Congenital Primary Lymphedema of Gordon

Mendelian MONDO:0035500 Pathograph 20 Show in embeddings browser lymphatic malformation

Congenital primary lymphedema of Gordon (hereditary lymphedema type ID, LMPH1D) is a rare autosomal dominant Milroy-like primary lymphedema caused by heterozygous loss-of-function variants in VEGFC, which encodes vascular endothelial growth factor C, the principal ligand of the lymphatic receptor VEGFR3 (FLT4). Truncating, frameshift and splice-altering VEGFC alleles yield a protein lacking an intact VEGF homology domain that is poorly secreted and biologically inactive, so the disease mechanism is haploinsufficiency rather than dominant-negative interference. Reduced VEGFC-VEGFR3 signaling leads to hypoplasia and dysfunction of the dermal lymphatic network of the lower limbs. Affected individuals usually present at or soon after birth with painless bilateral pedal or below-knee lymphedema, often with prominent wide-calibre veins over the shins and feet, upslanting dysplastic toenails and, in some males, hydrocele. Penetrance is incomplete and expressivity varies within and between families. Lymphoscintigraphy shows tortuous lymphatic tracts with rerouting and reduced inguinal uptake, a pattern that differs from the absent main-tract uptake typical of FLT4-related Milroy disease. Management is supportive, centred on compression.

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1
Inheritance
4
Pathophys.
7
Phenotypes
20
Pathograph
1
Genes
6
Variants
1
Medical Actions
1
Differentials
2
Models
1
Deep Research
🏷

Classifications

Harrison's Part
CARDIOVASCULAR
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous VEGFC variants co-segregate with lymphedema across multiple generations in the reported families. Penetrance is incomplete: some variant carriers have no clinical swelling or only occasional ankle swelling, although lymphoscintigraphy can still show abnormal drainage in clinically unaffected carriers. Severity varies within families. A single proband carrying biallelic VEGFC variants (one inherited from each parent) has also been reported.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (4 references)
PMID:23410910 SUPPORT Human Clinical
"The variant cosegregated with the affected status in the family."
Co-segregation of the heterozygous VEGFC frameshift variant with lymphedema in the founding family supports dominant transmission.
PMID:24744435 SUPPORT Human Clinical
"The mutation segregates with the phenotype in the family according to a dominant model with full penetrance."
An independent family with a VEGFC stop variant shows dominant segregation. This particular family happened to be fully penetrant; across all reported families penetrance is incomplete (see the next item).
PMID:30071673 SUPPORT Human Clinical
"There were also reports of reduced penetrance since six individuals carrying a VEGFC mutation had no clinical signs of primary lymphedema (n = 4) or reported occasional swelling (n = 2) of feet and ankles."
Pooled across the five families reported to that date, six variant carriers were clinically unaffected or minimally affected, establishing incomplete penetrance.
+ 1 more reference
⚙

