lymphoedema (2010), GATA2 in Emberger syndrome (2011), KIF11 in microcephaly with lymphoedema and chorioretinopathy (2012), VEGFC in «Milroy-like» lymphoedema (2013), FAT4 (2014), PIEZO1 (2015), EPHB4 (2016) and ADAMTS3 (2017) [22–24, 37, 40–42, 57–59]. From 2018 onwards, CALCRL, THSD1, CELSR1, ANGPT2, TIE1, MDFIC, ERG and HGF were added, the last with a yield of about 2% in European primary lymphoedema cohorts [6, 25–27, 29, 31, 32, 34]. In 2010 two primary lymphoedema genes were known; the 2020 St George's update recorded eight new causal genes since 2013, and a 2024 review counted 32 established and 22 suggested genes or loci [3, 6]. Despite this expansion, series from 2017 to 2024 indicate that pathogenic variants explain about one third of primary lymphoedemas [27, 29, 41].

1.4. Nomenclature and reclassifications

OMIM regrouped the non-syndromic hereditary lymphoedemas into a phenotypic series designated «Lymphatic malformation» (LMPHM): LMPHM1 corresponds to Milroy disease (formerly hereditary lymphoedema IA), LMPHM2 to the 6q16.2-q22.1 locus without a gene (formerly IB), LMPHM3 to GJC2-related lymphoedema (formerly IC), LMPHM4 to VEGFC-related lymphoedema (formerly ID), LMPHM5 to Meige disease (formerly hereditary lymphoedema II), LMPHM6 to PIEZO1-related generalised lymphatic dysplasia (formerly hereditary lymphoedema III) and LMPHM7 to LMPHM14, successively, to EPHB4, CALCRL, CELSR1, ANGPT2, TIE1, MDFIC, THSD1 and ERG [4]. Phenotypic series PS153100 confirms the 14 entries, with LMPHM2 placed by statistical methods (linkage) and LMPHM5 without a map location; LMPHM8 (CALCRL) is flagged as provisional («?»), and LMPHM6, LMPHM8, LMPHM12 and LMPHM13 are the only ones with autosomal recessive inheritance [8]. The text of entry 153100 assigns LMPHM10 the number 610369, which differs from the 619369 of the phenotypic series and NCBI, which is the correct number [2, 8]. Other entities keep their own entries: lymphoedema-distichiasis (#153400), primary lymphoedema with myelodysplasia or Emberger syndrome (#614038), Hennekam 1–3 (#235510, #616006, #618154), HLTS and HLTRS (#607823, #137940), lymphoedema-choanal atresia (#613611), MCLMR (#152950, now titled «microcephaly with or without chorioretinopathy, lymphoedema or intellectual disability») and IKBKG-related ectodermal dysplasia with immunodeficiency (EDAID1, #300291), which includes the form with osteopetrosis and lymphoedema described in textbooks as OLEDAID (MIM 300301) [4, 45]. The St George's clinical classification had a first version in 2010, an update in 2013 that incorporated molecular findings and a second update in 2020, aligned with the 2018 classification of the International Society for the Study of Vascular Anomalies (ISSVA) [3, 51]. The 2020 version abandoned the distinction between lymphoedema «praecox» and «tarda», because the same genotype (FOXC2) causes both [3].

1.5. Scope of this article

Milroy disease is the most frequent congenital form; this article treats the class of hereditary primary lymphoedemas uniformly, with the common syndromic description, the 2020 St George's classification, the OMIM nomenclature, the table of all types (table 0.2) and in-depth subsections for Milroy disease, lymphoedema-distichiasis, Meige disease and the late-onset lymphoedemas related to GJC2, CELSR1, HGF and TIE1, the Hennekam syndromes, PIEZO1-related generalised lymphatic dysplasia, HLTS/HLTRS, the hydrops of lymphatic origin (EPHB4, CALCRL, THSD1, MDFIC, ANGPT2) and the syndromic forms with dominant lymphoedema (GATA2, KIF11, PTPN14, IKBKG). GATA2 deficiency, MCLMR, the RASopathies, Turner syndrome, PROS and FLT4-related tetralogy of Fallot are described here in their lymphatic dimension.

2. Molecular Genetics and Pathophysiology

2.1. Lymphatic physiology and common molecular pathways

The lymphatic system begins in the initial lymphatic capillaries of the dermis, valveless and permeable, which collect interstitial fluid and drain into collectors with intraluminal valves and smooth muscle cells that ensure propulsion to the lymph nodes and the thoracic duct. The genes of the class fall into four functional axes that explain the phenotypes. The first is the VEGF-C/VEGFR-3 signalling axis: CCBE1 (an extracellular matrix protein) does not cleave VEGF-C, but promotes cleavage of the weakly active 29/31 kDa form by the metalloprotease ADAMTS3 into the mature 21/23 kDa form, which activates VEGFR-3 on the lymphatic endothelium [60, 61]. This axis explains the convergence of Milroy disease (FLT4), «Milroy-like» lymphoedema (VEGFC) and Hennekam syndromes 1 and 3 (CCBE1, ADAMTS3) [39, 60]. The second axis is the formation of lymphatic and venous valves, which depends on FOXC2, GJC2, CELSR1 (planar cell polarity), EPHB4 and MDFIC; variants in these genes cause lymphatic reflux rather than absence of vessels [31, 49, 62–64]. The third is mechanotransduction and endothelial stability, with the mechanosensitive channel PIEZO1 and the angiopoietin-TIE system (ANGPT2, TIE1) [27, 29, 65]. The fourth brings together transcription factors and proteins with pleiotropic functions (SOX18, GATA2, ERG, KIF11, PTPN14, CALCRL, IKBKG), whose phenotypes associate lymphoedema with cutaneous, haematological, ocular or immunological disease [25, 33, 36, 43, 44, 66, 67].

2.2. FLT4 and Milroy disease

The locus was mapped to 5q34-q35 by Ferrell and colleagues in 1998 (multipoint LOD of 8.8 in three families, with exclusion of linkage in another, early evidence of heterogeneity) and to the more telomeric region of 5q35.3 by Evans and colleagues in 1999 (combined LOD of 16.55 in five families); Ferrell identified the first FLT4 variant in one of these families, and Evans described in 2003 eight heterozygous variants, all in the tyrosine kinase domains, in 12 European families, several with incomplete penetrance [2, 68]. FLT4 encodes VEGFR-3, a transmembrane receptor tyrosine kinase expressed in the lymphatic endothelium and activated by VEGF-C and VEGF-D; ligand binding induces dimerisation and transautophosphorylation of the intracellular kinase domains, recruitment of CRK, SHC and GRB2 and activation, with PI3K, of the AKT, ERK1/2 and JNK pathways, which regulate the growth and function of lymphatic vessels [1]. Milroy disease variants are mainly missense in the exons encoding the two tyrosine kinase domains (TK1, exons 17–20; TK2, exons 22–26) [1, 7]. The mutant products form homodimers without kinase activity or mutant/wild-type heterodimers with residual activity; as the mutant receptor is more stable in the membrane and degraded more slowly, the fraction of dimers containing the mutant receptor is greater than expected, which constitutes a dominant negative effect [1, 55]. By this mechanism, deletions and duplications of FLT4 do not cause Milroy disease, and none has been recorded in HGMD [1]. The review by Gordon and colleagues gathered 58 different variants in 95 families, most of them missense, with some intragenic deletions and one splicing variant, and created the FLT4 LOVD database; a patient with p.(Ile1053Phe) had the same substitution as the Chy mouse, a model of congenital lymphoedema [69]. Mellor and colleagues showed that the lymphoscintigraphic pattern of «functional aplasia» corresponds to initial lymphatic vessels that are present but non-functional, and not to anatomical absence [70, 71].

Heterozygous loss-of-function variants of FLT4, including whole-gene deletions and deletions of several kb, cause a distinct allelic phenotype, conotruncal heart disease and above all tetralogy of Fallot (OMIM 618780), through haploinsufficiency of VEGF signalling in outflow tract development and with no lymphoedema described in these cohorts [72, 73]. In a genome study of 175 adults with tetralogy of Fallot, 9 (5.1%) had novel FLT4 variants (7 loss-of-function, including an 8 kb deletion), and variants in VEGF pathway genes (19/175, 10.9%) were associated with absent pulmonary valve (26.3% versus 3.4%) and right aortic arch (52.6% versus 29.1%) [73]. In an exome study of 2871 probands with congenital heart disease, FLT4 was the most frequent dominant gene in tetralogy of Fallot (2.3%) [74]. Variants in the extracellular immunoglobulin-like domain have been associated with tetralogy, and those in the kinase domain with lymphoedema [7]. The heterogeneity of classic Milroy disease is real: up to 75% of patients with a typical clinical diagnosis have a variant in FLT4, linkage has suggested oligogenic inheritance in some families and a fraction of the remainder have variants in VEGFC [1, 75]. Autosomal recessive forms of FLT4 have been described in rare cases: Ghalamkarpour and colleagues reported in 2009 a Hispanic girl, the daughter of unaffected first cousins, with congenital lymphoedema below the knees and hypoplasia of the fourth toe, homozygous for a hypomorphic missense variant in the ATP-binding domain, for which the parents were heterozygous; the recessive hypothesis had already been raised by two Japanese siblings from an island with 1500 inhabitants [2, 7]. In the series of Connell and colleagues, variants were found in 22 (42%) of 52 patients with primary lymphoedema, none outside the kinase domains, which makes analysis of the non-kinase domains of little use in Milroy disease [2, 75].

2.3. VEGFC and «Milroy-like» lymphoedema

VEGFC (4q34.3) encodes the main VEGFR-3 ligand. In 2013, exome sequencing in five «Milroy-like» patients without an FLT4 variant identified the frameshift NM_005429.5:c.571_572insTT p.(Pro191LeufsTer10) in one proband, cosegregating, with loss of activity in zebrafish, the first VEGFR-3 ligand implicated in human disease [22]. The known variants are heterozygous frameshift, nonsense and splicing variants with loss of function and complete penetrance in the few published families [76]. Orphanet records 23 cases [10].

2.4. FOXC2 and lymphoedema-distichiasis

FOXC2 (16q24.1) encodes a forkhead family transcription factor essential for the embryonic formation of lymphatic and venous valves and the recruitment of mural cells, and participates in the migration of cardiac neural crest cells [11, 62]. The 16q24.1 location comes from NCBI Gene and OMIM; the 16q23 cytoband given in one edition of Smith's Recognizable Patterns of Human Malformation does not correspond to the current annotation [4, 52]. The variants are loss-of-function (nonsense and frameshift in the original families) and the mechanism is haploinsufficiency; gain-of-function variants have been described [52, 56]. The defect is valvular and not numerical: unlike most primary lymphoedemas, lymphoedema-distichiasis is associated with a normal or increased number of lymphatic vessels and inguinal lymph nodes, with small, dysplastic valves causing lymphatic and venous reflux [11, 35]. FOXC2 variants are associated with primary valvular failure of the lower limb veins in all carriers studied, and a sibling-pair study linked the FOXC2 region to early-onset varicose veins [11, 77]. No large partial or whole deletions of FOXC2 have been described; a contiguous 256 kb deletion at 16q24.3 including FOXC2 caused microcephaly, intellectual disability, vesicoureteral reflux and distichiasis [11]. There are no genotype-phenotype correlations for the main signs [11].

2.5. Genes of late-onset lymphoedemas: GJC2, CELSR1, HGF, TIE1, ANGPT2 and ERG

The 2020 St George's classification recognised five late-onset lymphoedema genes: FOXC2, GJC2, GATA2, HGF and CELSR1 [3]. GJC2 (1q42.13) encodes connexin 47; six probands with unique missense variants in families with dominant lymphoedema and a LOD of 6.5 in two families established the gene, until then associated only with dysmyelination [58]. In the lymphatic endothelium, loss of gap junction coupling causes lymphoedema of the lower limbs and sometimes the hands, with reduced penetrance and a tendency to local infection; biallelic variants of the same gene cause an allelic disease without lymphoedema, Pelizaeus-Merzbacher-like hypomyelinating leukodystrophy (PMLD1, OMIM 608804), with neonatal nystagmus, hypotonia progressing to spasticity, and ataxia [21]. CELSR1 (22q13.31) encodes an atypical planar cell polarity cadherin, needed for the formation of intraluminal lymphatic valves; in an Italian series of 95 probands with an NGS panel, 5 (5.3%) had loss-of-function variants, with almost complete penetrance and early onset in women and incomplete penetrance and late onset in men [26, 49]. A second multigenerational family had lymphoedema in all heterozygous women and in none of the men, with lymphangiectasia, valvular dysfunction and thoracic duct reflux; a de novo missense variant, NM_001378328.1:c.3953G>A p.(Cys1318Tyr), was described in two female fetuses with pleural effusions and progressive hydrops; and biallelic variants were found in 5 of 6 patients with congenital yellow nail syndrome [49]. The p.(Cys1318Tyr) variant has no ClinVar record under that designation and was not normalised to the MANE transcript [49].

HGF (7q21.11) encodes hepatocyte growth factor, the ligand of the MET receptor. In the Brussels cohort of 770 probands with primary lymphoedema, Alpaslan and colleagues found 10 predicted loss-of-function variants (6 nonsense, 2 frameshift, 2 splicing; 1.3%) and 14 possibly pathogenic missense variants in 17 families (2.21%), with degradation of the nonsense allele, reduced secretion in 9/14 missense variants and reduced AKT and ERK1/2 activation in 3; in a second independent cohort, rare HGF variants explained about 2% of primary lymphoedema [6]. TIE1 (1p34.2) was proposed as a candidate gene in a series of 235 Italian patients negative for the known genes (3 probands, 2 with cosegregation) and established by Brouillard and colleagues in 755 patients, with 2 missense variants and 1 truncating loss-of-function variant; the two missense variants reproduced in the mouse by CRISPR caused oedema and lethality in homozygosity [29, 78]. ANGPT2 (8p23.1) encodes angiopoietin 2, which signals through TIE2 and TIE1: in 543 patients with primary lymphoedema, a de novo whole-gene deletion and 4 heterozygous missense variants were found, 3 of them with reduced secretion and blockade of secretion of the wild-type protein (dominant negative effect); the variant designated p.Thr299Met in the literature reduced binding to integrin α5 and caused cutaneous lymphatic hyperplasia in the mouse [27]. A homozygous null frameshift of ANGPT2 caused severe early non-immune hydrops fetalis, with reduced serum levels in the heterozygous parents [28]. ERG (21q22.2), an ETS transcription factor, was identified by Bayesian rare-variant association analysis in 77,539 genomes from the UK 100,000 Genomes Project, with 4 probands with loss-of-function variants and cosegregation; a mosaic father developed lymphoedema more than 20 years after his daughter, and other families with ERG variants have cytopenias and leukaemia before 40 years of age [33, 34].

2.6. Hennekam syndromes and generalised lymphatic dysplasia: CCBE1, FAT4, ADAMTS3, FBXL7 and PIEZO1

Hennekam syndrome is autosomal recessive (familial cases with an equal sex ratio, increased consanguinity and absence of vertical transmission) [39]. Type 1 is due to biallelic variants of CCBE1 (18q21.32), identified by homozygosity mapping in 7 patients and validated in zebrafish; CCBE1 explains about 25% of classic cases (13 of 29 in one series) and was not found in 158 patients with less generalised lymphatic dysplasias [57, 79]. Type 2 is due to FAT4 (4q28.1), an atypical cadherin acting as a DCHS1 receptor upstream of the YAP effector of the Hippo pathway, identified in homozygosity in Hennekam's original family and in 4 of 24 CCBE1-negative families; FAT4 and DCHS1 also cause Van Maldergem syndrome, with facial overlap [40, 80]. Type 3 is due to ADAMTS3 (4q13.3): in a non-consanguineous family with two children, biallelic missense variants in the prodomain and the peptidase domain produced poorly processed proteins, retained intracellularly, unable to activate pro-VEGF-C; a second patient had a homozygous nonsense variant [41, 61]. A homozygous single-exon deletion of FBXL7 has been described in a patient with a Hennekam phenotype, and the gene appears in the 2020 algorithm as a suggestion, although PanelApp classifies it as having insufficient evidence [3, 5]. The three main genes do not explain all cases [39].

PIEZO1 (16q24.3) encodes a mechanosensitive endothelial cation channel that senses shear stress and guides vascular patterning. Biallelic loss-of-function variants cause Fotiou generalised lymphatic dysplasia (LMPHM6), autosomal recessive, with frequent non-immune hydrops and facial and four-limb lymphoedema in childhood [23]. Heterozygous gain-of-function variants (delayed channel inactivation) cause the autosomal dominant allelic disease dehydrated hereditary stomatocytosis (xerocytosis, DHS1, OMIM 194380), with compensated haemolytic anaemia, iron overload and perinatal oedema not attributable to the anaemia [3, 65]. PIEZO1 also carries the antigens of the Er blood group system [65].

2.7. Other genes with dominant lymphoedema: SOX18, GATA2, KIF11, EPHB4, CALCRL, THSD1, MDFIC, PTPN14, IKBKG and GJA1

SOX18 (20q13.33) encodes a transcription factor with a DNA-binding domain and a transactivation domain. Irrthum and colleagues described homozygous missense variants in the DNA-binding domain, W95R and A104P, in two consanguineous families (recessive form, HLTS), and a de novo heterozygous nonsense variant truncating the transactivation domain in a third family (dominant form, HLTRS), in which a sibling died in utero with hydrops [42]. Dominant truncating variants, usually de novo, act as dominant negatives [43]. GATA2 (3q21.3) encodes a transcription factor; an allelic series of 8 variants showed that haploinsufficiency causes primary lymphoedema and predisposition to acute myeloid leukaemia (Emberger syndrome), an entity unified in 2011 with MonoMAC and dendritic cell, monocyte, B and NK lymphoid deficiency [36, 37]. KIF11 (10q23.33) encodes kinesin-5 (Eg5), a motor required for the bipolar mitotic spindle; the mechanism is haploinsufficiency, with nonsense, frameshift, splicing and missense variants distributed throughout the gene, and causal microdeletions; the deficiency restricts the proliferation of neural progenitors and has distinct requirements in the retinal and lymphatic endothelium [59, 66].

EPHB4 (7q22.1) encodes an ephrin receptor that marks the venous side and, with the ligand EFNB2, segregates arterial and venous territories and participates in the formation of lymphovenous valves; two heterozygous missense variants without kinase activity caused hydrops fetalis of lymphatic origin in two families, and this mechanism was estimated to explain about 15% of non-immune hydrops of lymphatic origin in that series [24]. The variant NM_004444.4:c.2334+1G>C (= NM_004444.5:c.2334+1G>C in MANE), in a 4-generation family with central conducting lymphatic anomaly, caused retention of 12 intronic bp and hyperactivation of mTORC1, and mTOR or RAS-MAPK pathway inhibitors rescued the phenotype in zebrafish [81]. Loss-of-function variants of EPHB4 also cause CM-AVM2, because RASA1 is a direct effector of EPHB4 [82]. CALCRL (2q32.1) encodes the calcitonin gene-related peptide receptor, which with RAMP2 forms the adrenomedullin receptor, necessary and sufficient for lymphatic proliferation in three murine models; a homozygous in-frame deletion p.Val205del caused fetal death from hydrops in a Saudi family, and heterozygous women had spontaneous miscarriages and subfertility [25]. THSD1 (13q14.3) was associated in homozygosity with non-immune hydrops, congenital heart disease and haemangiomas in four patients from a consanguineous family from the United Arab Emirates [32]. MDFIC (7q31.1-q31.2) regulates the collective migration of lymphatic endothelial cells, an early step in valve formation, through activation of integrin β1; biallelic variants in 7 individuals from 6 families caused central conducting lymphatic anomaly, and mice homozygous for the human truncations died perinatally with chylothorax and defective valves; MDFIC does not belong to the RAS-MAPK pathway [18, 31]. PTPN14 (1q32.3-q41) encodes a non-receptor phosphatase recruited to VEGFR-3 in a VEGF-C-dependent manner; a homozygous deletion of about 2 kb removing exon 7 caused lymphoedema and choanal atresia in a consanguineous family, with no second independent family published [44, 83]. IKBKG (Xq28) encodes NEMO, the regulatory subunit of IκB kinase: complete loss causes incontinentia pigmenti (X-linked dominant, lethal in males) and hypomorphic variants with residual NF-κB signalling cause ectodermal dysplasia with immunodeficiency in boys, with osteopetrosis and lymphoedema in some [45, 67]. GJA1 (6q22.31), connexin 43, causes oculodentodigital dysplasia through dominant negative missense variants, with occasional lymphoedema [46, 47].

2.8. Variant spectrum and normalised nomenclature

The variants cited were normalised in VariantValidator (GRCh38, MANE Select transcript) and checked against ClinVar; the table records the source notation, the validated notation and numbering discrepancies [3, 7, 27, 32, 42, 69, 81, 84, 85].

The MANE Select transcripts of the remaining genes are FOXC2 NM_005251.3, VEGFC NM_005429.5, CCBE1 NM_133459.4, FAT4 NM_001291303.3, PIEZO1 NM_001142864.4 (the NM_014745 used in some databases is not MANE), GJC2 NM_020435.4, CELSR1 NM_001378328.1, KIF11 NM_004523.4, TIE1 NM_005424.5, MDFIC NM_001166345.3, ERG NM_182918.4, HGF NM_000601.6, PTPN14 NM_005401.5, CALCRL NM_005795.6 and IKBKG NM_001099857.5; for FLT4, the RefSeqGene NM_001354989 cited in some sources differs from MANE NM_182925.5. A report using another transcript should be reconverted before comparison with the literature, as the ANGPT2 and THSD1 cases show.

2.9. Penetrance, expressivity and mosaicism

In Milroy disease, 85–90% of carriers of a pathogenic FLT4 variant develop lower limb lymphoedema by 3 years and 10–15% remain clinically unaffected; in the series of Brice and colleagues, 90% of 71 carriers from 10 families had oedema [1, 15]. Older estimates, from linkage families, are similar: 80% (76 affected among 191 offspring of affected × unaffected matings, in 13 North American and Canadian families) and 0.84 (4 unaffected carriers in five families) [2]. In lymphoedema-distichiasis, about 80% have lymphoedema by 30 years and 94% have distichiasis; in all published families with a FOXC2 variant, at least one member had distichiasis [11]. In GATA2 deficiency, lymphoedema occurs in 11–20% of carriers and the penetrance of MCLMR for lymphoedema is 46% [36, 38]. In EPHB4-related CM-AVM, the penetrance of vascular lesions is 93% (102/110) [12]. CELSR1 has sex-dependent penetrance [26]. Mosaicism has two expressions: parental mosaicism of germline variants (for example, the father with a mosaic ERG variant; EPHB4 mosaicism in about 20% of the blood cells of a proband) and post-zygotic variants of the PIK3CA and RAS-MAPK spectra, which are rarely detected in blood and require affected tissue [3, 12, 33].