Pathophysiology

4
VEGFC Haploinsufficiency
Heterozygous frameshift, nonsense and splice-site VEGFC variants are all predicted to truncate the protein so that it lacks a complete VEGF homology domain, which is required to activate VEGFR3. The c.571_572insTT protein is stable but poorly secreted. In a zebrafish floorplate overexpression assay the mutant proteins lose the ability to induce vessel sprouting, and co-expression with wild-type VEGFC does not suppress wild-type activity, so the mutant allele acts by loss of function (haploinsufficiency) rather than as a dominant negative. VEGFC is secreted as an inactive precursor that becomes an active VEGFR3 ligand only after proteolytic processing by the ADAMTS3-CCBE1 complex. The biallelic p.Ser65Arg allele, reported in one patient, altered this processing in vitro.
VEGFC hgnc:12682 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VEGFC (hgnc:12682). hgnc:12682 is a gene from the HUGO Gene Nomenclature Committee.
vascular endothelial growth factor receptor 3 binding GO:0043185 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased vascular endothelial growth factor receptor 3 binding (GO:0043185). GO:0043185 is a molecular function from the Gene Ontology.
Downstream
Reduced VEGFR3 Signaling in Lymphatic Endothelium A truncated VEGFC lacking the VEGF homology domain cannot activate VEGFR3, halving the available ligand dose.
Show evidence (6 references)
PMID:23410910 SUPPORT Model Organism
"However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC."
In vivo zebrafish assay showing that the patient frameshift allele has lost VEGFC biological activity.
PMID:30071673 SUPPORT Model Organism
"Therefore, we conclude that the vegfc-intron 2–3 c.325+5G>A variant does not result in a protein with dominant negative properties but most likely leads to a haplo-insufficient phenotype."
Co-expression of mutant and wild-type Vegfc in zebrafish excludes a dominant-negative effect, supporting haploinsufficiency.
PMID:30071673 SUPPORT Human Clinical
"All reported mutations are predicted to form a truncated protein, which is deemed to be dysfunctional."
Summarizes that every VEGFC allele reported in this disorder is truncating.
+ 3 more references
Reduced VEGFR3 Signaling in Lymphatic Endothelium
VEGFC is the paracrine factor that drives sprouting, migration and proliferation of lymphatic endothelial cells through VEGFR3. With only one functional VEGFC allele, VEGFR3 signaling in lymphatic endothelium is insufficient for normal lymphatic development, the same pathway that is disrupted by kinase-dead FLT4 variants in Milroy disease.
lymphatic endothelial cell CL:0002138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphatic endothelial cell, annotated with endothelial cell of lymphatic vessel (CL:0002138). CL:0002138 is a cell type from the Cell Ontology.
vascular endothelial growth factor receptor-3 signaling pathway GO:0036325 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased vascular endothelial growth factor receptor-3 signaling pathway (GO:0036325). GO:0036325 is a biological process from the Gene Ontology.
Downstream
Dermal Lymphatic Vessel Hypoplasia Insufficient VEGFR3 activation reduces sprouting and growth of the dermal lymphatic plexus.
Show evidence (2 references)
PMID:14634646 SUPPORT Model Organism
"Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development."
Mouse genetics show that both Vegfc alleles are needed, establishing a dosage-sensitive VEGFC-VEGFR3 axis.
PMID:35817543 SUPPORT REVIEW SYNTHESIS Other
"VEGF-C/VEGFR3 signaling is necessary for every step of lymphatic vascular development and maintenance."
Review synthesis placing VEGFC-VEGFR3 signaling at the centre of lymphatic development and maintenance.
Dermal Lymphatic Vessel Hypoplasia
Vegfc heterozygous mice and Chy-3 mice, which are hemizygous for a deletion including Vegfc, develop a hypoplastic dermal lymphatic network with lymphedema of the hind limbs, while the blood vasculature is unaffected. Drainage from the superficial dermal lymphatics to the deep lymphatics of the lower limbs fails, matching the lower-limb predilection of the human disease.
lymphangiogenesis GO:0001946 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased lymphangiogenesis (GO:0001946). GO:0001946 is a biological process from the Gene Ontology.
Animal models
Vegfc heterozygous mouse Mouse recapitulates Heterozygous loss of Vegfc reproduces the human genotype and produces cutaneous lymphatic hypoplasia with lymphedema.
Downstream
Impaired Lower Limb Lymphatic Drainage A hypoplastic dermal lymphatic network cannot carry lymph from the superficial dermis of the lower limbs to the deep truncal lymphatics.
Abnormal lymphatic tracts on lymphoscintigraphy The structurally abnormal lymphatic network is visualized clinically as tortuous, rerouted tracts on lymphoscintigraphy.
Show evidence (2 references)
PMID:14634646 SUPPORT Model Organism
"The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema."
Vegfc heterozygous mice, the genetic counterpart of the human disorder, develop cutaneous lymphatic hypoplasia.
PMID:17584866 SUPPORT Model Organism
"Visual lymphangiography and immunofluorescence staining showed a hypoplastic dermal lymphatic network, whereas the blood vasculature appeared unaffected."
An independent Vegfc-haploinsufficient mouse model shows dermal lymphatic hypoplasia with sparing of blood vessels.
Impaired Lower Limb Lymphatic Drainage
In patients, lymphoscintigraphy shows reduced tracer uptake at the groin with tortuous tracts and rerouting around the feet, ankles and lower legs, indicating dysfunctional initial lymphatics. Interstitial fluid that is not cleared accumulates as lymphedema of the feet and lower legs.
Animal models
Chy-3 mouse (Vegfc-containing deletion, hemizygous) Mouse recapitulates Chy-3 mice show failed dermal-to-deep lymphatic transport in the lower limbs with hind-paw lymphedema, mirroring the lower-limb predilection of the human disorder.
Downstream
Predominantly lower limb lymphedema Failure to clear interstitial fluid from the lower limbs produces pedal and below-knee lymphedema.
Hydrocele testis Hydrocele is reported in a subset of affected males, as in Milroy disease, and is attributed to defective lymphatic drainage; the specific genital lymphatic defect has not been characterized in VEGFC patients.
Edema of the dorsum of hands Transient neonatal hand edema has been reported in one proband, implying that the drainage defect can extend beyond the lower limbs.
Cellulitis Lymph stasis predisposes to skin infection in primary lymphedema generally; this edge is extrapolated and has not been documented in VEGFC patients.
Upslanting toenail Upslanting dysplastic toenails result from chronic edema of the nail bed.
Show evidence (1 reference)
PMID:30071673 SUPPORT Human Clinical
"In summary, the cases with VEGFC mutations where lymphoscintigraphy has been performed all show some uptake in the groin at a reduced rate."
Reduced inguinal uptake in every imaged VEGFC case documents impaired lower-limb lymph drainage in patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Congenital Primary Lymphedema of Gordon Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Cardiovascular 2
Abnormal lymphatic tracts on lymphoscintigraphy Abnormal lymphatic vessel morphology HP:0100766 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tortuous lower limb lymphatic tracts, annotated with Abnormal lymphatic vessel morphology (HP:0100766). HP:0100766 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30071673 SUPPORT Human Clinical
"The tracer is following tortuous tracts with rerouting around feet, ankles, and lower legs, which indicates that the tracer is not following the normal tracts to the groin area seen in healthy controls."
Describes the characteristic abnormal lymphatic tracts on imaging in VEGFC cases.
Prominent superficial veins FREQUENT HP:0001015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent superficial veins (HP:0001015). HP:0001015 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30071673 SUPPORT Human Clinical
"Congenital primary lymphedema of Gordon typically presents, like Milroy disease, with congenital, pedal lymphedema with prominent, wide caliber veins over the shins and on the dorsa of the feet."
States prominent veins as a typical presenting sign.
PMID:30071673 SUPPORT Human Clinical
"Not all the reports on VEGFC cases confirm the absence or presence of prominent veins but, in the nine individuals where a note has been made, five of those (55%) had such veins."
Pooled frequency of 55% maps to the FREQUENT band.
Genitourinary 1
Hydrocele testis OCCASIONAL HP:0000034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocele testis (HP:0000034). HP:0000034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30071673 SUPPORT Human Clinical
"Of other clinical signs, 27% (3/11) of the males presented with hydrocele."
27% of males maps to the OCCASIONAL band.
Integument 1
Upslanting toenail HP:0032344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upslanting toenail (HP:0032344). HP:0032344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30071673 SUPPORT Human Clinical
"The patients have upslanting, dysplastic toenails and deep, interphalangeal creases of the toes."
Lists upslanting dysplastic toenails among the typical features.
Metabolism 2
Predominantly lower limb lymphedema FREQUENT HP:0003550 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Predominantly lower limb lymphedema (HP:0003550). HP:0003550 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:30071673 SUPPORT Human Clinical
"For example, 17 of the 23 individuals (74%) have some forms of swelling in which most had bilateral below-knee lymphedema (n = 12) but some cases had isolated ankle and foot lymphedema (n = 5)."
Pooled frequency (74%) of lower-limb lymphedema among VEGFC variant carriers maps to the FREQUENT band.
PMID:30071673 SUPPORT Human Clinical
"The majority of individuals (70%, nine of the 13 where the age of onset has been recorded) presented with congenital (<1 year) primary lymphedema."
Supports congenital onset of the lymphedema in most affected individuals.
PMID:24744435 SUPPORT Human Clinical
"We report a newborn patient with an external phenotype consistent with Milroy disease and a truncating mutation (p.R210X) in the VEGFC gene detected by exome sequence analysis."
A newborn presentation with Milroy-like congenital lymphedema in an independent VEGFC family.
Edema of the dorsum of hands HP:0007514 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Edema of the dorsum of hands (HP:0007514). HP:0007514 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30071673 SUPPORT Human Clinical
"Albeit mild, the proband also had lymphedema of the dorsi of both hands post-natally, which is a little unusual."
Single-case report of transient hand lymphedema; frequency omitted.
Musculoskeletal 1
Cellulitis HP:0100658 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cellulitis (HP:0100658). HP:0100658 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33407666 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"The main acute lymphedema complication is cellulitis (erysipelas)."
National care protocol for primary lymphedema naming cellulitis as the main acute complication; applies to this disorder only by extrapolation.
🧬