2.10. Gene-disease validity and reference panels

The «Primary lymphoedema» panel of Genomics England PanelApp (panel 65, version 5.7 of 14 August 2026, NHS test R136) includes 60 genes. Green-rated (diagnostic evidence) are ADAMTS3, CCBE1, FAT4 and PTPN14 (biallelic), CELSR1, EPHB4, ERG, FLT4, FOXC2, GATA2, GJA1, GJC2, IKBKG (X-linked), KIF11, PIEZO1 (mono- and biallelic), RASA1, SOX18 (mono- and biallelic), TIE1, VEGFC, PMM2, SHANK3, NSD1, TSC1, TSC2 and the RAS-MAPK genes (BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, NF1, NRAS, PPP1CB, PTPN11, RAF1, RIT1, SHOC2, SOS1, SOS2, SPRED1); amber-rated (moderate evidence) are ANGPT2, ARAP3, DCHS1, HGF, MDFIC, PLXNB2, RORC, UNC45A (Aagenaes) and ZNHIT3; and with insufficient evidence are ALG8, ALX3, AQP1, CCDC88A, CDC42, CHD7, FBXL7, MET, MPI and TTR [5]. ARAP3, of the PI3K/AKT pathway, has been described in three families negative for the known genes [86, 87]. For clinical validity, ClinGen has no validity curation for most lymphatic genes; GenCC classifies CCBE1 as definitive, ADAMTS3 between moderate and strong, SOX18 strong in the recessive form and moderate in the dominant form, CELSR1 strong, ANGPT2 between limited and strong and ERG limited [28, 33, 43, 49, 61, 79]. Classification of a variant in an amber or red gene requires greater caution in clinical interpretation.

3. Clinical Spectrum and Manifestations by System

3.1. Common features of primary lymphoedema

Primary lymphoedema produces oedema of the extremities which, without treatment, progresses from soft pitting oedema to thickened, fibrotic skin; later, skin-coloured papules (papillomatosis) appear owing to dilatation and fibrosis of superficial dermal lymphatics, lymphatic vesicles and leakage of lymph after minimal trauma (lymphorrhoea) [19, 48]. Stemmer's sign, the inability to pinch the skin fold at the base of the second toe, reflects skin thickening and is considered characteristic of lymphoedema [48]. The complications of uncontrolled lymphoedema are repeated cellulitis and lymphangitis, elephantiasic trophic changes, disability and, rarely, lymphangiosarcoma (Stewart-Treves syndrome) [16]. Hereditary lymphoedema is generally autosomal dominant, with reduced penetrance, variable expressivity and variable age at onset, and may affect one or all limbs [48]. The natural history descriptions that follow come from series from European reference centres, above all St George's Hospital in London, and from family reports; they largely correspond to patients already managed with compression and skin care, so they do not represent untreated natural history. The 2019 French PNDS lists as signs of progression and complication lymphatic vesicles with lymphorrhoea, papillomatosis of the toes, interdigital and skin-fold intertrigo, ingrown toenails, onychomycosis, warts and nail changes (verticalisation and shortening of the nail plate); in genital involvement, men may have skin thickening of the scrotum, hydrocele and lymphoedema of the penis, foreskin or pubis, and women lymphoedema of the labia minora or majora or the pubis, sometimes with vesicles draining lymph or chyle [20].

3.2. Milroy disease

The most common finding is congenital bilateral lower limb lymphoedema, present at birth or before, which in the newborn mainly affects the dorsum of the feet [1]. It may be asymmetrical or unilateral, may progress or improve, especially in the first years, and with age may extend below the knee, rarely above; genital involvement is rare [1, 3]. In the series of Brice and colleagues (71 individuals from 10 UK families, all with a VEGFR-3 variant), 90% had oedema, always limited to the lower limbs and present from birth in all but 2; hydrocele was the most frequent finding after oedema (37% of males), followed by prominent leg veins (23%), cellulitis (20%), papillomatosis (10%) and «upslanting» toenails (10%) [15]. The GeneReviews adds urethral anomalies (hypospadias, urethral stenosis) in 4% of males, deep interphalangeal creases of the toes and small, dysplastic «ski-jump» nails, and gives 14% for «upslanting» nails, a frequency different from the 10% of the 2005 series [1, 48]. Cellulitis is significantly more frequent in males and worsens oedema through lymphatic damage [1]. By definition, there is no clinically significant internal lymphatic involvement (intestinal lymphangiectasia, pleural or pericardial effusions) [1]. The prenatal presentation is oedema of the dorsum of the feet on 2nd or 3rd trimester ultrasound; mild pleural effusion, which often resolves before birth, and hydrops fetalis are rare [1, 3]. In a series of 6 Korean patients with Milroy disease and chylothorax (mean age 12 years), all with bilateral lower limb lymphoedema of late ISL stage 2 or stage 3, chylothorax coexisted with peripheral lymphoedema, which limits the scope of absence of internal involvement as a criterion [88]. No genotype-phenotype correlation has been described [1, 69]. OMIM adds series that broaden the spectrum: Brice and colleagues examined 211 individuals from the 10 families and confirmed the variant in 64 affected and 7 unaffected individuals, and noted that prominent leg and foot veins are not seen in other forms of congenital lymphoedema; in Ferrell's 13 families of western European descent (105 affected), the male:female ratio was 1:2.3 and onset ranged from the prenatal period to 55 years, in an era before systematic molecular confirmation; Ghalamkarpour and colleagues described elephantiasis up to the inguinal ligaments with venous ulcers, cellulitis and papillomatosis, a 22-week fetus with hydrops, leg oedema, pleural effusions and pulmonary hypoplasia, and a case of spontaneous resolution; in a 3-generation consanguineous Israeli Muslim Arab family, with 14 affected individuals and 2 asymptomatic carriers, there was prenatal hydrothorax progressing to hydrops and late degenerative knee disease; and congenital chylous ascites with intestinal albumin loss and persistent protein-rich pleural effusions have been reported [2].

3.3. VEGFC-related «Milroy-like» lymphoedema

The phenotype is clinically indistinguishable from Milroy disease, with congenital or adolescent onset, but lymphoscintigraphy shows a pattern different from «functional aplasia»; UniProt and the published families add varicose veins, nail dysplasia, hyperkeratosis and papillomatosis [1, 76]. In a newborn, lymphoscintigraphy performed after the exome corrected the diagnosis from Milroy to Milroy-like [76].

3.4. Lymphoedema-distichiasis

Lymphoedema begins in late childhood or at puberty (range 7 to 40 years), rarely at birth, and in women may be precipitated by pregnancy or oral contraceptives; it is confined to the lower limbs, with or without genital involvement, is often asymmetrical and may be unilateral [11]. The series of Brice and colleagues (74 patients from 18 families and 6 isolated cases, all with a FOXC2 variant except one family linked to 16q24) is the basis of the frequencies: distichiasis in 94.2%, ptosis in 31%, congenital heart disease in 6.8%, cleft palate in 4% and early-onset varicose veins in 49% [35]. The GeneReviews rounds these values to 94%, about 30%, 7–10% and about 50% [11]. Distichiasis consists of aberrant eyelashes arising from the Meibomian glands on the inner surface of the eyelids, ranging from a complete row to a single hair; about 75% of patients have ocular symptoms (corneal irritation, recurrent conjunctivitis, photophobia) and about 25% are unaware of it [11]. Men have earlier oedema and more cellulitis: 65% of men and 25% of women reported recurrent cellulitis in the oedematous leg [11]. Varicose veins, due to incompetence of the saphenofemoral junction and the great saphenous vein, may precede lymphoedema and appear at puberty or in early adulthood [11, 77]. Heart disease includes ventricular septal defect, atrial septal defect, patent ductus arteriosus, bicuspid aortic valve and tetralogy of Fallot, and there is sinus bradycardia [11]. Cleft palate may be associated with Pierre Robin sequence [11]. Spinal extradural arachnoid cyst (SEDAC) is a feature of the syndrome and may be the isolated finding, more often with a family history; renal anomalies (hydronephrosis, ectopic kidney, renal agenesis) are detected on prenatal ultrasound [11]. Non-immune hydrops fetalis and prenatal hydrothorax are rare and may resolve completely; a 5-generation family showed worsening up to hydrops in the youngest generation [11]. Other findings are scoliosis, webbed neck, uterine anomalies, strabismus, synophrys, microphthalmia, partial ectropion of the lower eyelid and discoloured nails, the latter common in chronic lymphoedema of any cause [11, 52]. Lymphoscintigraphy shows reflux («dermal backflow») rather than aplasia [71]. There are families with FOXC2 and lymphoedema without slit-lamp-documented distichiasis, and families with distichiasis without lymphoedema [11].

3.5. Meige disease and late-onset lymphoedemas related to GJC2, CELSR1, HGF, TIE1, ANGPT2 and ERG

Meige disease is lower limb lymphoedema of pubertal onset, without other features, more frequent in women, with apparently dominant inheritance and reduced penetrance and no identified gene; it is probably heterogeneous [1, 48]. In a study of 23 probands diagnosed with Meige disease, only 1 had a FOXC2 variant, in a family in which 4 relatives had distichiasis on slit-lamp examination [89]. In the 2016 St George's audit, Meige disease accounted for 36% (31/85) of the late-onset category and no patient had a causal gene [3]. GJC2-related lymphoedema affects the lower limbs and sometimes the hands or all four limbs, with variable severity and recurrent local infections; in the audit, one GJC2 case had an unusual onset at birth [3, 21]. CELSR1-related lymphoedema is non-syndromic, of the lower limbs, with onset in childhood and female predominance, extensive dermal reflux and tortuous lymphatics on imaging [3, 26]. HGF-related lymphoedema is predominantly bilateral in the lower limbs, with onset from childhood to adulthood [6]. TIE1-related lymphoedema typically appears in the 2nd or 3rd decade, with subclinical lymphatic malformations in some carriers [29, 30]. The ANGPT2-related phenotype is oedema of the lower limbs in the first year of life, sometimes of the neck, upper limbs and scrotum or labia majora, with usual gradual resorption and progression with cellulitis in some [28]. In ERG-related lymphoedema, age at onset varies within the family, and haematological risk (cytopenias, acute myeloid leukaemia, myelodysplastic syndrome, acute lymphoblastic leukaemia before 40 years) has been described in other families [33]. Late unilateral oedema may become bilateral, and lymphoscintigraphy may show changes in the clinically unaffected limb [3].

3.6. Hennekam syndromes

Hennekam syndrome combines congenital lymphoedema, usually asymmetrical and slowly progressive, of the distal limbs, face and genitalia, with lymphangiectasias of the small and large intestine and also of the pleura, pericardium, thyroid, skin and kidney, with chylothorax, ascites and pericardial effusion; severe hydrops in utero may cause prenatal or early postnatal death [39]. The facial features include a flat face, flat and broad nasal bridge, hypertelorism, epicanthus, smooth philtrum, small mouth, hypertrophic alveolar ridges, dental anomalies and low-set dysplastic ears; camptodactyly and cutaneous syndactyly, mild growth deficiency in more than half, microcephaly in less than 20%, intellectual disability of variable degree (from absent to severe) and seizures in about one third may occur [39]. The emphasis on intellectual disability in the original description has been attenuated in recent series [1]. Cardiovascular anomalies include atrial and ventricular septal defects, coarctation, anomalous pulmonary venous drainage and interruption of the inferior vena cava [39]. Intestinal lymphangiectasia causes protein-losing enteropathy with hypoalbuminaemia, hypogammaglobulinaemia, lymphopenia, deficiency of fat-soluble vitamins (A and E) and of electrolytes; seizures may be due to hypocalcaemia, hypomagnesaemia or brain anomalies [39, 90]. There are no major phenotypic differences between the three genes, but with CCBE1 lymphoedema is always present from birth and with FAT4 it may begin later in childhood [39]. The CCBE1 spectrum ranges from non-immune hydrops fetalis to mild forms with segmental intestinal lymphangiectasia, minimal lymphoedema, normal development and no dysmorphism, and includes presentations such as refractory pericardial effusion in adults, neonatal cholestasis and paediatric common variable immunodeficiency [79]. In the St George's supplement, 9 patients from 5 families with FAT4 had lymphoedema of the extremities at birth or in childhood and 7/9 had intestinal lymphangiectasia; the two siblings with ADAMTS3 had polyhydramnios, hydroceles, congenital lymphoedema of the lower limbs and genitalia and protein-losing enteropathy [3]. The patient with FBXL7 had resolved neonatal facial and scrotal oedema, persistent bilateral lower limb oedema at 3 months, and facial features and camptodactyly similar to those of Hennekam 2 [3].

3.7. PIEZO1-related generalised lymphatic dysplasia and dehydrated stomatocytosis

In the recessive form, lymphoedema is uniform and generalised, affecting all segments, with systemic involvement (intestinal or pulmonary lymphangiectasia, pleural effusions, chylothorax, pericardial effusions); prenatal presentation as non-immune hydrops is frequent, there may be perinatal death and, in survivors, oedema may resolve and reappear as lymphoedema of the face, genitalia and all four limbs in childhood [3, 23]. The dominant gain-of-function form, dehydrated hereditary stomatocytosis, causes mild to moderate compensated haemolytic anaemia with raised mean corpuscular haemoglobin concentration and decreased osmotic fragility, almost universal iron overload even without transfusions, thrombosis, pseudohyperkalaemia and perinatal oedema, ascites or effusions unrelated to the anaemia; splenectomy should be avoided because it increases thrombotic risk without correcting the anaemia [65].

3.8. Hypotrichosis-lymphoedema-telangiectasia (SOX18)

The triad is sparse hair up to total alopecia (including eyebrows and eyelashes), lymphoedema mainly of the lower limbs with onset in childhood and cutaneous telangiectasias, mainly palmar [1, 43]. In the dominant form with renal defect, two unrelated children with the same truncating variant had renal failure and severe hypertension in childhood and were transplanted [43]. Other findings described are hydrops fetalis, pericardial effusion, hydrocele, systemic or pulmonary hypertension, progressive dilatation of the ascending aorta, ileal atresia, poor wound healing and mucosal bleeding with low von Willebrand factor; about 11–12 patients had been published up to 2022 [43, 84].

3.9. Hydrops fetalis of lymphatic origin and central conducting lymphatic anomaly

The EPHB4-related phenotype (LMPHM7) is dominant and of variable expressivity: some family members had severe non-immune hydrops fetalis, lethal perinatally or resolved after the neonatal period, with prenatal pleural effusions and postnatal chylothorax, and peripheral leg lymphoedema later; others had only atrial septal defect or adult varicose veins, often early and severe [3, 24]. A 4-generation family with EPHB4 had central conducting lymphatic anomaly (CCLA, dysfunction or obstruction of the conducting lymphatic channels of the thorax and abdomen) [81]. MDFIC-related CCLA (LMPHM12) ranges from hydrops with fetal or perinatal death to a chronic course in childhood with pleural and pericardial effusions, chylothorax, chylous ascites and peripheral lymphoedema; one survivor had severe group A Streptococcus sepsis at 13 years and another child died after S. pyogenes infection, which suggests a susceptibility to infection not established with two cases [18, 31]. CALCRL-related hydrops was lethal in homozygosity [25]. The four patients with THSD1 had fetal pleural and peritoneal effusions and moderate to severe hydrops that resolved with age, then mild ascites and haemangiomas in all, recurrent hydrocele in all the boys, intestinal malabsorption in 2 and congenital heart disease in 3 [32]. The recessive form of ANGPT2 caused severe early hydrops [28]. Hydrops of lymphatic origin accounted for 5.7% (310/5437) of causes in a systematic review of non-immune hydrops; the St George's classification cites 15% of non-immune hydrops as lymphatic and about 20% as idiopathic, some possibly lymphatic [3, 91, 92]. Central conducting lymphatic anomaly and the other complex lymphatic anomalies (GLA, GSD and KLA) enter the differential.

3.10. Emberger syndrome (GATA2 deficiency)

Primary lymphoedema occurs in 11–20% of carriers of a GATA2 variant, typically of one or both lower limbs, often with genital involvement (hydrocele); with acute myeloid leukaemia, frequently preceded by pancytopenia or myelodysplastic syndrome, and sometimes congenital sensorineural deafness, it constitutes Emberger syndrome [36, 48]. About 75% of carriers develop a myeloid neoplasm, and GATA2 deficiency is the most frequent germline cause of paediatric myelodysplastic syndrome (7% of all primary paediatric myelodysplastic syndrome and 72% of adolescents with monosomy 7, in the European EWOG-MDS series of 426 children and adolescents) [36]. Infections with non-tuberculous mycobacteria, human papillomavirus (HPV) with extensive warts, herpesviruses and fungi, and alveolar proteinosis, accompany the progressive loss of dendritic cells, monocytes and B and NK lymphocytes; in a Franco-Belgian series of 79 patients, the probability of remaining asymptomatic at 40 years was 8% and mortality up to that age 35% [36].

3.11. Microcephaly with chorioretinopathy and lymphoedema (KIF11)

In the review by Jones and colleagues (37 individuals from 22 families), microcephaly occurred in 86%, ocular changes in 78%, lymphoedema in 46%, mild to moderate learning difficulties in 73%, epilepsy in 8% and heart disease in 8%; variants were de novo in 8 of 20 families (40%) and 3 carriers had no signs [38]. Lymphoedema, when present, is congenital, of the dorsum of the feet, indistinguishable from that of Milroy disease, with the same lymphoscintigraphic pattern, and may be complicated by intestinal lymphangiectasia [1, 66]. Chorioretinopathy is the most common ocular change and may mimic familial exudative vitreoretinopathy (FEVR) with peripheral retinal avascularity, falciform folds and detachment; a child with FEVR should be assessed for microcephaly and lymphoedema, and vice versa [66, 93].

3.12. Lymphoedema-choanal atresia, ectodermal dysplasia with immunodeficiency and oculodentodigital dysplasia

In the PTPN14 family, bilateral posterior choanal atresia was evident at birth and constitutes a respiratory emergency in the newborn, an obligate nasal breather; it was associated with a high palate, hypoplastic nipples, mild pectus excavatum and pericardial effusion, and 5 of the 7 affected individuals developed hard, non-pitting lymphoedema of the lower limbs between 4 and 5 years [44, 83]. In IKBKG-related ectodermal dysplasia with immunodeficiency, the form with osteopetrosis and lymphoedema (OLEDAID) presents with absent sweating, delayed tooth eruption and conical teeth, sparse hypopigmented hair, multiple severe and sometimes fatal bacterial infections with a poor inflammatory response (absent or delayed fever, leucocytosis and C-reactive protein), failure to thrive, lymphoedema and, radiologically, mild bone sclerosis with a «bone within bone» appearance [45]. Mothers may have incontinentia pigmenti [45]. In oculodentodigital dysplasia, lymphoedema is an occasional finding, alongside cardiomyopathy and arrhythmia [47].

3.13. Lymphoedema in chromosomal syndromes, RASopathies and mosaic disorders

In Turner syndrome, congenital lymphoedema of the dorsum of the hands and feet occurs in more than 80%, usually regresses in early childhood, may reappear at any age, often with the start of growth hormone or oestrogens, and the lax skin of the neck leaves the webbed neck [94]. In Noonan syndrome, lymphatic dysplasia manifests as oedema of the dorsum of the hands and feet at birth and, before birth, as increased nuchal translucency, cystic hygroma, chylothorax or hydrops; it may reappear in childhood or adulthood with oedema of the lower limbs and genitalia, and there may be CCLA with chylous reflux, chylothorax and chylopericardium [1, 95]. The lymphatic anomaly is more frequent with PTPN11 and is absent in patients with loose anagen hair and with MAP2K1/2 variants [96]. In mosaic disorders of the PIK3CA spectrum (fibroadipose hyperplasia, isolated lymphatic malformation, CLOVES, MCAP and Klippel-Trénaunay syndrome), lymphoedema is associated with congenital or early asymmetric segmental overgrowth, sometimes progressive; in Klippel-Trénaunay, the lower limb is affected in 95%, the upper limb in 5% and both in 15% [3, 97]. Mosaic RASopathies cause high- and low-flow arteriovenous malformations, sometimes with congenital unilateral lymphoedema and a Klippel-Trénaunay phenotype [3]. In RASA1- and EPHB4-related Parkes Weber syndrome and CM-AVM there are multiple 1–2 cm capillary malformations with a halo, arteriovenous malformations and fistulae, occasional lymphoedema and chylothorax; lymphangiography showed dilated collectors with slow flow in the unaffected limb [12, 98].

3.14. Cellulitis as a cross-cutting complication

In a specialised French centre with 1846 analysable patients, 695 (37.6%) had had at least one episode of cellulitis and 23.3% had recurrent cellulitis; in primary lower limb lymphoedema (mean duration 243 months), cellulitis occurred in 38.6%, and male sex, higher body mass index (BMI) and earlier onset were associated with cellulitis [99]. Most episodes are due to group A streptococci, and some to Staphylococcus aureus; the picture ranges from severe sepsis to mild episodes without fever [19]. The male predominance of cellulitis is consistent with what is seen in Milroy disease and lymphoedema-distichiasis [1, 11].

3.15. Primary intestinal lymphangiectasia (Waldmann disease)

Definition and pathophysiology. Primary intestinal lymphangiectasia (PIL) was described by Waldmann in 1961 in 18 patients with oedema, hypoalbuminaemia and hypogammaglobulinaemia, gastrointestinal albumin loss and dilatation of the mucosal and submucosal lymphatics of the small intestine; it is called primary once causes of secondary lymphangiectasia have been excluded [90, 100]. The cause is unknown: dysregulation of lymphatic development genes (FLT4/VEGFR3, PROX1, FOXC2, SOX18) and possible involvement of HGF/MET have been described, but no gene is established for the isolated form [100]. Leakage of lymph (chyle) into the intestinal lumen causes exudative gastroenteropathy; the fall in plasma proteins results from synthesis failing to compensate for luminal loss and affects mainly long half-life proteins (albumin, IgG), while prealbumin, fibrinogen and IgA, IgM and IgE remain normal or only slightly low; the loss of lymph rich in T lymphocytes and chylomicrons explains lymphopenia, hypocholesterolaemia, essential fatty acid deficiency and steatorrhoea [100].

Epidemiology. Prevalence is unknown, partly because there are asymptomatic or mildly symptomatic forms; onset is usually before 3 years or in young adulthood, but diagnosis may be late, and familial forms are very rare [90, 100]. PIL is more frequent in the RASopathies (Noonan syndrome, PTPN11, RIT1, SOS1), Turner syndrome and Hennekam syndrome (CCBE1) [100].

Clinical features. Peripheral oedema, due to low oncotic pressure, is the main sign: it ranges from moderate, sometimes asymmetrical, lower limb oedema to forms with oedema of the face and genitalia; serous effusions (pleura, peritoneum, pericardium) are frequent and, in severe forms, life-threatening (tamponade, suffocating pleural effusions) [100]. In the young infant, the most frequent age at diagnosis, oedema is located on the face, lumbar region and genitalia, owing to the lying position [100]. Other signs are asthenia, which worsens with viral infections; true lymphoedema of the limbs, rarer, which is distinguished from hypoproteinaemic oedema by less marked pitting and by Stemmer's sign, and which may be the late presenting form of mildly symptomatic PIL; moderate or intermittent diarrhoea, the main digestive symptom; an epigastric pseudomass due to wall oedema; pallor due to sometimes severe iron-deficiency anaemia; subocclusion due to localised wall oedema or jejunal pseudocystic dilatations; cutaneous chylous reflux with vesicles of milky fluid (abdomen, lower limbs, perineum, genitalia); necrolytic migratory erythema; and digital clubbing [100]. Fetal ultrasound may show ascites or oedema, nonspecific findings [100]. In children, forms may be very extensive and lethal; diarrhoea, abdominal pain, nausea or vomiting, weight loss or stagnation, growth retardation and symptomatic fat-soluble vitamin deficiency, with hypocalcaemia (sometimes with seizures) or osteomalacia, are added; an association with coeliac disease has been described [100].

Syndromes with intestinal lymphangiectasia. In addition to Hennekam syndrome (section 3.6) and PIEZO1-related generalised lymphatic dysplasia (section 3.7), the French protocol lists yellow nail syndrome (with chronic cough, bronchiectasis, lymphoedema and chronic sinusitis), tuberous sclerosis (TSC1, TSC2), neurofibromatosis type 1, CD55 deficiency (CHAPLE syndrome, with complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy) and WILD syndrome (warts, immunodeficiency, lymphoedema and anogenital dysplasia) [100]. In the series that redefined WILD syndrome (21 patients), all had multisegmental primary lymphoedema and 70% (14 of 20) had systemic involvement, intestinal lymphangiectasia or pleural or pericardial effusions, and not only PIL as the French protocol summarises; 95% had a cutaneous lymphovascular malformation of the anterior chest wall, 81% warts, 89% CD4 lymphopenia with a low CD4/CD8 ratio and normal monocytes (unlike GATA2 deficiency), and anogenital dysplasia was rare (14%) [100, 101].

Complications. Since 1961, 14 lymphomas have been described in adults with PIL, 11 well documented: they appeared 3 to 45 years after diagnosis, were always of B lineage, mostly large cell, and gastrointestinal in 70%; chemotherapy made the exudative gastroenteropathy disappear in 4 of 11, 9 of 11 were in remission and 2 died of complications [100]. Despite hypogammaglobulinaemia and lymphopenia, the risk of bacterial or opportunistic infections does not appear greater than in the general population; recurrent bacterial infections (sinusitis, Klebsiella pneumoniae pneumonia, sometimes fatal in children), streptococcal empyema, disseminated cryptococcosis, profuse HPV warts (usually with lymphoma) and persistent Cryptosporidium diarrhoea have rarely been described [100]. Other rare complications are gelatinous transformation of the bone marrow, recurrent haemolytic uraemic syndrome with hypocomplementaemia, hepatic fibrosis (partially reversible on a strict fat-free diet) and, in the elderly, malabsorption limited to osteomalacia [100].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

In the fetus, a primary lymphatic anomaly is suspected in the presence of peripheral oedema (thickening of the subcutaneous tissue of the dorsum of the feet), pleural effusions, ascites, increased nuchal translucency, cystic hygroma or non-immune hydrops [7, 17, 92]. In the newborn and child, the diagnosis is considered in the presence of oedema of one or more limbs, chylothorax, pleural effusions or ascites without another explanation; in the adult, in the presence of lymphoedema of one or more limbs or of other regions without a secondary cause, especially with associated congenital anomalies [17]. Congenital bilateral pedal oedema with dysplastic nails and deep interphalangeal creases suggests Milroy disease; in a girl with congenital lymphoedema, especially of the hands and feet, Turner syndrome is always considered [1]. Pubertal lower limb lymphoedema requires a slit-lamp search for distichiasis, because about 25% of patients with lymphoedema-distichiasis are unaware of it; and every patient with SEDAC should be examined for the other features of the syndrome [11, 52]. Lower limb lymphoedema with genital involvement, extensive warts, mycobacterial infections or cytopenias suggests GATA2 deficiency; with microcephaly or retinal changes it suggests KIF11; with alopecia and telangiectasias it suggests SOX18 [3, 43, 66]. Generalised neonatal oedema in a sick and poorly nourished newborn is usually non-genetic and overlaps with the causes of hydrops, once severe anaemia and hypoalbuminaemia have been excluded by the neonatal team [48]. The history should include a three-generation pedigree with consanguinity, oedema, lymphoedema, varicose veins, distichiasis and heart disease, and the pregnancy history (polyhydramnios, fetal movements) [48]. On examination, look for Stemmer's sign, the affected limbs, microcephaly, coarse facies and markers of resolved intrauterine oedema (epicanthic folds, low-set ears, broad or webbed neck, redundant nuchal folds, widely spaced nipples) [48].

The French PNDS stresses that diagnosis is often late, owing to confusion with venous insufficiency or lipoedema, and that it should be considered in the presence of persistent unexplained distal oedema [20]. The adult history includes family history of lymphoedema and chronic venous insufficiency, circumstances and age at onset, residence in an area endemic for filariasis, personal venous insufficiency, reversibility of the oedema, the number and frequency of erysipelas episodes, socio-occupational, psychological and aesthetic impact, and pain or other symptoms pointing to another diagnosis; in children, prematurity, fetal growth restriction and prenatal ultrasound findings (anasarca, serous effusions, abnormal volume of hands or feet, nuchal thickness, multiple malformation syndromes) are added [20]. The examination records weight, height and BMI (in children, growth charts and head circumference), comparative limb circumferences with a tape measure or automated system, taking as reference the tip of the patella in the lower limb and the elbow crease in the upper limb, skin consistency (firm or hardened, with scant or absent pitting owing to fibrosis), Stemmer's sign and topography (unilateral or bilateral, limbs, face, genitalia), with photographs for follow-up [20]. Pointing to secondary lymphoedema are palpable lymphadenopathy, deterioration in general condition (asthenia, weight loss, anorexia) and proximal topography (thigh, pubis); pointing to a syndromic form are yellow nails, profuse warts, distichiasis and ptosis, associated vascular malformations (capillary, venous or lymphatic), hypertrophy or asymmetry in limb length, digestive, pulmonary, cardiac or bone involvement, facial dysmorphism and intellectual disability; in children, the signs of Turner or Noonan syndrome are especially sought, such as short stature in a girl and renal or cardiac malformations [20].

4.2. Warning and emergency signs

Emergencies are cellulitis with signs of sepsis (hypotension, tachycardia, high fever, confusion, tachypnoea or vomiting), which is an absolute indication for admission, persistence or worsening of systemic signs after 48 hours of antibiotics, and facial cellulitis with orbital or periorbital involvement [19]. Bilateral choanal atresia in the newborn with PTPN14 requires an immediate oral airway [83]. Hydrops fetalis, chylothorax and pericardial effusion with haemodynamic compromise (as in HLTRS) require specialised care [3, 84]. A sudden increase in the volume of a limb, especially in pregnancy, requires exclusion of deep vein thrombosis by duplex ultrasound [17]. In unilateral lymphoedema in adults, exclusion of solid tumours, lymphomas and sarcomas obstructing proximal lymphatics is part of the diagnosis [16]. Fluctuating neurological signs in the lower limbs in lymphoedema-distichiasis suggest compression by SEDAC [11]. In GATA2 deficiency, cytopenias, opportunistic infections and alveolar proteinosis indicate haematological progression [36]. There is no newborn screening for primary lymphoedemas.

4.3. 2020 St George's classification

The St George's classification is a «criteria matching» algorithm that integrates history, examination, investigation (for example, lymphoscintigraphy) and targeted genetic testing, with the aim of guiding molecular diagnosis, natural history, prognosis, counselling and management [3]. The second update, of 2020, organises patients into five colour-coded groups, assessed in this order: yellow (vascular malformations associated with other anomalies and lymphatic malformations, post-zygotic mosaic disorders), blue (syndromic lymphoedema, in which lymphoedema is not the dominant feature), pink (lymphoedema with systemic or visceral involvement of prenatal or postnatal onset), green (congenital onset, before 1 year) and lilac (late onset, after 1 year); a post-publication correction replaced the figure to set the late-onset threshold at «>1 year» [3]. The sections are not mutually exclusive, and a newborn with «isolated» lymphoedema may later reveal developmental delay, systemic involvement, overgrowth or vascular malformation and change group, which is why neonatal molecular diagnosis has clinical utility [3]. The genes indicated do not explain all patients in each group: only about 70% of patients with Milroy disease have an FLT4 variant [3].

Table 4.1. Groups and subgroups of the 2020 St George's algorithm (reading of figure 1) [3].

Figure 2 of the paper represents the distribution of the 227 audited patients across the five categories and illustrates them with photographs (asymmetric overgrowth in a KRAS mosaic, webbed neck in Noonan syndrome, generalised oedema with biallelic CCBE1, oedema of the dorsum of the foot in an infant with a VEGFR-3 variant, lower limb oedema and distichiasis with FOXC2, HPV warts in GATA2 deficiency); the legend was read, the image was not [3]. The supplement recommends considering the pink group genes (ADAMTS3, CCBE1, EPHB4, FAT4, PIEZO1, SOX18) in any infant with congenital lymphoedema not limited to the lower limbs or with genital oedema at birth, and in any fetus with hydrops [3]. When central lymphatic dysfunction is suspected, the suggested investigation includes the prenatal history (hydrothorax, hydrops), chronic diarrhoea, distension or discomfort with fatty foods, weight loss or failure to thrive and exertional dyspnoea, with serum albumin, immunoglobulins, lymphocyte subsets, faecal calprotectin or alpha-1-antitrypsin, echocardiography and chest radiography [3].

Table 4.2. Genetic diseases with frequent and dominant primary lymphoedema, by inheritance and onset (table 1 of St George's 2020) [3].

Table 4.3. Known syndromes in which primary lymphoedema is a non-dominant association (table 2 of St George's 2020) [3].

Table 2 of the original paper writes «CDH7» for CHARGE syndrome; the correct gene is CHD7 [3]. The 2013 version of the algorithm, reproduced in the Oxford Desk Reference, followed the same decision order (syndromic; systemic involvement; growth disturbance, cutaneous manifestations or vascular anomalies; congenital; late-onset) and already distinguished multisegmental lymphatic dysplasia with systemic involvement from generalised dysplasia, but did not include the groups of lymphatic-related hydrops or CCLA or the genes discovered after 2013 [48, 51].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria by entity

The diagnosis of Milroy disease is established in a proband with congenital or childhood-onset lower limb lymphoedema and absent uptake of radioactive colloid in the ilioinguinal lymph nodes on lymphoscintigraphy, or with a heterozygous pathogenic FLT4 variant, or with both [1]. Suggestive features are bilateral oedema present at birth or shortly after, prominent veins below the knees, small, dysplastic and «upslanting» nails, deep interphalangeal creases, hydrocele in males, absence of internal lymphatic problems and a family history compatible with dominant inheritance, the absence of which does not exclude the diagnosis [1]. The clinical diagnosis of lymphoedema-distichiasis is made with one of three combinations: distichiasis and lymphoedema (the young child may not yet have lymphoedema), distichiasis and a family history of lower limb lymphoedema, or lower limb lymphoedema and a family history of distichiasis; when the clinical criteria are insufficient, a heterozygous pathogenic FOXC2 variant confirms the diagnosis [11]. The diagnosis of the Hennekam syndromes requires molecular confirmation (biallelic variants), because no non-molecular test distinguishes CCBE1, FAT4 and ADAMTS3 from each other or from the secondary causes of intestinal lymphangiectasia [61, 79]. Meige disease is a clinical diagnosis of exclusion, within the lilac group, when late-onset lymphoedema is limited to the lower limbs, there is a family history and there is neither distichiasis nor an identified gene [1, 3].

5.2. Staging and quantification

The diagnosis of lymphoedema is usually clinical (history and examination); confounders are morbid obesity, lipodystrophy, lipoedema, endocrine dysfunction, venous insufficiency, trauma and repeated infection [16]. The ISL uses four stages: stage 0, latent or subclinical, with impaired transport without evident oedema, assessable by bioimpedance spectroscopy (BIS) or tissue dielectric constant (TDC); stage I, early accumulation of protein-rich fluid that subsides with elevation, with possible pitting; stage II, permanent accumulation of solids (fat, proteins), in which elevation rarely reduces the oedema and pitting is manifest, possibly disappearing in late stage II owing to fat and fibrosis; and stage III, lymphostatic elephantiasis without pitting, with trophic changes (acanthosis, skin thickening, fat, fibrosis, warty overgrowths) [16]. Within each stage, functional severity is defined by excess volume: minimal from more than 5% to less than 20%, moderate 20–40% and severe above 40%; an excess of 3–5% from baseline corresponds to subclinical lymphoedema [16]. Volumetry is performed with a non-stretch tape and the truncated cone formula, by water displacement or by perometry (which does not include the hand or foot); in bilateral lymphoedema, differences between limbs are interpreted with caution, and quality of life is assessed with the LYMPQOL [16]. Of the 14 guidelines assessed in a systematic review, 13 recommend confirming lymphoedema with a volume difference greater than 10% in the affected limb [102].

5.3. Lymphatic and venous imaging

Ultrasound and venous duplex ultrasound are, in many centres, the first test, to exclude venous disease and characterise the varicose veins of lymphoedema-distichiasis [11, 16]. Lymphoscintigraphy, with radioactive colloid injected into the interdigital spaces of the feet and measurement of ilioinguinal uptake at intervals, demonstrates the lymphatic nature of the oedema, has replaced contrast lymphangiography, can be repeated, is used in newborns and children and shows patterns of aplasia, hypoplasia or hyperplasia; it is not strictly standardised (radiopharmaceuticals, doses, volumes, injection routes) [1, 11, 16]. In a study of genetically confirmed patients, 8/12 (67%) with Milroy disease had little or no uptake by the initial lymphatics and poor visualisation of the inguinal nodes («functional aplasia»), and 12/16 (75%) with lymphoedema-distichiasis had reflux in the collectors; inguinal uptake was lower and residual activity in the feet at 2 hours greater in Milroy disease [71]. In unilateral oedema, lymphoscintigraphy assesses the clinically unaffected limb [1]. The KIF11 pattern is identical to that of Milroy disease, and the VEGFC pattern is different [1]. Indocyanine green (ICG) lymphography, by near-infrared fluorescence, studies the superficial lymphatics and selects vessels for surgery, but protocols are heterogeneous and the patterns («splash», «stardust», «diffuse») have uncertain diagnostic value in primary lymphoedema, according to a systematic review of 11 studies [16, 103]. In a Chinese series of 378 patients with primary lower limb lymphoedema studied by magnetic resonance lymphangiography, 17% had only inguinal node defects, 32% only vessel anomalies (aplasia, hypoplasia or hyperplasia) and 51% anomalies of both vessels and nodes, with no difference in age at onset or severity between groups [2]. Magnetic resonance lymphangiography, with or without intranodal contrast, is used in specialised centres, including in newborns, for CCLA and chylous reflux; oil-based contrast lymphography is reserved for chylous reflux and thoracic duct lesions; the vital blue test may cause anaphylaxis and is misleading [3, 16]. Enlarged lymph nodes in long-standing lymphoedema should not be excised; fine-needle aspiration cytology is preferred if malignancy is suspected [16].

The French PNDS considers lymphoscintigraphy frequently useful to confirm lymphoedema and describes the usual technique: bilateral subcutaneous injection between the first and second interdigital spaces of the feet (or hands, in the rare upper limb forms) of technetium-99m-labelled albumin nanocolloids (sometimes rhenium colloids), whose size ensures uptake by lymphatic and not blood capillaries, with a bilateral and comparative functional study of inguinal or axillary nodal uptake, lymphostasis, dermal backflow and passage to the deep network (popliteal or epitrochlear nodes), with acquisitions after exercise at 40–45 minutes and sometimes later [20]. Radiation exposure is very low, but the test is contraindicated in pregnant and breastfeeding women; in children it is possible and is generally performed at around 7–8 years of age [20]. The same protocol reserves for complex cases, without systematic prescription, CT or MRI of the limb, hybrid lymphoscintigraphy, MR lymphography and high-frequency skin ultrasound, and places bioimpedance (extracellular water), dual-energy absorptiometry (body composition) and indocyanine green lymphofluoroscopy in the research domain, a more restrictive position than that of the ISL, which uses ICG in surgical selection and bioimpedance in stage 0 [16, 20].

5.4. Laboratory assessment and assessment of systemic involvement

The VASCERN patient pathway includes, as first line, renal function (blood and urine), liver function and echocardiography, venous duplex ultrasound and abdominal and pelvic ultrasound; in the specialised centre, albumin, full blood count and immunoglobulins, faecal alpha-1-antitrypsin and calprotectin when there is malabsorption or hypoalbuminaemia, chest and limb radiography (if segmental hypertrophy) and genetic testing when appropriate are added [104]. The karyotype excludes 45,X and rearrangements; when Turner syndrome is suspected with a normal karyotype, mosaicism is sought; urinalysis excludes nephrotic syndrome; leucocyte enzymes are justified when GM1 gangliosidosis or another lysosomal disease is suspected [48]. In the Hennekam syndromes, exudative enteropathy is confirmed by raised 24-hour faecal alpha-1-antitrypsin clearance; endoscopy with biopsy shows dilated lacteals but may be normal, and capsule endoscopy is used if endoscopy is inconclusive [79, 90]. When dehydrated stomatocytosis is suspected, full blood count with mean corpuscular haemoglobin concentration, reticulocytes, bilirubin, haptoglobin, LDH, osmotic fragility, blood smear, ferritin and transferrin saturation and osmotic gradient ektacytometry are requested; potassium in a sample kept at room temperature may be falsely raised [65]. In HLTS/HLTRS, renal function, blood pressure, echocardiography and, if there is bleeding, von Willebrand factor are assessed [43]. In lymphoedema-distichiasis, the initial assessment includes slit-lamp examination, echocardiography, renal ultrasound and spinal MRI if there are symptoms [11].

In adults, the French PNDS requests as initial tests venous duplex ultrasound, to exclude post-thrombotic syndrome and document the venous avalvulation exceptionally associated with lymphoedema-distichiasis; albumin, protein electrophoresis and proteinuria; and abdominopelvic CT (or ultrasound) to exclude compression, the risk of which increases with age, repeated or supplemented by PET-CT if suspicion of neoplasia is strong [20]. In children, the same protocol does not systematically request venous duplex ultrasound or laboratory tests and focuses assessment on the clinical search for signs of a malformation syndrome, which differs from the VASCERN pathway, which includes renal function, liver function and echocardiography as first line regardless of age [20, 104].

5.5. Genetic testing

The ISL 2023 recommends genetic testing for patients with suspected primary lymphoedema and segregation analysis when the proband is positive, and considers a targeted NGS panel of all known genes the most common choice; utility includes the mode of inheritance, transmission risk, prognosis and complications (for example, haematological surveillance in GATA2 deficiency), access to targeted therapies and prenatal diagnosis [16]. VASCERN recommends referring to genetics patients with more than one affected relative or syndromic features and not performing routine genetic testing without expertise in lymphovascular medicine or clinical genetics or without informed consent [17]. The GeneReviews proposes two strategies: with a suggestive phenotype, sequencing of FLT4 or FOXC2 or a multigene lymphoedema panel, which tends to identify the cause at reasonable cost while limiting variants of uncertain significance (VUS); with a phenotype indistinguishable from other lymphoedemas, exome sequencing and, if not diagnostic, analysis of (multi)exonic deletions and duplications [1, 11]. The St George's authors argue that associating the phenotype with a likely gene reduces unnecessary tests and helps interpret VUS even in the panel era [3]. In mosaic disorders of the yellow group, the appropriate sample is a skin or affected tissue biopsy, because post-zygotic variants are rarely detected in blood [3].

The French PNDS adopts a more restrictive position: isolated primary lymphoedema is mostly sporadic, and searching for the genetic cause in a patient with isolated lymphoedema, even familial, is indicated only case by case, by decision of a reference or competence centre; morphological or developmental signs (facial dysmorphism, developmental or growth delay, malformations) lead to a genetics clinic, which identifies the syndrome, adapts follow-up and enables counselling of relatives; and chromosomal anomalies with incomplete presentation, such as monosomy X and trisomy 21, should be sought because of the need for specific care from early childhood [20]. This position, whose literature search ended in June 2018, diverges from the 2023 ISL recommendation to test all patients with suspected primary lymphoedema and is close to that of VASCERN, which restricts testing to familial or syndromic forms and to the specialised setting (section 7.14) [16, 17, 20].

These percentages describe the proportion of patients with a variant found in tertiary-centre cohorts with selected phenotypes; they are not equivalent to the clinical sensitivity of a test for an individual patient. Technical limits condition the interpretation of a negative result. Deletions and duplications of FLT4 do not cause Milroy disease, so testing for FLT4 copy number changes does not contribute to the diagnosis of Milroy disease, although deletions of the gene are associated with the allelic cardiac phenotype [1, 72]. For FOXC2, the rate of deletions and duplications is unknown and none has been reported [11]. Low-fraction mosaicism in blood escapes standard sequencing, as in the RASopathies and PROS, and parental mosaicism may escape leucocyte testing [1, 3]. With about two thirds of primary lymphoedemas still without a molecular cause, a negative result does not exclude hereditary lymphoedema, and Meige disease remains without a gene [3, 29]. The report should state the gene, the transcript with version (MANE Select), the HGVS c. and p. notation, zygosity, the ACMG/AMP class with the criteria applied and the origin when known; VUS in genes with moderate evidence require family segregation and phenotype correlation, and the same protein name may correspond to different numbers in different transcripts (table in section 2.8) [7, 27, 32]. In children, the phenotype may change over time and lead to reclassification of the St George's group [3]. Prenatal diagnosis and preimplantation genetic testing are possible only when the familial variant has been identified or there is a chromosomal anomaly [1, 48].

5.6. Practical algorithm

The pathway begins with confirmation that the oedema is lymphatic and exclusion of secondary causes and high-output oedema; this is followed by phenotyping using the St George's algorithm (table 4.1): first, look for segmental overgrowth or vascular malformation (yellow group, tissue biopsy for PIK3CA or RAS genes); then, syndromic features (blue group, karyotype or microarray and panel); then, systemic involvement with albumin, immunoglobulins, lymphocytes, faecal alpha-1-antitrypsin, echocardiography and chest radiography (pink group, GLD and CCLA genes); and finally age at onset [3]. In congenital lymphoedema limited to the lower limbs, FLT4, VEGFC and KIF11 (or the panel) are requested, with head circumference and fundoscopy; in congenital genital oedema, PIEZO1 is considered [1, 3]. In late-onset lymphoedema, slit-lamp examination is performed looking for distichiasis (FOXC2) and, if absent, the panel with GJC2, HGF, CELSR1, TIE1 and GATA2 is requested, the last with a full blood count and a search for warts and infections [3, 105]. Lymphoscintigraphy is useful but not mandatory when the molecular diagnosis is established, and VASCERN advises against requesting genetic testing, lymphoscintigraphy and routine laboratory tests outside the guidance of a lymphovascular specialist or clinical geneticist [1, 17]. A positive result leads to family segregation and counselling; a negative result leads to phenotypic reassessment and, in atypical forms without a diagnosis, to exome sequencing [1, 16].

5.7. Diagnosis of primary intestinal lymphangiectasia

The aim is to confirm PIL and exclude secondary causes before treating; the pathway is the same in children and adults [100]. The history records age and circumstances at onset (oedema, effusions, diarrhoea), family history and consanguinity, and syndromic signs (lymphoedema, Hennekam, Noonan, yellow nails) [100].

Endoscopy. Upper gastrointestinal endoscopy with systematic duodenal biopsies is the diagnostic test: it shows yellowish-brown elevations (chylomicrons) and biopsies show lymphatic dilatations of the mucosa and submucosa with milky content, without villous atrophy, cellular changes or microorganisms [100]. The test should be performed on a normal diet, not fat-restricted; a long-chain triglyceride load (butter, olive oil) 24 to 72 hours beforehand increases sensitivity [100]. As lesions may be segmental or distal to the duodenum, normal biopsies do not exclude the disease, and endoscopy may need to be repeated [100]. Capsule endoscopy assesses extent (millimetric whitish spots, flat or raised, sometimes coalescent), makes the diagnosis when the duodenum is spared, looks for ulceration in marked iron-deficiency anaemia, helps in lymphoma screening and is used for follow-up; below 6–8 years it is usually placed in the stomach during endoscopy [100]. Push or double-balloon enteroscopy (in children, from 6 years, case by case) is reserved for atypical areas, above all to exclude lymphoma; if the area is not accessible, surgical biopsy is discussed [100].

Laboratory tests. Suggestive of PIL are constant hypoalbuminaemia, sometimes below 10 g/L, without proteinuria or liver failure, with normal or only slightly low prealbumin; hypogammaglobulinaemia with low IgG (especially IgG1, IgG2 and IgG4) and near-normal IgA and IgM; and lymphopenia with a fall in the CD4/CD8 ratio [100]. Protein loss is confirmed by faecal alpha-1-antitrypsin clearance (plasma level and 24-hour stool collection), increased above 24 mL/24 h in children and 15 mL/24 h in adults; scintigraphy with technetium-99m-labelled albumin, with images over 24 hours, localises the leak but is little used in France [100]. The deficiency screen, at diagnosis and then at least annually in adults and six-monthly in children, includes vitamins A, D and E, prothrombin time and factors II, VII, IX and X (vitamin K), folate, vitamin B12, vitamin C, iron, copper, zinc, selenium and chromatography of plasma and red cell essential fatty acids [100].

Imaging and other tests. Contrast-enhanced abdominopelvic CT is a first-line test to exclude central lymphatic or venous obstruction; it shows diffuse or nodular thickening of the small bowel wall and sometimes the halo sign; CT enterography with distension (oral mannitol) clarifies focal lesions [100]. Ultrasound shows indirect signs in adults (dilated loop, wall and fold thickening, mesenteric oedema, ascites) and in children is used mainly for ascites [100]. Lymphoscintigraphy shows gastrointestinal uptake in fewer than 50% of patients with a histological diagnosis; direct lymphography with Lipiodol® is no longer performed in France [100]. Non-contrast MR lymphography shows wall thickening, submucosal dilatations and channel anomalies; the best argument for PIL is the association with other lymphatic anomalies (retroperitoneum, spleen, thorax, limbs), and the test is possible in children, under anaesthesia if needed [100]. Immunophenotyping shows a T-cell deficiency (very low naive CD4+) and a mild B-cell deficiency, which may mimic late-onset combined immunodeficiency; unlike common variable immunodeficiency with lymphangiectasias, IgA and IgM are little affected [100]. Echocardiography and, if necessary, cardiac catheterisation exclude constrictive pericarditis and other cardiac causes [100]. In children, extent is defined by MR lymphography and, when age allows, capsule endoscopy [100].

6. Differential Diagnosis

6.1. Comparative table

6.2. Differential between primary lymphoedemas

Among congenital lower limb lymphoedemas, Milroy disease, VEGFC-related lymphoedema and MCLMR have similar oedema; VEGFC is distinguished by lymphoscintigraphy and KIF11 by microcephaly, retinal changes and learning difficulties, although 3 KIF11 carriers had no signs [1, 38]. In Milroy disease, genital oedema is rare; with congenital genital oedema or oedema of more segments, PIEZO1 and the other pink group genes are considered [3]. Among late-onset lymphoedemas, distichiasis separates lymphoedema-distichiasis from Meige disease, from the forms related to GJC2, CELSR1, HGF and TIE1 and from Emberger syndrome; the latter is distinguished by myelodysplasia, immunodeficiency and deafness [11]. HLTS/HLTRS is distinguished by hair loss and palmar telangiectasias, and the renal disease of the dominant form modifies surveillance [11, 43]. Yellow nail syndrome has nails different from the discoloured nails of chronic lymphoedema of any cause [1]. In generalised lymphatic dysplasia, facial features and intellectual disability point to Hennekam, hydrops fetalis with generalised oedema points to PIEZO1, and CCLA points to Noonan, EPHB4 or MDFIC [3, 31]. GLD is a generalised anomaly of lymphatic development and is distinguished from generalised lymphatic anomaly (GLA, lymphangiomatosis), which is an overgrowth of lymphatic vessels with cystic lymphangiomas in lung, pleura, bone and soft tissue, and which includes Gorham-Stout disease [3]. Undiagnosed multisegmental («patchy») lymphatic dysplasia in the 2016 audit raises the hypothesis of mosaicism or WILD syndrome [3]. Loss-of-function FLT4 causes tetralogy of Fallot without lymphoedema [73]. In children, the French PNDS adds three situations: in infants, the «chubby» foot makes diagnosis difficult, which is clarified in the following months or years; hypertrophy of a limb may reflect a hamartomatous or vascular anomaly, which justifies referral to a reference or competence centre for magnetic resonance imaging; and, in adolescent girls after puberty, lipoedema arises as in adults [20].

6.3. Differential of cellulitis and acute oedema

Lipodermatosclerosis and acute venous hypertension mimic cellulitis; lipodermatosclerosis is usually bilateral, whereas cellulitis is usually unilateral [19]. Mild erythema without systemic signs does not necessarily mean infection [16]. A sudden increase in the volume of a limb requires exclusion of deep vein thrombosis [17].

6.4. Differential of exudative gastroenteropathy and intestinal lymphangiectasia

The diagnosis of PIL requires exclusion of the causes of lymphangiectasia or exudative gastroenteropathy summarised in table 6.4a, according to the French protocol, which notes that some histological descriptions neither seek nor mention lymphangiectasias [100].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

No drug has Food and Drug Administration (FDA) or European Medicines Agency (EMA) authorisation for primary lymphoedema, and no therapeutic method has a satisfactory meta-analysis of rigorous trials; the basis of treatment is complex decongestive therapy, with skin care, compression, exercise and prevention of cellulitis, and early treatment gives better results [16, 76]. The specific evidence for the monogenic forms comes down to expert recommendations in the GeneReviews, case series and consensus statements (ISL 2023, British Lymphology Society and Lymphoedema Support Network 2025, VASCERN 2026), without formal grades of recommendation; one of the recommendations of the lymphoedema-distichiasis GeneReviews, to start stockings before lymphoedema appears, comes from personal communication [11, 105]. VASCERN recommends, after diagnosis, an individual inter- and multidisciplinary plan monitored by lymphoedema therapists, in two phases (intensive and maintenance), and advises against a wait-and-see approach without scheduled follow-up [17]. The systematic review of 14 guidelines concluded that aetiology changes the recommendations little: decongestive therapy followed by lifelong self-management [102]. In France, the 2019 PNDS asks that the diagnosis be confirmed and regular follow-up ensured by a specialist physician in liaison with a reference or competence centre, in coordination with the general practitioner, whose role is to direct the patient to that centre, share follow-up, and offer psychological support and social assistance; treatment involves physiotherapists, nurses, orthotists and orthopaedic pharmacists, therapeutic education teams, physicians, surgeons, podiatrists, psychologists, dietitians and social workers trained in adult and paediatric lymphoedema, and each patient should have specialised multidisciplinary treatment, in most cases an intensive phase followed by maintenance [20].

7.2. Complex decongestive therapy, compression and exercise

Complex decongestive therapy (CDT) has two phases and applies to children and adults. Phase 1, intensive and daily when there is pitting oedema or wounds, combines skin care, manual lymphatic drainage (MLD), muscle pump exercises and short-stretch multilayer bandaging applied only by trained staff; phase 2, maintenance, uses made-to-measure low-elasticity compression garments, with skin care, exercise and MLD when needed [16, 104]. The highest tolerated compression class, between about 20 and 60 mmHg, is probably the most beneficial; contraindications include arterial disease, painful post-phlebitic syndrome, occult neoplasia, acute infection and some dermatoses [16]. VASCERN prefers flat-knit to circular-knit garments, considers compression the cornerstone of treatment at all ages and advises against removing it without monitoring; the ISL notes that there are no trials comparing the two knits [16, 17]. CDT failure is declared only after intensive treatment in a specialised clinic [16]. In a French series of 222 consecutive patients with unilateral primary lymphoedema of the whole lower limb (2009–2017, median age 45.8 years, median duration 73 months), median volume fell from 2845 mL to 1276 mL after a median of 11 days of intensive CDT (median reduction in excess volume of 34%); age, a BMI above 40, previous cellulitis and dermal backflow on lymphoscintigraphy (39% versus 31%) were associated with greater reduction [107]. MLD alone has limited evidence, mainly in recent and mild lymphoedema in young children without fat or fibrosis; vigorous classic massage brings no benefit and may cause harm; intermittent pneumatic compression may displace oedema to the root of the limb and the genitalia; «tuyautage» is probably harmful [16]. Exercise helps in all its modalities, with at least 150 minutes per week of moderate mixed aerobic and resistance activity [16]. VASCERN imposes no restrictions on physical activity at any age («Let the children play!»), proposes 10,000 to 15,000 steps a day in adults and considers that a transient increase in volume with exercise does not justify stopping; compression is removed during exercise if not tolerated, or a lighter garment is used [17]. In children, compression is explained in an age-appropriate way, with routines, the child's participation, colours and contact with other families, information to the school and without excessive pressure [17]. Podiatry is involved for the foot with irreversible lymphoedema [17].

The French PNDS describes the same two-phase division of complete decongestive physiotherapy, systematised by Földi in the 1980s, allows the intensive phase to be omitted when volume is moderate and provides for repeated intensive phases over time; the volume reduction obtained in adults ranges from 30% to 60%, depending on the method of calculation (circumference or volumetry) [20].

Table 7.6. Phases of complete decongestive physiotherapy according to the 2019 French PNDS [20].

Low-elasticity bandages are the only ones recommended by the international consensus statements and the HAS; some French centres superimpose an elastic or cohesive bandage on the short-stretch ones, without comparative data [20]. MLD has not been evaluated in primary lymphoedema; by extrapolation from lymphoedema after breast cancer, a 2015 Cochrane review could not conclude on the benefit of MLD in volume reduction, but accepted a small additive effect to bandaging when volume was moderate [20]. For maintenance, the PNDS calls for made-to-measure high-pressure compression, in the French classification class 3 (20.1–36 mmHg) or class 4 (more than 36 mmHg), with layering of garments to reach high pressures; circular and flat knits have advantages and drawbacks (thickness, stiffness, comfort, cost), and flat knit is reserved for very deformed limbs, marked folds at the ankle or leg and separate garments for the toes (toe caps) or fingers (gloves); layering is easy with circular knit or a combination of circular and flat knit, but difficult with flat knit alone [20]. This case-by-case choice differs from VASCERN's general preference for flat knit (section 7.14) [17]. Therapeutic education, in a programme authorised by the regional health agency, aims at theoretical skills (understanding lymphoedema), procedural skills (applying a bandage, putting on compression), experiential skills (starting treatment when erysipelas develops) and adaptation skills, and is essential to the maintenance phase [20]. In children, parental participation is essential and parents may perform drainage after training; the compression modality is discussed with the family and the child according to age, stockings and sleeves are replaced several times a year because of growth, there are therapeutic education programmes and stays aimed at children and young adults, and vaccination and sport are not contraindicated; there is no consensus on compression in infants before walking and some lymphoedemas improve spontaneously, so some experts treat from diagnosis and others adjust compression to the clinical course or wait for walking to be acquired [20]. This last approach contrasts with that of VASCERN, which advises against a wait-and-see approach without scheduled follow-up [17]. As for physical activity, the PNDS restricts no sport in adults or children, requires supervision and progression in duration, repetition and intensity, recommends compression during exertion without making it mandatory and insists on early prevention of excess weight in children [20].

7.3. Skin care, weight, diet and daily life

Skin care (cleansing, low-pH lotions, emollients, drying of skin folds and interdigital spaces, sun protection, nail care) and education are the basis of all approaches [16, 17]. Tinea pedis is treated with terbinafine cream daily for 2 weeks, followed by daily alcohol wipes if the skin is intact [19]. Lymphorrhoea requires clean, dry skin under compression and specialised assessment [17]. Obesity is the most important risk factor for worsening of lymphoedema; a healthy weight and weighing every 3–6 months are recommended [17]. No special diet has proven value in uncomplicated peripheral lymphoedema, and fluid restriction brings no benefit [16]. In intestinal lymphangiectasia, chylothorax, chylous reflux or chylous ascites, the diet should be strictly low in long-chain triglycerides and supplemented with medium-chain triglycerides (MCT), absorbed directly through the portal vein, with fat-soluble vitamin supplements and possibly a high-protein diet; dietary control is permanent, because the findings recur when the diet is stopped [16, 17, 90]. For hair removal, the least aggressive method is used (trimmer, cream; laser or pulsed light in a reliable clinic) and wet shaving of affected areas is avoided; tattoos avoid the affected area; when travelling, compression, walking during the journey and hydration are maintained, and those with a history of cellulitis carry antibiotics with them [17]. One should not sleep in an armchair with the legs dependent or remain immobile for long periods with the legs dependent, as on long flights [1, 17].

7.4. Treatment of acute cellulitis

Treatment should be immediate, with systemic antibiotics, and anyone who has had cellulitis should have a 2-week antibiotic reserve («rescue pack») of a previously effective drug, to start as soon as the usual symptoms appear, then seeking medical assessment [17, 19]. At home, the extent of the erythema (mark and date the edge) and systemic signs are recorded and, if possible, C-reactive protein, erythrocyte sedimentation rate and white cell count, and microbiology is taken from skin breaks before antibiotics; reassessment is needed if there is no response within 48 hours [19]. The 2025 British guideline recommends 14 days of antibiotics, because shorter courses are associated with early relapse; the VASCERN flowchart indicates 10–14 days or less according to local guidance [19, 108]. Rest, elevation and analgesia with paracetamol, with ibuprofen as an alternative, form part of treatment in the British guideline, which considers the association between non-steroidal anti-inflammatory drugs and necrotising fasciitis unproven (a trial of 48 patients with neither benefit nor fasciitis with ibuprofen); VASCERN considers associated corticosteroids and anti-inflammatory drugs useless [19, 108]. Compression may be removed if painful and should be reapplied as soon as tolerated, with a lower-class garment or a short-stretch bandage, reviewing the fit [19, 108]. If Clostridioides difficile diarrhoea occurs, the antibiotic is stopped immediately [19]. Penicillin allergy should be confirmed (anaphylaxis or generalised rash), considering allergy testing and desensitisation; after penicillin anaphylaxis, cephalosporins are not used [19]. In hospital, intravenous flucloxacillin 2 g every 6 hours is frequently used, with a total duration of at least 2 weeks including the oral phase [19].

Table 7.1. Antibiotic treatment of cellulitis in lymphoedema in adults, orally: the reference doses are those of the 2025 BLS/LSN guideline (duration 14 days); when the SmPC was consulted and differs, it is shown alongside for comparison [19, 109].

The 2025 guideline aligned the choice with the World Health Organization AWaRe classification (2023): macrolides («watch» category) are no longer the first alternative to penicillin and have been replaced by doxycycline («access» category) [19]. In Portugal, the SmPC of Floxapen® (flucloxacillin sodium, 500 mg capsules, Generis Farmacêutica) includes streptococcal and staphylococcal cellulitis and lymphangitis and indicates, in adults and children over 12 years, 500 mg every 8 hours, up to 3 g a day in 3 or 4 doses if needed; below 12 years, 50 mg/kg/day in 3 doses every 8 hours, with powder for oral suspension if the child is under 12 years or under 30 kg; with creatinine clearance below 10 mL/min, 1 g every 8 or 12 hours; it is taken at least 1 hour before or 2 hours after meals, with 250 mL of water, for at least 10 days in beta-haemolytic streptococcal infections [109]. The reference dose in adults is that of the British guideline, 500 mg to 1 g every 6 hours, with no maximum dose defined in the source, with preference for the 1 g every 6 hours dose (4 g/day) according to EUCAST 2025, at the cost of more gastrointestinal effects [19]. For comparison, the SmPC indicates 500 mg every 8 hours with a maximum of 3 g/day, so the 4 g/day dose exceeds the oral maximum of the Portuguese SmPC and also falls outside the British SmPC [19, 109]. The doses in table 7.1 without a consulted SmPC (amoxicillin, doxycycline, clarithromycin, erythromycin, clindamycin, co-amoxiclav, co-trimoxazole, metronidazole) come only from the guideline [19]. The same SmPC contraindicates flucloxacillin in hypersensitivity to beta-lactams and in previous drug-associated jaundice or hepatic dysfunction, and warns of anaphylaxis, acute generalised exanthematous pustulosis, hepatotoxicity (more severe above 50 years and in HLA-B*57:01 carriers, without routine screening), C. difficile colitis, hypokalaemia at high doses and high anion gap metabolic acidosis in combination with paracetamol; it also states that penicillin G or V is the first-choice treatment for beta-haemolytic group A streptococcal infections, such as erysipelas [109]. Before prescribing, interactions are checked, especially those of macrolides, and the combination of a macrolide with a statin is avoided [19].

In children, the British guideline maintains the same approach, sends to hospital for intravenous antibiotics those with systemic symptoms or local worsening, does not recommend doxycycline below 8 years and refers doses to the British paediatric formulary [19]. The oral paediatric doses available in the SmPCs consulted are those of flucloxacillin (50 mg/kg/day in 3 doses below 12 years) and of phenoxymethylpenicillin for treatment of streptococcal skin and soft tissue infections, including erysipelas (up to 1 year, 62.5 mg every 6 hours; 1–5 years, 125 mg every 6 hours; 6–12 years, 250 mg every 6 hours; above 12 years, 250–500 mg every 6 hours) [109, 110]. For penicillin allergy in children under 8 years, the British SmPC of clarithromycin oral suspension indicates, from 6 months to 12 years, about 7.5 mg/kg twice a day, up to a maximum of 500 mg twice a day, for 5–10 days in the general indications; the 14-day duration for cellulitis in lymphoedema is an extrapolation from the adult guideline, to be discussed with microbiology [19, 111].

The French PNDS uses the term erysipelas (acute bacterial dermohypodermitis due to beta-haemolytic streptococcus, of which lymphoedema is the main risk factor) and proposes, in adults, oral amoxicillin 3 g a day in 3 doses or pristinamycin 3 g a day in 3 doses for 10–14 days, or clindamycin 600 mg 3 times a day (1.8 g a day), fixed doses with no distinct maximum defined in the source, with the parenteral route in the first days if there are signs of severity (hypotension, shock); in children, amoxicillin about 50 mg/kg/day in 3 doses or co-amoxiclav, with no maximum dose defined in the source [20]. These regimens were superseded by the HAS good practice recommendation on bacterial skin infections, published in the same month, which is the current French standard for non-necrotising bacterial dermohypodermitis (a designation that replaces erysipelas): in adults, amoxicillin 50 mg/kg/day in 3 doses (maximum 6 g/day), a dose that exceeds the fixed 3 g of the PNDS from 60 kg, or, in penicillin allergy, pristinamycin 1 g 3 times a day or clindamycin 1.8 g/day in 3 doses (up to 2.4 g/day above 100 kg); in children, co-amoxiclav 80 mg/kg/day of amoxicillin in 3 doses (maximum 3 g/day) or, in allergy, clindamycin 40 mg/kg/day in 3 doses above 6 years or co-trimoxazole 30 mg/kg/day of sulfamethoxazole in 3 doses below 6 years; the duration is 7 days and not 10–14 days, with no adjuvant corticosteroids or NSAIDs [112]. It does not recommend an associated corticosteroid and contraindicates non-steroidal anti-inflammatory drugs; fever disappears within 48–72 hours and local signs in less than 10 days, but the limb may take weeks to recover its previous volume; compression may be maintained in the acute phase as tolerated [20]. The criteria for admission are poor clinical tolerance, severe local signs (skin detachment, bullous erysipelas) and associated risk factors (diabetes, advanced or very young age, other comorbidities) [20]. The protocol reports an incidence of erysipelas in children with lymphoedema similar to that in adults [20]. Compared with the British guideline (table 7.1), the French first line is amoxicillin and not flucloxacillin, the daily amoxicillin dose (3 g) is double the British alternative of 500 mg every 8 hours (1.5 g), the French clindamycin dose (1.8 g a day) exceeds the British second-line dose (300 mg every 6 hours, 1.2 g a day), the minimum duration is 10 and not 14 days and anti-inflammatory drugs are contraindicated, whereas the British guideline accepts ibuprofen as an alternative analgesic; the British guideline, more recent and specific to lymphoedema, remains the reference, and in France the current standard is the 2019 HAS recommendation on skin infections, which replaces the PNDS regimen [19, 20, 112].

7.5. Prophylaxis of recurrent cellulitis

The British guideline recommends considering antibiotic prophylaxis in patients with two or more episodes of cellulitis per year, decided with the specialised lymphoedema service or microbiology, after confirming that all episodes were bacterial cellulitis (and not acute venous hypertension or lipodermatosclerosis), that they were not incompletely treated episodes with 5–7-day courses (a relapse within 2–3 weeks counts as the same episode) and that there is no reversible cause such as tinea pedis [19]. VASCERN recommends considering long-term prophylaxis in children and adults with «more than two episodes per year», and the ISL recommends prophylactic penicillin when limb sepsis recurs despite optimal CDT, without stating the dose [16, 17]. Phenoxymethylpenicillin 250 mg every 12 hours is the first choice, with 500 mg every 12 hours if BMI is 33 or above; these doses coincide with the prophylactic doses labelled in the British SmPC (250 mg twice a day in prophylaxis of rheumatic fever; 500 mg every 12 hours in pneumococcal prophylaxis above 12 years), which are the reference, while the indication (prophylaxis of cellulitis) is off-label [19, 110]; the guideline's guide translates this threshold into weight (for example, more than 82 kg for 1.58 m, more than 95 kg for 1.70 m, more than 114 kg for 1.86 m) [19]. The GeneReviews on Milroy disease («250 mg twice a day for 1–2 years») and lymphoedema-distichiasis («500 mg a day») cite the 2016 British consensus and give the same total daily dose; the 2025 edition replaces it and adds the BMI adjustment [1, 11, 19]. In penicillin allergy, doxycycline 100 mg once a day is used, with photoprotection; in allergy with doxycycline intolerance, clarithromycin 250 mg a day; in pregnancy, erythromycin 250 mg every 12 hours; in anogenital cellulitis, phenoxymethylpenicillin and, if ineffective, trimethoprim 100 mg at night; if the response is inadequate, cefalexin 125 mg a day or clindamycin 150 mg a day, with a risk of C. difficile and resistance and specialist review [19]. After 1 year of effective prophylaxis, stopping is considered, especially if risk factors have been corrected; if important factors persist, a further year is considered; if there is relapse after stopping with persistent factors, prophylaxis may be lifelong, with at least annual review; prophylaxis is suspended during treatment of an acute episode [19]. No penicillin resistance has been observed in group A streptococci, unlike the alternatives [19].

The French PNDS proposes antibiotic prophylaxis from 2–3 erysipelas episodes per year, combined with treatment of portals of entry (mycotic interdigital intertrigo, fissured hyperkeratosis of the heels, onychomycosis) and, if necessary, podiatric follow-up, with benzathine benzylpenicillin 2.4 million units every 2–3 weeks (intramuscularly) or oral phenoxymethylpenicillin 1 million units 2 to 3 times a day, for a prolonged period without consensus on duration; the effect is suppressive, with a risk of relapse after stopping [20]. The later 2019 HAS recommendation on skin infections lowered the threshold to two episodes in the previous year with uncontrollable risk factors, limits prophylaxis to adults and sets benzathine benzylpenicillin at 2.4 million units intramuscularly every 2–4 weeks, penicillin V at 1–2 million units a day in 2 doses, according to weight, and azithromycin 250 mg/day in penicillin allergy; the PNDS penicillin V dose (2–3 million units a day) therefore exceeds that of the current French standard [112]. By the FDA label equivalence (250 mg corresponds to 400,000 units), 1 million units of penicillin V is equivalent to about 625 mg, so the French daily dose (about 1.25–1.9 g) is 2.5 to almost 4 times the British dose of 250 mg every 12 hours (500 mg a day); benzathine benzylpenicillin is not in the British guideline, and the French threshold (2–3 episodes per year) is higher than the British one (two or more) [19, 20, 113]. The reference in this article remains the British dose, adjusted for BMI, and in France the regimen of the 2019 HAS recommendation on skin infections is the current national alternative (section 7.14) [19, 20, 112].

Phenoxymethylpenicillin (penicillin V) is an oral penicillin active against streptococci. Prophylaxis of cellulitis is not in the labels: the FDA label of penicillin V potassium tablets indicates, in adults and children aged at least 12 years, 125–250 mg every 6 to 8 hours for 10 days in erysipelas and streptococcal infections, 250–500 mg every 6 to 8 hours in mild skin and soft tissue infections and 125–250 mg twice a day continuously in prophylaxis of rheumatic fever, and gives no doses below 12 years [113]. The British SmPC of the oral suspension indicates 250 mg twice a day, continuously, in prophylaxis of rheumatic fever and chorea, and, in pneumococcal prophylaxis in asplenia and sickle cell disease, 500 mg every 12 hours above 12 years, 250 mg every 12 hours from 6 to 12 years and 125 mg every 12 hours below 5 years; it is taken at least 30 minutes before or 2 hours after meals, and the dose is reduced in marked renal impairment [110]. In the absence of a paediatric dose for prophylaxis of cellulitis in lymphoedema, the doses for pneumococcal prophylaxis in asplenia and sickle cell disease, which is continuous antibacterial prophylaxis with the same drug, are the available extrapolation: 125 mg every 12 hours below 5 years and 250 mg every 12 hours from 6 to 12 years; the SmPC does not assign the 5-year-old child to either of the two bands, and above 12 years the adult dose of the guideline applies [19, 110]. The extrapolation is declared as such: the efficacy of prophylaxis was demonstrated in adults with recurrent leg cellulitis, not in children with primary lymphoedema [114, 115]. The most common adverse effects are nausea, vomiting, abdominal pain or discomfort, diarrhoea, black hairy tongue and skin reactions (urticarial, erythematous or morbilliform rash, pruritus); anaphylaxis is rare but serious and may be fatal, there is cross-reactivity with cephalosporins and a risk of C. difficile colitis; the contraindication is hypersensitivity to any penicillin [110, 113]. The efficacy of this prophylaxis rests on the PATCH I trial and the Cochrane review (table 7.5), conducted in populations with recurrent leg cellulitis and not specifically with primary lymphoedema [114, 115]. In Portugal, Infomed searches for authorised and marketed «fenoximetilpenicilina» and «penicilina V» returned no medicinal products, which makes the choice of the Portuguese alternative a clinical decision not covered by the guidelines consulted [116].

7.6. Non-pharmacological prevention of cellulitis

Decongestive therapy reduces the frequency of cellulitis, and compression reduced recurrence in a randomised trial (table 7.5) [19, 117]. Prevention includes treating cracked or macerated skin between the toes, dermatitis, wounds and ulcers and cutaneous lymphangiectasias with lymphorrhoea, using emollients, washing wounds and bites with soap and water and applying antiseptic, and controlling weight, because a BMI above 30 is a risk factor [17, 19]. Prevention of foot infections (athlete's foot, infected ingrown toenails, infected eczema) is the measure most cited by the GeneReviews [1, 11]. Specialised lymphoedema surgery may reduce cellulitis in selected patients [19].

7.7. Surgery

The ISL accepts surgery in selected patients, by experienced surgeons, as an adjunct to CDT (after removal of the fluid component, without pitting) or when CDT has failed, always with subsequent compression in advanced stages [16]. Microsurgical techniques include lymphaticovenous anastomoses (LVA), with patency of more than 25 years in some cases, autologous lymphatic vessel transplantation and vascularised lymph node transfer (VLNT), the latter with a risk of lymphoedema at the donor site; the ISL warns that these procedures should be performed «with special caution» in children and in some forms of primary lymphoedema [16]. Specialised liposuction is effective in non-pitting lymphoedema with excess fat, with mandatory continuous compression; surgical resection is reserved for elephantiasis and advanced genital lymphoedema; the Charles and Thompson operations, omental transposition and enteromesenteric bridges should be avoided [16]. VASCERN lists among practices to avoid reconstructive surgery in primary lymphoedema and any lymphoedema surgery without an inter- and multidisciplinary team, which diverges from the ISL position [16, 17]. The specific evidence is level IV: in 6 patients with Milroy disease and chylothorax, LVA and peripheral node-to-vein anastomoses reduced limb volume and almost completely resolved chylothorax over 32 ± 17.9 months [88]. In chylous reflux syndromes, the ISL describes CT- or MRI-guided sclerotherapy, interventional radiology, ligation of dysplastic visceral lymphatics and lymphovenous shunting, including of the thoracic duct, after multimodal imaging [16]. In MDFIC-related CCLA, lymphaticovenous bypass in selected patients has unknown long-term benefit [18]. A child with a THSD1 variant and protein-losing enteropathy was treated with peripheral lymphatic shunts (2026 case report) [118]. Varicose vein surgery in lymphoedema-distichiasis may worsen oedema and the risk of cellulitis, so compression is preferred; cosmetic surgery for lymphoedema often has disappointing results [11].

The French PNDS is more restrictive than the ISL: it considers that lymphatic repair surgery currently has no place in treatment and does not recommend it outside clinical trials, because of the poor methodological quality of the studies and the risk of serious adverse effects; LVA are performed very marginally in France, and autologous lymph node transplantation (cervical, axillary or inguinal) lacks objective volumetric assessment and exposes the patient to donor-site lymphoedema, lymphocele, hydrocele and hypoaesthesia [20]. It accepts resection of excess skin persisting after a large volume reduction, always with bandaging and compression maintained, resection-plasty of genital lymphoedema in both sexes and isolated circumcision in troublesome lymphoedema of the foreskin; liposuction, used mainly in secondary upper limb lymphoedema, requires continuous lifelong high-class compression and has spread little for that reason [20]. In children, only resection of genital lymphoedema may be proposed, by decision of a reference or competence centre [20].

7.8. Entity-specific management

In lymphoedema-distichiasis, symptomatic distichiasis is treated conservatively with lubrication or epilation, or definitively with cryotherapy of the posterior lamella, electrolysis or lid splitting, with possible recurrence; ptosis is corrected surgically if it obstructs vision; symptomatic SEDAC is neurosurgical; heart disease, arrhythmia, cleft palate, scoliosis and renal malformations follow standard practice [11, 52]. The same GeneReviews recommends regular lymphoedema therapy every 6 months and clinical assessment of lymphoedema and varicose veins 1–2 times a year (surveillance table in section 11) [11]. In Milroy disease, hydroceles and urethral anomalies are managed in urology; for hydrocele in a patient with lymphoedema, a median scrotal incision is preferable to an inguinal one [1, 17]. In the Hennekam syndromes and intestinal lymphangiectasia, a low-fat diet with MCT is the cornerstone; albumin and immunoglobulins as needed, fat-soluble vitamins, drainage of effusions and, only in rare segmental cases, intestinal resection are added; octreotide, antiplasmin and corticosteroids have inconsistent effects; in an infant with protein-losing enteropathy, parenteral nutrition with transition to a special enteral formula corrected the oedema, ascites, albumin and IgG; triggers such as cytomegalovirus are sought and treated, and hypogammaglobulinaemia requires immunological assessment [61, 79, 90]. In GATA2 deficiency, allogeneic haematopoietic stem cell transplantation is the only curative treatment (overall survival of 85% in 59 patients with a myeloablative regimen and post-transplant cyclophosphamide), it does not reverse lymphoedema, and related donors should be tested; early HPV vaccination, azithromycin prophylaxis, antimycobacterial treatment and immunoglobulins form part of management [36]. In dehydrated stomatocytosis, splenectomy is avoided [65]. In HLTS/HLTRS, renal function and blood pressure are monitored, with dialysis or transplantation if there is renal failure, echocardiography for the aorta and von Willebrand factor replacement for procedures if it is low [43]. In PTPN14-related choanal atresia, an immediate oral airway precedes surgical repair and ENT follow-up for restenosis; hard, non-pitting lymphoedema limits compression [83]. In ectodermal dysplasia with immunodeficiency and osteopetrosis, antibiotics treat infections and haematopoietic stem cell transplantation reconstituted immunity and reversed osteopetrosis in some patients [45]. In MDFIC-related CCLA, treatment is supportive (drainage of chylous effusions, MLD, physiotherapy, immunological assessment and a protocol for severe bacterial infection) [18].

7.9. Drugs that worsen oedema and agents to avoid

VASCERN considers that no drug is absolutely contraindicated, but that calcium channel blockers, corticosteroids, non-steroidal anti-inflammatory drugs, sex hormones and related compounds, pregabalin, docetaxel, zoledronic acid and sirolimus may worsen oedema, and recommends considering alternatives [17]. The GeneReviews highlight calcium channel blockers, wounds on oedematous limbs and prolonged immobility with the legs dependent [1]. Sirolimus has been reported as a cause of generalised lymphoedema in a transplant recipient and of lymphoedema in patients with complex lymphatic malformations [16, 28]. Diuretics have no proven benefit in lymphoedema: VASCERN includes their use to treat lymphoedema among practices to avoid, as they are ineffective in most cases, and the ISL discourages prolonged administration because of marginal benefit and the risk of fluid and electrolyte imbalance, accepting them in comorbidities, cavity effusions, protein-losing enteropathy and palliative care [1, 16, 17]. Anti-inflammatory and antifibrotic drugs have no documented clinical value, benzopyrones (rutosides, bioflavonoids) do not replace CDT and high-dose coumarin has been associated with hepatotoxicity; mesotherapy with hyaluronidase has uncertain and possibly harmful benefit [16]. Starting anticoagulation solely because of lymphatic oedema is not recommended [17]. The French PNDS adds that venotonics are not effective, that diuretics are never indicated in isolated lymphoedema and are dangerous in that indication, that pneumatic pressotherapy has no quality studies in primary lymphoedema, that adhesive tapes («K-taping»), acupuncture, balneotherapy and endermology have not shown volume reduction, that spa treatments have not been evaluated and that readjustable day and night compression orthoses are under evaluation; psychological support, relaxation and yoga may help some patients, without published data [20].

7.10. Targeted therapies and off-label use

Propranolol is a non-selective beta-blocker. Its R(+) enantiomer directly inhibits the transcription factor SOX18, independently of beta-blockade, which underpins its use in HLTRS [84]. In a Jordanian child with HLTRS and the variant NM_018419.3:c.492_505dup, diagnosed at 11 months, a progressive pericardial effusion appeared at 17 months requiring pericardiocentesis and recurred within 6 weeks despite ibuprofen for 3 weeks and prednisone for 10 days, with haemodynamic compromise; oral propranolol was started at 0.8 mg/kg/day in 3 doses and increased every 2–3 weeks up to a maximum of 4.1 mg/kg/day, limited by wheezing; the effusion resolved after about 3 mg/kg/day was reached, without further pericardiocentesis or recurrence up to June 2018 [84]. The evidence is a single case with preclinical data (rescue of corneal neovascularisation in the Ragged Opossum mouse), and a propranolol dose-escalation trial (1, 2 and 3 mg/kg/day) in primary lymphoedema from 12 years of age ended for lack of funding with 1 patient enrolled [84, 119]. The available labels are those for proliferating infantile haemangioma: Hemangeol® (propranolol hydrochloride, oral solution 4.28 mg/mL, FDA, approval of 14 March 2014) is started between 5 weeks and 5 months at 0.6 mg/kg twice a day, at least 9 hours apart, increasing to 1.1 mg/kg twice a day after 1 week and to 1.7 mg/kg twice a day (target maintenance dose; no maximum dose defined in the source) after 2 weeks, for 6 months, during or shortly after a feed (risk of hypoglycaemia), withholding the dose if the child does not eat or vomits and monitoring heart rate and blood pressure 2 hours after initiation and each increase; Hemangiol® (EU, authorisation of 23 April 2014) is started at 0.5 mg/kg twice a day and increased to maintenance of 1.5 mg/kg twice a day (target dose, with no additional maximum dose defined in the source consulted) for 6 months, with monthly monitoring [120, 121]. The FDA label expresses the dose as propranolol hydrochloride, and the sources consulted do not explain the numerical difference between the two labels [120, 121]. Labelled contraindications include preterm infants with a corrected age below 5 weeks, weight below 2 kg, asthma or bronchospasm, heart rate below 80 bpm, atrioventricular block greater than first degree, decompensated heart failure, blood pressure below 50/30 mmHg and phaeochromocytoma; safety and efficacy have not been established above 1 year of age [120]. The dose used in HLTRS (about 3–4 mg/kg/day) is therefore higher than the labelled maintenance dose for haemangioma (3–3.4 mg/kg/day) and off-label.

Sirolimus, an mTOR inhibitor, is used in specialised centres in complex lymphatic malformations (macrocystic, microcystic or mixed), especially in newborns and children, under medical supervision because of serious adverse effects; it is not authorised for lymphatic anomalies (the FDA indications are prophylaxis of renal rejection and lymphangioleiomyomatosis) [16, 18]. In the phase II trial of Adams and colleagues in complicated vascular anomalies, the starting dose was 0.8 mg/m² per dose twice a day, adjusted to trough levels of 10–15 ng/mL, for 12 cycles of 28 days; of the 57 patients evaluable at cycle 6, none had a complete response, 47 had a partial response, 3 stable disease and 7 progression; grade 3 or higher toxicity was haematological in 27% [122]. In MDFIC-related CCLA, sirolimus produced no significant volume reduction [18]. In newborns with generalised lymphatic anomaly and hydrops fetalis, a 2026 series on the efficacy of sirolimus was published [123].

Trametinib, a MEK inhibitor (Mekinist®, authorised only in BRAF V600 tumours), has a rationale in lymphatic anomalies with RAS-MAPK activation and not in MDFIC, which does not belong to this pathway [18]. In a preterm infant with Noonan syndrome (PTPN11), congenital pulmonary lymphangiectasia and refractory chylothorax, a 5-week course with a maximum dose of 0.025 mg/kg/day resolved the chylothorax and allowed discharge; in a review of 16 published cases and this one, all improved in the short term, with 3 deaths presumed unrelated and no long-term data [124]. In 5 children with complex lymphatic malformations (kaposiform lymphangiomatosis, generalised lymphatic anomaly; NRAS mutated in 80%), trametinib resolved the coagulopathy and produced 80% radiological partial responses with minimal toxicity; in another patient, the combination of trametinib and sirolimus at subtherapeutic doses was effective after loss of efficacy of each drug alone [106, 125]. These data do not apply to monogenic peripheral lymphoedema.

Etacrynic acid (Edecrin®, a loop diuretic) is the only drug whose FDA label mentions lymphoedema, in the indication «short-term management of ascites due to malignancy, idiopathic oedema, and lymphedema»; the adult dose is 50–200 mg/day, starting with 50 mg and with progressive increases, and in children (excluding infants) 25 mg, with increments of 25 mg; it is contraindicated in anuria and in infants, and causes severe fluid and electrolyte losses, hypotension, hypokalaemia and sometimes permanent ototoxicity [126]. This historical indication does not correspond to the current ISL and VASCERN recommendations, which advise against diuretics in peripheral lymphoedema [16, 17]. Faricimab (Vabysmo®), a bispecific inhibitor of VEGF and angiopoietin 2, is authorised only by intravitreal route in retinal diseases and has not been studied in lymphoedema [28].

7.11. Regulatory status

In Brazil, ANVISA open data (updated on 13 October 2026) record 11 active registrations of phenoxymethylpenicillin, among them the reference product Pen-Ve-Oral® (Eurofarma, registration 100430685) and generic phenoxymethylpenicillin potassium (Teuto), and 689 active registrations with amoxicillin, including Amoxil® (amoxicillin) and Clavulin® (amoxicillin with potassium clavulanate), both from GlaxoSmithKline Brasil; prophylaxis of cellulitis with penicillin V is therefore feasible in Brazil, unlike what the Infomed search suggests for Portugal [116, 127]. The text of the package inserts was not consulted because the electronic package insert database returned a server error (HTTP 502), and the extract did not include flucloxacillin, propranolol or the other drugs [127, 129].

7.12. Intervention trials and studies

Table 7.5. Trials and studies with published results.

These studies do not allow indirect comparison: they differ in population (recurrent leg cellulitis without defined primary lymphoedema, lymphoedema secondary to breast cancer, complex vascular anomalies), design and outcome. The relative reduction in recurrence of cellulitis with penicillin (HR 0.55) corresponds to an absolute reduction of 15 percentage points over 12 months (37% to 22%), with loss of effect after discontinuation [114]. No randomised trial has specifically included patients with Milroy disease, lymphoedema-distichiasis or another monogenic form, and the ClinicalTrials.gov search found no pharmacological trials targeting these forms, which does not demonstrate that none exist [72, 134]. The negative or inconclusive trials (Lymfactin® phase 2, ubenimex) and the terminated propranolol trial form part of the body of evidence [119, 128, 132].

7.13. Developments in the last 12 months and research

Immediately before the October 2025 to October 2026 window, the British Lymphology Society and the Lymphoedema Support Network published the August 2025 guideline on cellulitis in lymphoedema (available from 15 September 2025), which replaces the 2016 consensus, swaps macrolides for doxycycline as the alternative to penicillin and adds BMI adjustment of prophylaxis (guideline) [19]. Within the window, VASCERN published in July 2026 version 2 of the «Do's and Don'ts» factsheets on paediatric and primary lymphoedema and an e-learning course (expert consensus) [17, 135]. Stanford Medicine announced in September 2026 the results of a 1-year open-label study of acebilustat, a leukotriene A4 hydrolase inhibitor, in 23 patients with lower limb lymphoedema, with a mean loss of about 1 litre of volume and reduction in skin thickness and fibrosis; the Scientific Reports paper was not located in Europe PMC, the placebo-controlled upper limb trial (NCT05203835, 40 patients) ended in December 2025 without results in the registry and a phase 3 is planned (open-label human study and institutional press release, without a regulatory application) [133, 136]. A phase 1/2 mRNA therapy trial (APERNAVEC, FlashRNA® vector, CHU de Toulouse, 9 patients, secondary lymphoedema, planned start October 2026), an inelastic compression trial (23–32 mmHg) in 30 children and young people aged 1 to 25 years with primary lymphoedema (Kraków, planned start September 2026, because paediatric algorithms are extrapolated from adults with secondary lymphoedema) and an observational biomarker study (Ljubljana, VASCERN centre) have been registered [137–139]. At the molecular level, an FLT4 variant p.(Ala1059Pro) with reduced kinase activity in vitro has been characterised (preclinical study) [85]. Ongoing are a study of the expression of CELSR1 variants (Montpellier), a study of microbiopsies and transcriptomics (Toulouse) and the French prospective cohort COGRare5 of pregnancies in rare vascular diseases, including primary lymphoedema [140–142]. Lymphangiogenic therapies with VEGF-C, which produced functional lymphatics in the mouse, have not yet translated into the clinic [1, 16].

7.14. Divergences between guidelines

The 2019 French PNDS, which predates the other guidelines in the table (literature search up to June 2018), diverges from them on the following points [20]:

7.15. Pregnancy, lactation, perioperative care and transition

Pregnancy increases lymphatic filtration and may worsen lymphoedema, generally reversibly, and in lymphoedema-distichiasis pregnancy and oral contraceptives may precipitate the onset of oedema [11, 17]. Usual obstetric surveillance with a focus on lymphoedema is recommended, with more frequent assessments by the therapist, maintenance of adapted compression (for example, thigh-length stockings instead of tights), weight control and venous duplex ultrasound in the event of a sudden increase in volume; all compression should not be stopped nor anticoagulation started solely because of the oedema [11, 17]. In pregnancy, doxycycline and clarithromycin are not used; in true penicillin allergy, erythromycin 500 mg every 6 hours is used for treatment and 250 mg every 12 hours for prophylaxis [19]. The British SmPC of phenoxymethylpenicillin advises, as a precaution, avoiding the drug in pregnancy because of limited data, and states that metabolites pass into milk in quantities with probable effects on the infant; the British guideline keeps it for prophylaxis and VASCERN asks that it be confirmed that prophylaxis is not harmful to the fetus, so the decision is individual [17, 19, 110]. The Portuguese SmPC of flucloxacillin allows use in pregnancy if the benefit outweighs the risk and during breastfeeding [109]. Lymphoscintigraphy is contraindicated in pregnant and breastfeeding women, so imaging confirmation of lymphoedema arising in pregnancy is postponed until after breastfeeding [20]. Any surgery on a limb with lymphoedema, even for an unrelated cause, should be discussed with the reference centre, with lymphatic-sparing incisions, compression maintained after surgery and volume measurement before and after [17]. The British guideline recommends, for surgery in the lymphoedematous region (including LVA and liposuction), a therapeutic course of antibiotics started immediately before and continued for 5–7 days; for minor skin surgery, no antibiotic if there has been no previous cellulitis, a single dose if there has been 1 episode and a therapeutic course if cellulitis is recurrent; for more invasive surgery, a therapeutic course in all [19]. Anaesthesia poses no particular problems; blood sampling, infusions and blood pressure measurements may be performed on the affected limb, but the unaffected limb is preferred [17]. Transition from paediatric to adult care takes place within the same specialised centre or care network with local providers, with an «open door» policy and active self-management; the scope of the PPL-WG covers primary lymphoedemas in children and adults and secondary lymphoedema up to 18 years of age [14, 17].

In PIL, data on pregnancy are scarce; isolated cases describe normal pregnancies, without consequences for the newborn, with the diet and treatments maintained [100]. Transition to adult care is discussed from 15 years and should be completed by 20, with alternating or joint consultations, reassessment of complications and of adherence to the diet, vitamins and MCT, and therapeutic education without the parents [100]. Therapeutic education, individual with the dietitian and in group workshops in adolescence, is needed throughout life (fat content of foods, recipes with MCT oil, meals eaten away from home), with psychological support because of the dietary restriction [100].

7.16. Primary intestinal lymphangiectasia: treatment according to the French protocol (2022)

Objectives. Treatment aims to reduce gastrointestinal chyle loss, by limiting long-chain triglycerides, to recover albumin and reduce oedema; provide fat-soluble vitamins (A, D, E, K) and avoid essential fatty acid deficiency; supplement medium-chain triglycerides (fewer than 10 carbon atoms); monitor complications such as lymphoma and life-threatening serous effusions (pleural effusion, pericardial effusion with tamponade, ascites); and, in children, avoid deficiencies and malnutrition with growth retardation [100].

Diet. A strict low-fat diet (fat below 10% of total energy intake), enriched in medium-chain triglycerides (MCT) and high in protein, is the basis of treatment, prolonged and sometimes permanent; it reduces chylomicron formation and splanchnic lymphatic pressure, and MCT are absorbed via the portal vein without passing through the lymphatics [100]. In adults, MCT oil (at least one tablespoon per meal) brings lipid intake close to normal, and protein intake may reach 3 g/kg per day, with fat-free high-protein supplements if needed [100]. In infants, formulas without long-chain fat and enriched in MCT (more than 50%) and essential fatty acids are used, which may be continued beyond 3 years; from the start of diversification (4 full months), replacement fats with MCT are added and, if the formula does not cover requirements, small amounts of vegetable oil (rapeseed alternating with sunflower), as well as oily fish once a week and essential fatty acid capsules when the child can swallow them [100]. The essential fatty acid requirements cited by the protocol (source: AFSSA 2010) are, for linoleic acid, alpha-linolenic acid and docosahexaenoic acid respectively: 2.7% and 0.45% of energy intake and 70 mg/day from 0 to 3 years; 4% and 1% and 125 mg/day from 3 to 9 years; 4% and 1% and 250 mg/day from 10 to 18 years [100]. After a few weeks of well-followed diet, oedema, albumin, gammaglobulins and lymphocytes tend to improve without normalising, which allows albumin infusions to be spaced out or stopped; adherence should be reassessed in the event of inefficacy, and in children the diet may be progressively broadened under monitoring, because essential fatty acid requirements (especially omega-3) are high [100]. The diet is less effective than this description suggests in several series: in the Seoul paediatric series (2000–2020), only one patient responded to the diet [143].

Enteral and parenteral nutrition. In non-responders with severe malnutrition, enteral nutrition that is always low in fat (elemental, semi-elemental or polymeric, with no demonstrated difference in efficacy) is used with intravenous provision of essential fatty acids, vitamins and trace elements; exclusive parenteral nutrition is rare, but the young infant often needs a strict fat-free diet with monthly or bimonthly infusions of lipids and vitamins [100].

Octreotide. Used since 1998, off-label, always combined with the diet; there is no randomised trial, and clinical, albumin and histological improvement is inconstant [100]. In the Seoul series, octreotide had no effect in one patient and the disease relapsed in another after 3 months [143]. The proposed mechanisms include reduced fat absorption and thoracic duct flow and reduced splanchnic blood flow [100].

Sirolimus and everolimus. Sirolimus, owing to its antilymphangiogenic action (VEGFA and VEGFC signalling), is used with described benefit; the French protocol, based on Kwon and colleagues, proposes in children a strategy by extent: exclude secondary causes, define extent (MR lymphography, capsule endoscopy), control the enteropathy with a high-protein fat-free diet or bowel rest with parenteral nutrition, treat localised forms by surgery or lymphatic embolisation, use octreotide and then sirolimus in diffuse gastrointestinal forms, and sirolimus before octreotide in systemic forms with effusions [100, 143]. In the Seoul series, the 4 patients treated with sirolimus improved, after 3–4 months when the lesions were only intestinal and after 1 month when they were extensive, and one patient was cured after two lymphatic embolisations [143]. Before sirolimus, full blood count, electrolytes, urea, creatinine, liver tests, cholesterol, triglycerides, blood glucose, HIV and hepatitis B and C serology, a pregnancy test if applicable, a tuberculosis test (and chest radiograph if at risk) and stool testing for strongyloidiasis are requested, with ivermectin if there are risk factors [100]. Everolimus (1.6 mg/m² per day, trough 5 to 15 ng/mL) gave a partial response in a 12-year-old child [100].

Other measures. Propranolol has been proposed in isolated cases in infants before 12 months, without studies [100]. Albumin infusions are symptomatic for large effusions and disabling oedema, every 1–3 weeks, with a transient effect [100]. In repeated bacterial infections with profound hypogammaglobulinaemia, subcutaneous immunoglobulins are used (sometimes with octreotide), with high requirements owing to gastrointestinal leakage; in children, supplementation may be proposed for profound hypogammaglobulinaemia even without infections [100]. Despite hypoalbuminaemia sometimes below 15 g/L, thrombotic risk is not increased, and anticoagulation follows the indications for the general population [100]. Diuretics (furosemide, spironolactone) are used for persistent oedema in adults, and iron deficiency may need to be treated [100].

Surgery and embolisation. Intestinal resection is considered only in segmental and very localised forms, with marked clinical and biological improvement; lymphatic embolisation, which can be repeated, has shown efficacy in some children with PIL limited to one territory and the protocol accepts it as first line in these cases [100, 143]. In large or recurrent pleural effusions, the basis is the diet, with evacuation or drainage by a fine drain (about 16 French); if the leak persists, pleural talc poudrage is proposed, preferably by video-assisted thoracoscopy (symphysis in more than 80% of cases in neoplastic effusions, from which the data come); parietal pleurectomy should be avoided as first line, because it damages the parietal lymphatics and may worsen the leak [100].

Associated lymphoedema. It is treated like the other primary lymphoedemas (section 7.2): an intensive phase with low-elasticity bandages and a maintenance phase with elastic compression, skin care and exercise; bandaging is taught to parents as early as possible, and made-to-measure French class 3 compression (20–36 mmHg) is possible from the acquisition of walking [20, 100].

Divergences and limits. The protocol's sirolimus trough target (5–15 ng/mL initially, 4–15 ng/mL during monitoring) coincides with that of the lymphangioleiomyomatosis label, but the paediatric dose (0.08–0.1 mg/kg/day) is extrapolated from vascular malformations and is not on the label [100, 145]. The protocol's paediatric octreotide doses are off-label; the label does not demonstrate safety in children and describes serious events below 2 years [100, 144]. The protocol's alpha-1-antitrypsin clearance thresholds (24 mL/24 h in children, 15 mL/24 h in adults) are those of French practice and depend on the laboratory [100]. The guideline is the reference for dosing, and the label serves for comparison.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by inheritance and scenario

In Milroy disease, most patients have an affected parent and about 10% are simplex cases; the proportion of de novo variants is unknown, because parental testing is incomplete and reduced penetrance and germline mosaicism conceal transmission [1]. In lymphoedema-distichiasis, about 75% of patients have an affected parent and about 25% have a de novo variant; an apparently negative family history is confirmed only after slit-lamp examination of the parents or molecular testing, because of variable expressivity [11, 35]. In MCLMR, variants are de novo in 40% of families [38]. In both main dominant diseases, the risk to siblings is 50% when a parent is affected or a carrier, and about 1% when the variant is not detected in the parents' leucocytes, owing to the possibility of germline mosaicism (theoretical in lymphoedema-distichiasis, with no cases reported); clinically unaffected parents of unknown genetic status confer a low risk but higher than that of the population [1, 11]. Each child of a patient has a 50% probability of inheriting the variant, with unpredictable manifestations because of intrafamilial variability and incomplete penetrance [1, 11].

In isolated PIL no gene is implicated and familial forms are very rare, so there is no specific genetic counselling; genetic testing is useful in syndromic forms, such as Hennekam syndrome [100].

8.2. Cascade testing and assessment of relatives

The parents of a proband should be tested for the identified variant [1, 16]. When the variant is not present in either parent, it is de novo (once parentage is confirmed) or there is parental mosaicism, germline or somatic, which leucocyte testing may not detect [1]. In asymptomatic at-risk relatives, clarification of genetic status allows compression and advice to reduce cellulitis to begin early: molecular testing is performed if the familial variant is known and clinical examination if it is not [1]. In lymphoedema-distichiasis, slit-lamp examination of relatives detects subclinical distichiasis and changes the assessment of inheritance [11]. Molecular diagnosis allows surveillance to be targeted: leukaemia in GATA2 deficiency and congenital heart disease in lymphoedema-distichiasis [3]. In GATA2 deficiency, related haematopoietic stem cell donors should be tested, because an asymptomatic carrier cannot be a donor [36]. The ISL stresses that the number of de novo germline variants in these genes is increasing with testing [16].

8.3. Counselling of minors and family planning

Counselling should be offered to affected or at-risk young adults, ideally before pregnancy, with discussion of risk, prenatal diagnosis and preimplantation genetic testing; DNA banking may be considered [1, 11]. The justification for testing asymptomatic minors is early intervention (compression, prevention of cellulitis, cardiac and ophthalmological surveillance in lymphoedema-distichiasis, haematological surveillance in GATA2 deficiency) [1, 3]. Non-medical explanations for an apparently de novo variant (alternative paternity or maternity, assisted reproduction, adoption) should be considered with discretion [11]. VASCERN recommends that a pregnant woman with primary lymphoedema contact the reference centre for counselling on the risk of fetal lymphatic complications and the options for prenatal diagnosis [17].

8.4. Prenatal and preimplantation diagnosis

With the familial variant identified, prenatal diagnosis and preimplantation genetic testing are possible; perspectives on their use differ and the decision is personal [1, 11]. The French PNDS notes that lymphoedema may be detected on prenatal ultrasound and includes in the child's history the anasarca, serous effusions, abnormal volume of hands or feet and nuchal thickness observed on pregnancy scans [20]. In Milroy disease, 2nd or 3rd trimester ultrasound may show oedema of the dorsum of the feet and mild pleural effusions, which often resolve before birth; hydrops is very rare [1, 3]. In a Chinese series of 3 fetuses with FLT4 variants, lymphoedema manifested at 22–24 weeks as thickening of the subcutaneous tissue of the legs and dorsum of the feet (3.9–7.5 mm) with normal nuchal translucency; diagnosis was made by amniocentesis with trio exome and copy number variation sequencing, and the postnatal course was variable (spontaneous regression, persistence, surgery in the first month) [7]. In lymphoedema-distichiasis, fetal echocardiography at 16–20 weeks, ultrasound targeted at cleft palate and additional ultrasound in the 3rd trimester for hydrothorax and hydrops are recommended [11]. Increased nuchal translucency, cystic hygroma and hydrops frequently reflect fetal lymphatic dysplasia and are associated with aneuploidy, heart disease (fetal echocardiography is recommended with nuchal translucency of 3.5 mm or above) and syndromes, especially Turner and Noonan [92]. In first-trimester cystic hygroma, the series cited by the Oxford Desk Reference found a chromosomal anomaly in 47.6–52.7% of cases; of the euploid cases in a series of 92 that continued without additional risk factors, 89% were normal at 1–5 years [92]. The outcome of euploid fetuses with increased nuchal translucency depends on the measurement:

Source: Bilardo and colleagues, 451 euploid fetuses, reproduced in the Oxford Desk Reference; with a normal 20-week scan and resolved translucency, the risk returns to baseline [92, 148]. In non-immune hydrops fetalis, assessment includes a three-generation pedigree, anomaly scan and fetal echocardiography, examination of the parents for Noonan syndrome, fetal karyotype or microarray and a panel, exome or genome including the RAS-MAPK genes, exclusion of alloimmunisation, parvovirus B19 infection and fetal anaemia and, in the event of death, autopsy with placenta, skeletal radiography, a fibroblast line and DNA [92]. The French prospective cohort COGRare5 collects pregnancy data in women with primary lymphoedema, with no results published [142].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The available figures measure different things and should not be added together or converted into one another. Orphanet assigns primary lymphoedema (ORPHA:77240) a point prevalence of 1–5/10,000 in Europe, with a mean value of 16.7/100,000, based on expert opinion and one publication, with validated status [10]. VASCERN estimates, for a population of 500 million inhabitants of the European Union, an incidence of 600 cases of lymphoedema per year and a prevalence of primary lymphoedema of «approximately 50,000», a network estimate and not a population study [14]. For Milroy disease, worldwide point prevalence is unknown; the only quantified value, 3/100,000 at birth (class 1–9/100,000), comes from a prenatal diagnosis study in one region of Israel and does not represent a worldwide or European prevalence [10, 13]. The GeneReviews describes Milroy disease as one of the most common causes of primary lymphoedema, present in all ethnic groups, and lymphoedema-distichiasis as a relatively frequent cause of dominant primary lymphoedema, probably underdiagnosed because a quarter of patients are unaware of their distichiasis and lymphoedema may appear only in adulthood [1, 11, 105]. The remaining entities are ultra-rare according to Orphanet (less than 1/1,000,000): Hennekam with about 50 cases, PIEZO1-related generalised lymphatic dysplasia with about 10, HLTS/HLTRS with 4, MCLMR with about 50 families, Gordon lymphoedema with 23 cases, EPHB4-related hydrops with 2 families, CELSR1 with 11 cases, lymphoedema-choanal atresia with 6, cholestasis-lymphoedema with 47 and yellow nail syndrome with about 400; the prevalence of Meige disease, lymphoedema-distichiasis and GJC2-related lymphoedema is unknown, and Orphanet has no epidemiological record for Emberger syndrome (ORPHA:3226) [10]. Turner syndrome occurs in 1/2500 to 1/3000 female live births, and more than 80% have congenital lymphoedema [1, 94]. CM-AVM has an estimated prevalence of 1/100,000 in northern Europeans, and variant frequencies in the ExAC database suggest about 1/20,000 for RASA1 and 1/12,000 for EPHB4, genetic rather than clinical estimates [12]. The yields of primary lymphoedema cohorts (section 5.5) measure the proportion of patients with a variant in a reference centre and not the population prevalence of each gene [6, 29]. In France, the prevalence of primary lymphoedema is unknown; the proportion of women was about 80% in the older series and 58–70% in the more recent ones, proportions from clinical series and not from the population [20]. The genetic annex of the PNDS, which uses the 2018 Orphanet classes, diverges from current sources on several points: it assigns Milroy disease and Turner, Down and Noonan syndromes to the class 1/2500–1/10,000 and lymphoedema-distichiasis to the class 1/10,000–1/100,000, whereas current Orphanet considers the point prevalences of Milroy disease and lymphoedema-distichiasis unknown; it associates Meige disease with the GJC2 gene (#613480), whereas OMIM keeps Meige disease without a gene (%153200) and separates GJC2-related lymphoedema; it attaches the yellow nail syndrome entry (%153300) to lymphoedema-distichiasis; it includes MET and HGF in the Emberger syndrome row, which is caused by GATA2; it classifies trisomy 21 as autosomal dominant, when it is an aneuploidy that is usually de novo; and it writes #16420 instead of #164200 for oculodentodigital dysplasia [4, 10, 20]. Table 0.2 follows OMIM nomenclature and current Orphanet prevalences.

9.2. United States, Europe and founder populations

Cohort data come mainly from Europe: the United Kingdom (St George's, with 227 patients audited in 2016; the 100,000 Genomes Project, with 77,539 genomes, which identified ERG), Belgium (Brussels cohort of 770 probands), Italy (95 and 235 probands), France (222 patients in decongestive therapy; 1846 patients in the cellulitis study) [3, 6, 26, 34, 78, 99, 107]. The linkage families of Ferrell (13 families from the USA and Canada, of western European descent) and Evans (one 4-generation North American family and 4 British families) mapped the Milroy locus; a consanguineous Israeli Muslim Arab family, a consanguineous Hispanic family with a recessive form and two Japanese siblings from an isolated island illustrate the disease in other populations [2]. The sources consulted present no North American population estimates of primary lymphoedemas; US data refer to the sirolimus trial, the Stanford patient registry and the pharmacological trials [1, 122, 133]. Cholestasis-lymphoedema (Aagenaes) is very rare outside Scandinavia, with a Norwegian founder effect and a linkage interval at 15q [48]. The recessive genes for hydrops of lymphatic origin were identified in families from populations with high consanguinity: CALCRL in a Saudi family, THSD1 in a family from the United Arab Emirates and PTPN14 in a Middle Eastern family; the original Hennekam syndrome also occurred in a consanguineous family [25, 32, 53, 83]. In dehydrated stomatocytosis, a common PIEZO1 allele is frequent in populations of African descent, and prevalence estimates range from 1/50,000 to a biochemical inference of 1/8000 adults in the USA; a Danish study of 109,039 people gave a class of 1–5/10,000 [65]. Incontinentia pigmenti has a birth prevalence of 2.37/100,000 (95% CI 1.74–3.25) in Denmark between 1995 and 2021 [67]. GATA2 deficiency accounts for 7% of primary paediatric myelodysplastic syndrome in the European EWOG-MDS series [36]. The sources consulted contain no epidemiological data from Portugal or Brazil for these diseases, which does not demonstrate their absence from the literature.

9.3. Special populations

In children, compression and decongestive therapy are extrapolated from adults with secondary lymphoedema, which prompted the paediatric inelastic compression trial registered in 2026 [138]. Sex conditions the phenotype: men with Milroy disease and lymphoedema-distichiasis have more cellulitis and earlier onset, and CELSR1-related lymphoedema is more penetrant and earlier in women [1, 11, 26]. In the French series, primary lymphoedema in boys is generally present at birth or appears in the first year, whereas in girls it usually appears later, at around 9–11 years, with overall female predominance; erysipelas appears from childhood, with an incidence similar to that in adults with lymphoedema [20]. In pregnant women, oedema worsens in a generally reversible way (section 7.15) [17]. Obesity worsens lymphoedema and increases the risk of cellulitis, and the penicillin V prophylaxis dose doubles from a BMI of 33 [17, 19]. All 14 guidelines assessed in a systematic review were from high-income countries, and their suitability for low-resource settings is uncertain; in endemic areas, filariasis is the cause to exclude [16, 102].

9.4. European Reference Network and patient associations

The European Reference Network is VASCERN (European Reference Network on Rare Multisystemic Vascular Diseases), through the «Paediatric and Primary Lymphoedema» working group (PPL-WG), chaired by R. J. Damstra (Nij Smellinghe, Drachten) with S. Thomis (UZ Leuven); in 2026, VASCERN had 48 teams from 44 providers in 19 Member States [14]. The PPL centres on the map consulted in October 2026 are UZ Leuven (Belgium), Bispebjerg Hospital in Copenhagen (Denmark), Helsinki University Hospital (Finland), the Hôpital Européen Georges Pompidou and the Hôpital Cognacq-Jay of AP-HP in Paris (France), the University Medical Center Freiburg with the Földi Clinic (Germany), Nij Smellinghe in Drachten (Netherlands) and the University Medical Centre Ljubljana (Slovenia); there is no Portuguese centre on the map, but a Portuguese collaborator, Manuela Lourenço Marques, is part of the working group for the 2026 factsheets and the 2023 patient pathway [14, 17]. The GeneReviews indicates AP-HP, Hôpital Bichat–Claude Bernard, as the coordinating centre of the PPL-WG [1]. St George's University Hospitals (London) runs the national primary and paediatric lymphoedema clinic, with lymphoscintigraphy, genetic screening, MR lymphography and ICG research [1, 3]. The PPL-WG resources include the «Do's and Don'ts» factsheets, the general patient pathway, the lymphatic malformation pathway, a cellulitis flowchart, a statement on SARS-CoV-2 vaccination, the «Charter of Care for Children and Young People with Lymphoedema», a colouring book and the 2026 e-learning course; the network has adopted the 2017 Dutch guideline, the 2017 German S2k guideline (marked as expired) and the 2022 Italian vascular anomalies guideline [14, 135, 149]. The patient associations and societies mentioned in the sources are the Lymphoedema Support Network (United Kingdom, https://www.lymphoedema.org), the British Lymphology Society (https://www.thebls.com), the Lymphatic Education & Research Network (LE&RN, USA, https://lymphaticnetwork.org), the National Lymphedema Network (USA), the International Lymphoedema Framework (https://www.lympho.org) and the VASCERN patient representatives (ePAG) [1, 14, 19]. The Stanford international patient registry and biobank for lymphatic diseases and lymphoedema, the FLT4 LOVD variant database and PanelApp panel R136 are research and diagnostic resources [1, 5, 69]. In France, the 2019 PNDS was coordinated by the «primary lymphoedema» constituent site of the reference centre for rare vascular diseases (Lymphology Unit of the Hôpital Cognacq-Jay, Paris), whose coordinating centre is the genetics department of the Hôpital Européen Georges Pompidou; the other constituent sites are that for lymphoedema and lymphatic malformations (vascular medicine at CHU de Montpellier), that for superficial arteriovenous malformations (CHU Lariboisière, Paris) and that for vascular malformations and cutaneous mosaicism of the MAGEC centre (paediatric dermatology in Tours, FIMARAD network); the listed competence centres are in Bordeaux, Caen, Bron (Lyon), Nantes, Rouen, Toulouse and Tours, and the rare disease health network is FAVA-Multi (https://www.favamulti.fr) [20]. The main French patient association is the Association Vivre Mieux le Lymphœdème (AVML, https://www.avml.fr), based in the vascular medicine department of the Hôpital Saint-Eloi in Montpellier, with local branches and partner associations, among them the Association Lymphœdème Rhône-Alpes; the protocol also lists the Partenariat Français du Lymphœdème (https://www.lympho.fr) and the Quebec lymphoedema association (http://fr.infolympho.ca) [20]. These associations inform patients and non-specialist professionals, organise workshops, study days and therapeutic education stays for self-management (self-massage and self-monitoring), maintain meeting spaces and telephone lines, represent patients before institutions and public authorities and fund research [20]. The sources consulted do not mention Portuguese or Brazilian patient associations.

In France, PIL has had a national protocol (PNDS) since November 2022 (published in December), coordinated by the reference centre for rare vascular diseases (lymphatic malformations, primary lymphoedema) of the FAVA-Multi network, with the reference centre for rare digestive diseases (MaRDI); the constituent sites for primary lymphoedema and lymphatic malformations are the Hôpital Cognacq-Jay (Paris) and the Hôpital Saint-Éloi (Montpellier), with competence centres in Bordeaux, Caen, Limoges, Lyon, Nantes, Rouen and Tours [100]. There is no specific patient association; the lymphoedema associations (AVML and partner associations) also inform these patients, and hospital dietary products may be 100% covered through ALD 17 [100].

10. Illustrative Clinical Case

10.1. Milroy disease diagnosed prenatally (Zhai and colleagues, 2025)

A 32-year-old primigravida, with a spontaneous pregnancy and normal nuchal translucency in the first trimester, was referred at 22 weeks to a Chinese hospital because ultrasound had shown thickening of the subcutaneous tissue of both legs and feet of the fetus; level IV ultrasound confirmed the thickening, at about 3.9 mm in the thickest areas (figure 1A of the paper, https://pmc.ncbi.nlm.nih.gov/articles/PMC12665350/figure/F1/) [7]. The father had had bilateral oedema of the dorsum of the feet at birth, never treated, which had disappeared at around 5 years of age [7]. Aetiological investigation of the fetal oedema included amniocentesis of 20 mL of amniotic fluid and blood from both parents for exome and copy number variation sequencing; the fetal exome identified the heterozygous variant NM_182925.5:c.3122G>A, p.(Arg1041Gln), in the tyrosine kinase domain of VEGFR-3, and Sanger sequencing showed it in the father and not in the mother [7]. The variant, previously described by Evans and colleagues in families with congenital lymphoedema, was classified as likely pathogenic by the ACMG/AMP criteria PM1, PM2_Supporting, PP3 and PP1_Strong [7, 68]. After genetic counselling, the couple decided to continue the pregnancy; subsequent scans showed worsening of the oedema of the dorsum of the feet, and delivery was spontaneous, at term, with marked oedema of the dorsum of both feet (figure 3A, https://pmc.ncbi.nlm.nih.gov/articles/PMC12665350/figure/F3/) [7]. The child underwent surgery in the first month of life, with improvement of the oedema (figure 3B), and at more than 4 years still had mild oedema of the toes; the paper does not describe the surgical technique or the use of compression [7].

10.2. Comparison with the other two families in the series

In the second family, a 24-year-old pregnant woman (G3P1) was seen at 24 weeks with oedema of both feet and dorsal skin thickening of 6.4 mm on the right and 7.5 mm on the left; the fetus had the novel variant c.3284G>A, p.(Ser1095Asn), inherited from the father, who had had thickening and oedema of the dorsum of the feet since childhood, and the paternal grandfather and aunt had unilateral oedema of the dorsum of the foot in adulthood, while the 5-year-old sister had oedema of the left foot and spoon-shaped nails [7]. The fetal oedema regressed during gestation; at term birth there was mild oedema of the dorsum of the feet, without intervention (figure 3C), and at more than 2 years deep skin creases persisted at the base of the toes and on the dorsum [7]. The paper describes the father as «homozygous» for the variant, an unusual finding in a dominant disease that the authors do not discuss and that cannot be interpreted from the published data [7]. In the third family, a 27-year-old pregnant woman (G2P0) was seen at 23 weeks with subcutaneous thickening of the feet (dorsum 6.1 and 5.4 mm; sole 5.0 and 4.5 mm); the fetus had the c.2560G>A, p.(Gly854Ser) variant, previously described in two probands, inherited from a mother without any symptoms since childhood; the couple opted for termination of pregnancy at 24 weeks, with confirmed oedema of the dorsum of the feet and no autopsy [7].

10.3. Clinical interpretation

The case illustrates the prenatal presentation of Milroy disease in the 2nd trimester with normal nuchal translucency, which differs from the increased translucency and hygroma of the syndromic lymphatic dysplasias, and intrafamilial variability: the father affected as a child had spontaneous resolution, whereas his son had severe oedema at birth [1, 7]. The asymptomatic carrier mother in the third family corresponds to the 10–15% of carriers without lymphoedema and makes the prognosis of a carrier fetus uncertain, which weighs in counselling [1, 7]. Three statements in the paper diverge from the reference sources and should not be generalised: the authors present FLT4 as the only known gene of primary congenital lymphoedema, when VEGFC, KIF11, PIEZO1 and the St George's pink group genes also cause it; they cite an incidence of 1/6000 taken from another publication, unrelated to the Orphanet prevalences; and surgery in the first month of life does not correspond to the usual treatment of Milroy disease, which is conservative, with adapted compression, skin care and prevention of cellulitis [1, 3, 7, 10, 17]. Figure 2 of the paper (Sanger chromatograms) was not consulted.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Primary lymphoedema is a chronic condition without cure, but with usual improvement under treatment: compression and skin care improve appearance and reduce limb volume and the risk of complications [1, 11]. In Milroy disease, oedema may progress or improve, especially in the first years, and rarely extends above the knee, and the most frequent complication is cellulitis, which occurs in about 20% and damages the lymphatics [1, 15]. In lymphoedema-distichiasis, about 80% have lymphoedema by 30 years, varicose veins appear in about half and ocular morbidity depends on the distichiasis [11, 35]. Intensive decongestive therapy reduced excess volume by 34% (median) in a series of 222 patients, but maintenance is lifelong [16, 107]. Penicillin prophylaxis reduces recurrence of cellulitis while it is being taken, with no lasting effect after discontinuation [114, 115]. The prognosis of the forms with systemic involvement is determined by hydrops (fetal or perinatal death in some cases of PIEZO1, EPHB4, MDFIC, CALCRL and Hennekam) and, in survivors, by protein-losing enteropathy, effusions and secondary immunodeficiency [23–25, 31, 39]. In GATA2 deficiency, prognosis is dominated by haematological disease and infections, with 8% of patients asymptomatic at 40 years and mortality of 35% up to that age in a series of 79 patients [36]. In HLTRS, renal failure and aortic dilatation condition prognosis [43]. In uncontrolled chronic lymphoedema there is a rare risk of lymphangiosarcoma [16].

11.2. Surveillance

There are no guidelines on the frequency of lymphoedema assessment; the ISL considers that it should probably be lifelong, with measurement of excess volume before, during and after treatment, and the quarterly intervals in the first year of prospective surveillance models come from secondary cancer-related lymphoedema and do not apply directly to primary lymphoedema [16]. VASCERN recommends regular follow-up in a specialised centre, with standardised practice adapted to the form of lymphoedema, the response and the associated problems, within a care network with local providers and an «open door» policy, and advises against discontinuing follow-up [17]. The Milroy disease GeneReviews recommends routine follow-up in a specialised lymphoedema clinic, without a specified interval [1]. The French PNDS also sets no intervals: the pace and distribution of follow-up between the general practitioner, the specialist and the physiotherapist depend on the course and the patient's involvement, and the objectives are to stabilise volume, ensure adherence and autonomy, adapt treatment to volume and complications (erysipelas, genital involvement), guarantee continuity between paediatric and adult care and consider the impact of the disease [20]. The consultation records erysipelas episodes and their treatment, adherence to compression (with regular replacement of garments) and bandaging, the impact on quality of life, dressing, body image and sexuality in genital forms (with possible referral to a sexology clinic), the psychological impact (isolation, with use of peer groups), and the aesthetic and functional impact (joint pain, therapeutic or orthopaedic footwear); the examination measures volume, the main criterion in adults and harder to interpret in children because of growth, but useful in unilateral lymphoedema, weight, the appearance and flexibility of the skin and cutaneous complications (papillomatosis, hyperkeratosis) [20].

The intervals of 6 months for lymphoedema therapy, 1–2 times a year for clinical assessment in lymphoedema-distichiasis, 3–6 months for weight and at least annual review of prophylaxis are the same as in section 7 [11, 17, 19]. Entities without a frequency defined in the sources follow the surveillance of the specialised centre.

11.3. Transition and self-management

Active self-management (daily compression, skin care, exercise, weight control, antibiotic reserve and early recognition of cellulitis) forms part of both phases of treatment in the VASCERN patient pathway, which includes education for self-management [17, 104]. Referral to gastroenterology, respiratory medicine or dermatology and to national and international support groups is part of the individual plan [104]. The French PNDS includes among the objectives of follow-up continuity of care between childhood and adulthood and provides for therapeutic education programmes aimed at children and young adults, sessions coordinated with care and longer stays, also organised by patient associations [20].

12. Summary and Final Considerations

Hereditary primary lymphoedemas result from developmental defects of the lymphatic vessels that compromise VEGF-C/VEGFR-3 signalling, valve formation, endothelial mechanotransduction or transcriptional programmes shared with other tissues; Milroy disease, caused by dominant negative variants in the kinase domain of FLT4, is the most frequent congenital form, with bilateral oedema of the dorsum of the feet at birth, penetrance of 85–90% and about 70–75% molecular detection in typical cases [1, 3, 75]. The 2020 St George's classification organises diagnosis into five groups (mosaic disorders and vascular malformations, syndromic, systemic involvement, congenital and late-onset) and associates with each the genes to be tested, which guides the NGS panel, the choice of sample (blood, or tissue in mosaic disorders) and the interpretation of variants of uncertain significance [3, 16]. OMIM nomenclature now groups the non-syndromic forms into the LMPHM1–14 series, joined by lymphoedema-distichiasis (FOXC2), the Hennekam syndromes (CCBE1, FAT4, ADAMTS3), HLTS/HLTRS (SOX18), Emberger syndrome (GATA2), MCLMR (KIF11) and the forms related to PTPN14, IKBKG and HGF, while Meige disease remains without a gene and about two thirds of patients remain without a molecular diagnosis [4, 29]. Molecular diagnosis has consequences beyond lymphoedema: haematological surveillance in GATA2 deficiency and ERG, cardiological, ophthalmological and spinal surveillance in lymphoedema-distichiasis, renal and aortic surveillance in HLTRS, nutritional and immunological surveillance in generalised dysplasias, and reproductive counselling with prenatal diagnosis when the familial variant is known [3, 11, 43]. Treatment remains physical and preventive, with two-phase decongestive therapy, made-to-measure compression, skin care, unrestricted exercise, weight control and treatment and prophylaxis of cellulitis with the doses of the 2025 British guideline as reference and those of the SmPCs for comparison when the guideline exceeds the label, including, in children, the declared extrapolation of phenoxymethylpenicillin pneumococcal prophylaxis doses [16, 17, 19, 110]. No drug is approved for primary lymphoedema, Lymfactin® failed its primary outcome in phase 2 in secondary lymphoedema, acebilustat has only open-label data, and targeted therapies (sirolimus, trametinib, propranolol in HLTRS) remain off-label and restricted to complex lymphatic anomalies or isolated cases [84, 122, 124, 128, 133]. Lifelong follow-up in a specialised centre linked to the VASCERN network, with local coordination and self-management, is the recommended model [14, 17]. In France, the 2019 PNDS organises care around the reference centre for rare vascular diseases and the FAVA-Multi network, and diverges from more recent guidelines in restricting genetic testing in isolated lymphoedema, in the antibiotic regimens for erysipelas and prophylaxis and in rejecting lymphatic repair surgery outside trials [20].

13. References

1. Van Zanten M, Mansour S, Ostergaard P, Mortimer P, Gordon K. Milroy Disease. 2006 Apr 27 [updated 2021 Feb 18]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1239/
2. Online Mendelian Inheritance in Man (OMIM). #153100 Lymphatic malformation 1; LMPHM1 [entry updated 06/04/2021; edit history 11/14/2023]. Baltimore: Johns Hopkins University. Available from: https://www.omim.org/entry/153100
3. Gordon K, Varney R, Keeley V, Riches K, Jeffery S, Van Zanten M, Mortimer P, Ostergaard P, Mansour S. Update and audit of the St George's classification algorithm of primary lymphatic anomalies: a clinical and molecular approach to diagnosis. J Med Genet. 2020;57(10):653-9. doi:10.1136/jmedgenet-2019-106084. PMID: 32409509; PMCID: PMC7525776.
4. Online Mendelian Inheritance in Man (OMIM). Entries #153100, %611944, #613480, #615907, %153200, #616843, #617300, #618773, #619319, #619369, #619401, #620014, #620244, #620602, #153400, #614038, #613611, #137940, #607823, #235510, #616006, #618154, #152950, #300291, %214900, #153300 [titles and gene links via NCBI E-utilities]. Baltimore: Johns Hopkins University. Available from: https://omim.org
5. Genomics England PanelApp. Primary lymphoedema (panel 65), version 5.7, 14 August 2026. Available from: https://panelapp.genomicsengland.co.uk/panels/65/
6. Alpaslan M, Fastré E, Mestre S, van Haeringen A, Repetto GM, Keymolen K, et al. Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function. Hum Mol Genet. 2024;33(14):1250-61. doi:10.1093/hmg/ddae060. PMID: 38676400.
7. Zhai S, Yuan L, Li J, Liu L, Hu L, Ban Y, et al. Phenotype and genetic variation analysis of primary congenital lymphedema caused by FLT4 gene mutations in a fetus. Front Genet. 2025;16:1700635. doi:10.3389/fgene.2025.1700635. PMID: 41328432; PMCID: PMC12665350.
8. Online Mendelian Inheritance in Man (OMIM). Phenotypic Series PS153100 — Lymphatic malformation (14 entries). Baltimore: Johns Hopkins University. Available from: https://www.omim.org/phenotypicSeries/PS153100
9. Orphanet. Milroy disease (ORPHA:79452). https://www.orpha.net/en/disease/detail/79452
10. Orphanet/Orphadata. Rare disease epidemiology API (rd-epidemiology). Available from: https://api.orphadata.com/rd-epidemiology/orphacodes/ [accessed 2026-10-26]; pages: https://www.orpha.net/en/disease/detail/
11. Mansour S, Brice GW, Jeffery S, Mortimer P. Lymphedema-Distichiasis Syndrome. 2005 Mar 29 [updated 2019 Apr 4]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1457/
12. Bayrak-Toydemir P, Stevenson DA. Capillary Malformation-Arteriovenous Malformation Syndrome. 2011 Feb 22 [updated 2019 Sep 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK52764/
13. Makhoul IR, Sujov P, Ghanem N, Bronshtein M. Prenatal diagnosis of Milroy's primary congenital lymphedema. Prenat Diagn. 2002;22:823-6.
14. VASCERN. Paediatric & Primary Lymphoedema (PPL-WG) [Internet]. Available from: https://vascern.eu/group/pediatric-and-primary-lymphedema/
15. Brice G, Child AH, Evans A, Bell R, Mansour S, Burnand K, et al. Milroy disease and the VEGFR-3 mutation phenotype. J Med Genet. 2005;42(2):98-102. doi:10.1136/jmg.2004.024802. PMID: 15689446.
16. Executive Committee of the International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2023 Consensus Document of the International Society of Lymphology. Lymphology. 2023;56(4):133-51. doi:10.2458/lymph.6372. PMID: 39207406.
17. VASCERN Paediatric and Primary Lymphoedema Working Group. Do's and Don'ts factsheets for rare vascular disease care in frequent situations: paediatric and primary lymphoedema. Version 2. Paris: VASCERN; July 2026. Available from: https://vascern.eu/app/uploads/Dos-Donts-Factsheets-for-Paediatric-and-Primary-Lymphoedema-%E2%80%93-Version-2-July-2026.pdf
18. GeneGuidance. Clinical curation of the MDFIC gene. User database, version of 26 Sep 2026.
19. British Lymphology Society; Lymphoedema Support Network. Guidelines on the management of cellulitis in lymphoedema. August 2025 [updated September 2025]. Available from: https://www.thebls.com/documents-library/guidelines-on-the-management-of-cellulitis-in-lymphoedema
20. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Lymphœdème primaire. Centre de référence des maladies vasculaires rares. Saint-Denis La Plaine: HAS; February 2019 (published 14-02-2019). Available from: https://www.has-sante.fr/jcms/c_2904792
21. GeneGuidance. Clinical curation of the GJC2 gene. User database, version of 26 Sep 2026.
22. Gordon K, Schulte D, Brice G, Simpson MA, Roukens MG, van Impel A, et al. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant Milroy-like primary lymphedema. Circ Res. 2013;112(6):956-60. doi:10.1161/CIRCRESAHA.113.300350. PMID: 23410910.
23. Fotiou E, Martin-Almedina S, Simpson MA, Lin S, Gordon K, Brice G, et al. Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis. Nat Commun. 2015;6:8085. doi:10.1038/ncomms9085. PMID: 26333996.
24. Martin-Almedina S, Martinez-Corral I, Holdhus R, Vicente A, Fotiou E, Lin S, et al. EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis. J Clin Invest. 2016;126(8):3080-8. doi:10.1172/JCI85794. PMID: 27400125.
25. Mackie DI, Al Mutairi F, Davis RB, Kechele DO, Nielsen NR, Snyder JC, et al. hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. J Exp Med. 2018;215(9):2339-53. doi:10.1084/jem.20180528. PMID: 30115739.
26. Maltese PE, Michelini S, Ricci M, Maitz S, Fiorentino A, Serrani R, et al. Increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants. Am J Med Genet A. 2019;179(9):1718-24. doi:10.1002/ajmg.a.61269. PMID: 31215153.
27. Leppänen VM, Brouillard P, Korhonen EA, Sipilä T, Jha SK, Revencu N, et al. Characterization of ANGPT2 mutations associated with primary lymphedema. Sci Transl Med. 2020;12(560):eaax8013. doi:10.1126/scitranslmed.aax8013. PMID: 32908006.
28. GeneGuidance. Clinical curation of the ANGPT2 gene. User database, version of 26 Sep 2026.
29. Brouillard P, Murtomäki A, Leppänen VM, Hyytiäinen M, Mestre S, Potier L, et al. Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema. J Clin Invest. 2024;134(14):e173586. doi:10.1172/JCI173586. PMID: 38820174.
30. GeneGuidance. Clinical curation of the TIE1 gene. User database, version of 26 Sep 2026.
31. Byrne AB, Brouillard P, Sutton DL, Kazenwadel J, Montazaribarforoushi S, Secker GA, et al. Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema. Sci Transl Med. 2022;14(634):eabm4869. doi:10.1126/scitranslmed.abm4869. PMID: 35235341.
32. Abdelrahman HA, Al-Shamsi A, John A, Hertecant J, Lootah A, Ali BR, Al-Gazali L. A recessive truncating variant in thrombospondin-1 domain containing protein 1 gene THSD1 is the underlying cause of nonimmune hydrops fetalis, congenital cardiac defects, and haemangiomas in four patients from a consanguineous family. Am J Med Genet A. 2018;176(9):1996-2003. doi:10.1002/ajmg.a.40424. PMID: 30055085.
33. GeneGuidance. Clinical curation of the ERG gene. User database, version of 26 Sep 2026.
34. Greene D; Genomics England Research Consortium; Pirri D, Frudd K, Sackey E, Al-Owain M, et al. Genetic association analysis of 77,539 genomes reveals rare disease etiologies. Nat Med. 2023;29(3):679-88. doi:10.1038/s41591-023-02211-z. PMID: 36928819.
35. Brice G, Mansour S, Bell R, Collin JR, Child AH, Brady AF, et al. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet. 2002;39(7):478-83. doi:10.1136/jmg.39.7.478. PMID: 12114478.
36. GeneGuidance. Clinical curation of the GATA2 gene. User database, version of 26 Sep 2026.
37. Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011;43(10):929-31. doi:10.1038/ng.923. PMID: 21892158.
38. Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, et al. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet. 2014;22(7):881-7. doi:10.1038/ejhg.2013.263. PMID: 24281367.
39. Jones KL, Jones MC, del Campo M. Hennekam lymphedema-lymphangiectasia syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 858–863.
40. Alders M, Al-Gazali L, Cordeiro I, Dallapiccola B, Garavelli L, Tuysuz B, et al. Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Hum Genet. 2014;133(9):1161-7. doi:10.1007/s00439-014-1456-y. PMID: 24913602.
41. Brouillard P, Dupont L, Helaers R, Coulie R, Tiller GE, Peeden J, et al. Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3. Hum Mol Genet. 2017;26(21):4095-104. doi:10.1093/hmg/ddx297. PMID: 28985353.
42. Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, et al. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet. 2003;72(6):1470-8. doi:10.1086/375614. PMID: 12740761.
43. GeneGuidance. Clinical curation of the SOX18 gene. User database, version of 26 Sep 2026.
44. Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, Kelley KA, et al. Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans. Am J Hum Genet. 2010;87(3):436-44. doi:10.1016/j.ajhg.2010.08.008. PMID: 20826270.
45. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Osteopetrosis, lymphedema, ectodermal dysplasia, immune defect (MIM 300301). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 607–610.
46. GeneGuidance. Clinical curation of the GJA1 gene. User database, version of 26 Sep 2026.
47. Jones KL, Jones MC, del Campo M. Oculodentodigital syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 392–395.
48. Firth HV, Hurst JA. Oedema—generalized or puffy extremities. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 260–264.
49. GeneGuidance. Clinical curation of the CELSR1 gene. User database, version of 26 Sep 2026.
50. Milroy WF. An undescribed variety of hereditary oedema. N Y Med J. 1892;56:505-8.
51. Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, et al. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet. 2013;84(4):303-14. doi:10.1111/cge.12173. PMID: 23621851.
52. Jones KL, Jones MC, del Campo M. Distichiasis-lymphedema syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 856–857.
53. Hennekam RC, Geerdink RA, Hamel BC, Hennekam FA, Kraus P, Rammeloo JA, et al. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet. 1989;34(4):593-600. doi:10.1002/ajmg.1320340429. PMID: 2624276.
54. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet. 2000;67(2):295-301. doi:10.1086/303019. PMID: 10856194.
55. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet. 2000;25(2):153-9. doi:10.1038/75997. PMID: 10835628.
56. Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, et al. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet. 2000;67(6):1382-8. doi:10.1086/316915. PMID: 11078474.
57. Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet. 2009;41(12):1272-4. doi:10.1038/ng.484. PMID: 19935664.
58. Ferrell RE, Baty CJ, Kimak MA, Karlsson JM, Lawrence EC, Franke-Snyder M, et al. GJC2 missense mutations cause human lymphedema. Am J Hum Genet. 2010;86(6):943-8. doi:10.1016/j.ajhg.2010.04.010. PMID: 20537300.
59. Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012;90(2):356-62. doi:10.1016/j.ajhg.2011.12.018. PMID: 22284827.
60. Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, et al. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation. 2014;129(19):1962-71. doi:10.1161/CIRCULATIONAHA.113.002779. PMID: 24552833.
61. GeneGuidance. Clinical curation of the ADAMTS3 gene. User database, version of 26 Sep 2026.
62. Petrova TV, Karpanen T, Norrmén C, et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med. 2004;10:974-81.
63. Lyons O, Saha P, Seet C, et al. Human venous valve disease caused by mutations in FOXC2 and GJC2. J Exp Med. 2017;214:2437-52.
64. GeneGuidance. Clinical curation of the EPHB4 gene. User database, version of 26 Sep 2026.
65. GeneGuidance. Clinical curation of the PIEZO1 gene. User database, version of 26 Sep 2026.
66. GeneGuidance. Clinical curation of the KIF11 gene. User database, version of 26 Sep 2026.
67. GeneGuidance. Clinical curation of the IKBKG gene. User database, version of 26 Sep 2026.
68. Evans AL, Bell R, Brice G, Comeglio P, Lipede C, Jeffery S, et al. Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphoedema. J Med Genet. 2003;40(9):697-703. doi:10.1136/jmg.40.9.697. PMID: 12960217.
69. Gordon K, Spiden SL, Connell FC, Brice G, Cottrell S, Short J, et al. FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update. Hum Mutat. 2013;34(1):23-31. doi:10.1002/humu.22223. PMID: 23074044.
70. Mellor RH, Hubert CE, Stanton AWB, et al. Lymphatic dysfunction, not aplasia, underlies Milroy disease. Microcirculation. 2010;17:281-96.
71. Sarica M, Gordon K, van Zanten M, Heenan SD, Mortimer PS, Irwin AG, et al. Lymphoscintigraphic abnormalities associated with Milroy disease and lymphedema-distichiasis syndrome. Lymphat Res Biol. 2019;17(6):610-9. doi:10.1089/lrb.2019.0016. PMID: 31721633.
72. GeneGuidance. Clinical curation of the FLT4 gene. User database, version of 26 Sep 2026.
73. Reuter MS, Jobling R, Chaturvedi RR, Manshaei R, Costain G, Heung T, et al. Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot. Genet Med. 2019;21(4):1001-7. doi:10.1038/s41436-018-0260-9. PMID: 30232381.
74. Jin SC, et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017;49:1593-601.
75. Connell FC, Ostergaard P, Carver C, Brice G, Williams N, Mansour S, et al. Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Hum Genet. 2009;124(6):625-31. doi:10.1007/s00439-008-0586-5. PMID: 19002718.
76. GeneGuidance. Clinical curation of the VEGFC gene. User database, version of 26 Sep 2026.
77. Mellor RH, Brice G, Stanton AW, et al. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Circulation. 2007;115:1912-20.
78. Michelini S, Ricci M, Veselenyiova D, Kenanoglu S, Kurti D, Baglivo M, et al. TIE1 as a candidate gene for lymphatic malformations with or without lymphedema. Int J Mol Sci. 2020;21(18):6780. doi:10.3390/ijms21186780. PMID: 32947856.
79. GeneGuidance. Clinical curation of the CCBE1 gene. User database, version of 26 Sep 2026.
80. GeneGuidance. Clinical curation of the FAT4 gene. User database, version of 26 Sep 2026.
81. Li D, Wenger TL, Seiler C, March ME, Gutierrez-Uzquiza A, Kao C, et al. Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly. Hum Mol Genet. 2018;27(18):3233-45. doi:10.1093/hmg/ddy218. PMID: 29905864.
82. Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation. 2017;136(11):1037-48. doi:10.1161/CIRCULATIONAHA.116.026886. PMID: 28687708.
83. GeneGuidance. Clinical curation of the PTPN14 gene. User database, version of 26 Sep 2026.
84. Overman J, Fontaine F, Wylie-Sears J, Moustaqil M, Huang L, Meurer M, et al. R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma. eLife. 2019;8:e43026. doi:10.7554/eLife.43026. PMID: 31358114; PMCID: PMC6667216.
85. Filina YV, Zolotykh MA, Miftakhova RR. Decreased kinase activity of the VEGFR3 variant c.3175G>C associated with primary lymphedema. Curr Issues Mol Biol. 2026;48(1):68. doi:10.3390/cimb48010068. PMID: 41614898.
86. Ricci M, Compagna R, Amato B, Kenanoglu S, Veselenyiova D, Kurti D, et al. Mutations in the ARAP3 gene in three families with primary lymphedema negative for mutations in known lymphedema-associated genes. Int J Genomics. 2020;2020:3781791. doi:10.1155/2020/3781791. PMID: 32908855.
87. Dundar MS, Belanova I, Bonetti G, Gelanova V, Kozacikova R, et al. Genetic variants in genes correlated to the PI3K/AKT pathway: the role of ARAP3, CDH5, KIF11 and RELN in primary lymphedema. Lymphology. 2023;56:152-9. PMID: 39207407.
88. Alshomer F, Cho J, Noh H, Pak CJ, Suh HP, Hong JP. Lymphaticovenous and lymph node-to-vein anastomosis to improve Milroy disease-related chylothorax and lymphedema. Plast Reconstr Surg. 2025;155(3):610e-617e. doi:10.1097/PRS.0000000000011635. PMID: 39023432.
89. Rezaie T, Ghoroghchian R, Bell R, et al. Primary non-syndromic lymphoedema (Meige disease) is not caused by mutations in FOXC2. Eur J Hum Genet. 2008;16:300-4.
90. Vignes S, Bellanger J. Primary intestinal lymphangiectasia (Waldmann's disease). Orphanet J Rare Dis. 2008;3:5. doi:10.1186/1750-1172-3-5. PMID: 18294365.
91. Bellini C, Hennekam RC, Fulcheri E, et al. Etiology of nonimmune hydrops fetalis: a systematic review. Am J Med Genet A. 2009;149A:844-51.
92. Firth HV, Hurst JA. Oedema—increased nuchal translucency, cystic hygroma, and hydrops. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 768–769.
93. Firth HV, Hurst JA. Retinal dysplasia. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 300–301.
94. Jones KL, Jones MC, del Campo M. Turner syndrome (45,X). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 70–75.
95. Jones KL, Jones MC, del Campo M. Noonan syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 148–151.
96. Firth HV, Hurst JA. Noonan syndrome and the Ras/MAPK pathway syndromes. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 512–515.
97. Firth HV, Hurst JA. Hemihypertrophy and limb asymmetry. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 164–167.
98. Jones KL, Jones MC, del Campo M. Parkes Weber syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 728–731.
99. Vignes S, Poizeau F, Dupuy A. Cellulitis risk factors for patients with primary or secondary lymphedema. J Vasc Surg Venous Lymphat Disord. 2022;10(1):179-85.e1. doi:10.1016/j.jvsv.2021.04.009. PMID: 33957278.
100. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Lymphangiectasies intestinales primitives (maladie de Waldmann). Centre de référence des maladies vasculaires rares (filière FAVA-Multi), en collaboration avec le Centre de référence des maladies rares digestives (MaRDI). Saint-Denis La Plaine: HAS; 2022 Nov (published 2022-12-12). PNDS text, supporting argument and summary for the general practitioner. Available from: https://www.has-sante.fr/jcms/p_3390524
101. Mansour S, Mansour S, Josephs KS, Ostergaard P, Gordon K, van Zanten M, Pearce J, et al. Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts. J Med Genet. 2023;60(1):84-90. doi:10.1136/jmedgenet-2021-107820. PMID: 34916230.
102. Torgbenu E, Luckett T, Buhagiar MA, Phillips JL. Guidelines relevant to diagnosis, assessment, and management of lymphedema: a systematic review. Adv Wound Care (New Rochelle). 2023;12(1):15-27. doi:10.1089/wound.2021.0149. PMID: 35196892.
103. Brezgyte G, Mills M, van Zanten M, Gordon K, Mortimer PS, Ostergaard P. A systematic review of indocyanine green lymphography imaging for the diagnosis of primary lymphoedema. Br J Radiol. 2025;98(1168):517-26. doi:10.1093/bjr/tqaf006. PMID: 39836641.
104. VASCERN Pediatric and Primary Lymphedema Working Group. General patient pathway for pediatric and primary lymphedema. Version 4, 06/10/2023. Available from: https://vascern.eu/app/uploads/2023/04/General-Patient-Pathway-for-PPL-V4_06102023.pdf
105. GeneGuidance. Clinical curation of the FOXC2 gene. User database, version of 26 Sep 2026.
106. Xu Y, Zhou J, Lan Y, Ji Y. Efficacy and safety of trametinib therapy for complex lymphatic malformations. Pediatr Blood Cancer. 2026;73(1):e32119. doi:10.1002/pbc.32119. PMID: 41116710.
107. Vignes S, Simon L, Benoughidane B, Simon M, Fourgeaud C. Clinical and scintigraphic predictors of primary lower limb lymphedema-volume reduction during complete decongestive physical therapy. Phys Ther. 2020;100(5):766-72. doi:10.1093/ptj/pzaa012. PMID: 31944248.
108. VASCERN Pediatric and Primary Lymphedema Working Group. Cellulitis flowchart for patients with lymphedema. Version 01/2022. Available from: https://vascern.eu/app/uploads/2023/03/Flowchart-graphic-EN-combined.pdf
109. INFARMED. Floxapen 500 mg cápsulas (flucloxacilina) — Resumo das Características do Medicamento, approved 18-07-2023. Marketing authorisation holder Generis Farmacêutica. Infomed med_id 3514. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=3514&tipo_doc=rcm
110. Flamingo Pharma UK Ltd. Phenoxymethylpenicillin 250 mg/5 ml powder for oral solution — Summary of Product Characteristics (PL 43461/0028; text revised 05/09/2024). electronic medicines compendium (emc). Available from: https://www.medicines.org.uk/emc/product/13526/smpc
111. Sun Pharma (Ranbaxy). Clarithromycin 125 mg/5 ml granules for oral suspension — Summary of Product Characteristics. electronic medicines compendium (emc). Available from: https://www.medicines.org.uk/emc/product/12806/smpc
112. Haute Autorité de Santé. Prise en charge des infections cutanées bactériennes courantes. Fiche de synthèse de la recommandation de bonne pratique. Saint-Denis La Plaine: HAS; February 2019. Available from: https://www.has-sante.fr/jcms/c_2911550/fr/prise-en-charge-des-infections-cutanees-bacteriennes-courantes. Accessed 7 Nov 2026.
113. Penicillin V potassium tablets USP [package insert]. DailyMed setid 73cd20d5-2521-4b93-a221-fa3fe490eba6; revised 2026-10-15. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=73cd20d5-2521-4b93-a221-fa3fe490eba6
114. Thomas KS, Crook AM, Nunn AJ, Foster KA, Mason JM, Chalmers JR, et al. Penicillin to prevent recurrent leg cellulitis. N Engl J Med. 2013;368(18):1695-703. doi:10.1056/NEJMoa1206300. PMID: 23635049.
115. Dalal A, Eskin-Schwartz M, Mimouni D, Ray S, Days W, Hodak E, et al. Interventions for the prevention of recurrent erysipelas and cellulitis. Cochrane Database Syst Rev. 2017;6(6):CD009758. doi:10.1002/14651858.CD009758.pub2. PMID: 28631307.
116. INFARMED. Infomed — search for «Fenoximetilpenicilina» and «Penicilina V» (authorised/marketed), 2026-10-26: no results. Available from: https://extranet.infarmed.pt/INFOMED-fo/
117. Webb E, Neeman T, Bowden FJ, Gaida J, Mumford V, Bissett B. Compression therapy to prevent recurrent cellulitis of the leg. N Engl J Med. 2020;383(7):630-9. doi:10.1056/NEJMoa1917197. PMID: 32786188.
118. Mortada H, Alshomer F, Noh H, Park CJ, Hong JP. Peripheral lymphatic shunts for protein-losing enteropathy in a child with THSD1 mutation: a case report. Arch Plast Surg. 2026;53:361-8. doi:10.1055/a-2777-5624. PMID: 42583604.
119. Columbia University. Propranolol dose escalation in patients with lymphedema. ClinicalTrials.gov NCT02595996.
120. HEMANGEOL (propranolol hydrochloride) oral solution [prescribing information]. Pierre Fabre Pharmaceuticals; DailyMed setid b6f9dd2a-632b-87eb-70f0-b2064d7ed48a; revised 2026-06-25. NDA 205410, approved 2014-03-14 (Drugs@FDA/openFDA).
121. European Medicines Agency. Hemangiol (propranolol): EPAR, EMEA/H/C/002621; CHMP opinion 20/02/2014; marketing authorisation 23/04/2014. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/hemangiol
122. Adams DM, Trenor CC 3rd, Hammill AM, Vinks AA, Patel MN, Chaudry G, et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics. 2016;137(2):e20153257. doi:10.1542/peds.2015-3257. PMID: 26783326.
123. Ueda M, Maeda T, Ozeki M, Fujito S, Suzuki T, Sato Y. Effectiveness of sirolimus therapy for neonates with generalized lymphatic anomalies with fetal hydrops. Pediatr Int. 2026;68(1):e70439. doi:10.1111/ped.70439. PMID: 42216259.
124. De Brouchoven I, Lorand J, Bofferding L, Sorlin A, Van Damme A, Danhaive O. Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome. Front Pediatr. 2025;13:1475143. doi:10.3389/fped.2025.1475143. PMID: 40041314.
125. Seront E, Froidure A, Revencu N, Dekeuleneer V, Clapuyt P, Dumitriu D, et al. Targeted treatment in complex lymphatic anomaly: a case of synergistic efficacy of trametinib and sirolimus. Orphanet J Rare Dis. 2024;19(1):199. doi:10.1186/s13023-024-03211-z. PMID: 38750525.
126. Ethacrynic acid tablets USP 25 mg [package insert]. Upsher-Smith Laboratories; DailyMed setid c0b17629-7e4a-4c9c-9577-4f7904564628; revised 2026-07-06. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c0b17629-7e4a-4c9c-9577-4f7904564628
127. Agência Nacional de Vigilância Sanitária (ANVISA). Dados abertos de medicamentos registados (DADOS_ABERTOS_MEDICAMENTOS.csv; updated 13/10/2026). Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
128. Rannikko EH, Pajula S, Suominen SH, Kiiski J, Mani MR, et al. Phase II study shows the effect of adenoviral vascular endothelial growth factor C and lymph node transfer in lymphedema. Plast Reconstr Surg. 2025;155:256e-267e. doi:10.1097/PRS.0000000000011675. PMID: 39137430.
129. ANVISA. Bulário eletrônico — search for «fenoximetilpenicilina»/«PEN-VE-ORAL», 2026-10-26. Available from: https://consultas.anvisa.gov.br/#/bulario/
130. Pajula S, Saarikko A, Suominen S, Kaartinen I, Kiiski J, et al. Lymfactin® gene therapy with vascularized lymph node transfer reduces compression-free swelling and enhances quality of life in breast cancer-related lymphedema: final phase I trial results. J Plast Reconstr Aesthet Surg. 2025;111:312-21. PMID: 41173769.
131. Hartiala P, Suominen S, Suominen E, Kaartinen I, Kiiski J, Viitanen T, et al. Phase 1 Lymfactin® study: short-term safety of combined adenoviral VEGF-C and lymph node transfer treatment for upper extremity lymphedema. J Plast Reconstr Aesthet Surg. 2020;73(9):1612-21. doi:10.1016/j.bjps.2020.05.009. PMID: 32513642.
132. Eiger BioPharmaceuticals. Ubenimex in adult patients with lymphedema of the lower limb (ULTRA). ClinicalTrials.gov NCT02700529.
133. Stanford Medicine. Lymphedema drug [news story]. September 2026. Available from: https://news.stanford.edu/stories/2026/09/lymphedema-drug
134. Herantis Pharma. Lymfactin® with lymph node transfer in secondary lymphedema (AdeLE). ClinicalTrials.gov NCT03658967.
135. VASCERN. New e-learning course and updated do's and don'ts from the PPL working group [news]. 2026. Available from: https://vascern.eu/news/new-ppl-elearning-and-dos-and-donts-2026/
136. Stanford University. Acebilustat (CTX 4430) in upper extremity lymphedema. ClinicalTrials.gov NCT05203835.
137. University Hospital, Toulouse. mRNA therapy to restore lymphatic flow in secondary lymphedema (APERNAVEC). ClinicalTrials.gov NCT07793656.
138. University School of Physical Education, Krakow. Inelastic compression in children and young people with primary lymphedema. ClinicalTrials.gov NCT07866599.
139. University Medical Centre Ljubljana. Biological profile of primary and secondary lymphedema. ClinicalTrials.gov NCT07770399.
140. University Hospital, Montpellier. CELSR1 mutations in primary lymphedema of lower limbs. ClinicalTrials.gov NCT04919655.
141. University Hospital, Toulouse. Lymphatic dysfunction in primary and secondary lymphedema. ClinicalTrials.gov NCT05629026.
142. Hospices Civils de Lyon. Pregnancies in patients with rare vascular anomalies (COGRare5). ClinicalTrials.gov NCT04194619.
143. Kwon Y, Kim ES, Choe YH, Kim MJ. Individual approach for treatment of primary intestinal lymphangiectasia in children: single-center experience and review of the literature. BMC Pediatr. 2021;21(1):21. doi:10.1186/s12887-020-02447-5. PMID: 33407260.
144. Novartis. SANDOSTATIN (octreotide acetate) injection; SANDOSTATIN LAR Depot. Prescribing information. NDA 019667 and NDA 021008. DailyMed set ID 4e2c9856-1836-49f0-9472-4dbeeb408f39. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4e2c9856-1836-49f0-9472-4dbeeb408f39](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4e2c9856-1836-49f0-9472-4dbeeb408f39). Accessed via openFDA on 6 Oct 2026.
145. Pfizer. Rapamune (sirolimus) tablets and oral solution — Prescribing Information. NDA 021110. U.S. Food and Drug Administration; label effective 2026-03-26. Available from: https://open.fda.gov (openFDA drug label API)
146. U.S. Food and Drug Administration / National Library of Medicine. Furosemide tablets [prescribing information]. DailyMed SPL set ID 01a5f094-b473-4e46-9e61-69d5ec6dd766; version of 1 Mar 2023 [accessed 18 Oct 2026, via openFDA]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=01a5f094-b473-4e46-9e61-69d5ec6dd766
147. Agence nationale de sécurité du médicament et des produits de santé (ANSM). UVESTEROL VITAMINE A.D.E.C., solution buvable: résumé des caractéristiques du produit. CIS 68202115. Base de données publique des médicaments; updated 2024 Jun 25 [cited 2026 Nov 7]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/68202115/extrait
148. Bilardo CM, Timmerman E, Pajkrt E, van Maarle M. Increased nuchal translucency in euploid fetuses—what should we be telling the parents? Prenat Diagn. 2010;30:93-102.
149. Damstra RJ, Halk AB; Dutch Working Group on Lymphedema. The Dutch lymphedema guidelines based on the International Classification of Functioning, Disability, and Health and the chronic care model. J Vasc Surg Venous Lymphat Disord. 2017;5(5):756-65. doi:10.1016/j.jvsv.2017.04.012. PMID: 28818234.