Genetic Associations

1
VEGFC (Heterozygous loss-of-function (truncating, frameshift, splice-site) variants)
Gene: VEGFC hgnc:12682 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VEGFC (hgnc:12682). hgnc:12682 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:23410910 SUPPORT Human Clinical
"This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema."
Founding report establishing VEGFC as a primary lymphedema gene.
PMID:30071673 SUPPORT Human Clinical
"In this study, we provide independent evidence that VEGFC mutations are causative of primary lymphedema of the type originally described by Gordon et al."
Independent family confirming VEGFC causality for this specific entity.
PMID:32592340 SUPPORT Human Clinical
"Two VEGF-C variations were found in the proband, a novel p.(Ser65Arg) and a pathogenic c.148-3_148-2delCA, of paternal and maternal origin, respectively."
A proband with congenital Milroy-like lymphedema carrying biallelic VEGFC variants, extending the allelic spectrum.
Variants (6)
c.571_572insTT Pathogenic
frameshift
Exon 4 two-base insertion found in the founding three-generation family; the encoded protein lacks activity in the zebrafish sprouting assay.
Show evidence (1 reference)
PMID:23410910 SUPPORT Human Clinical
"Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband."
Identifies the founding frameshift allele.
p.Arg210Ter (c.628C>T) Pathogenic
nonsense
Exon 4 stop-gain variant segregating with lymphedema in a Spanish family.
Show evidence (1 reference)
PMID:24744435 SUPPORT Human Clinical
"We report a newborn patient with an external phenotype consistent with Milroy disease and a truncating mutation (p.R210X) in the VEGFC gene detected by exome sequence analysis."
Reports the nonsense allele.
c.361+5G>A Pathogenic
splice site
Intron 2 donor splice-site variant causing exon 2 skipping, a frameshift and premature stop (p.Ala50ValfsTer18), removing the entire VEGF homology domain.
Show evidence (1 reference)
PMID:30071673 SUPPORT Human Clinical
"The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18)."
Patient cDNA analysis demonstrates the splicing consequence.
c.148-3_148-2delCA Pathogenic
splice site
Acceptor splice-site deletion causing exon skipping, first reported in its own family (Fastre et al. 2018) and later found in trans with p.Ser65Arg in a biallelic proband.
Show evidence (1 reference)
PMID:30071673 SUPPORT REVIEW SYNTHESIS Human Clinical
"a splice-variant (c.148-3_148-2delCA) and a synonymous variant (c.552G>A) both causing exon skipping"
Summarizes the previously reported splice allele and its exon-skipping effect.
c.552G>A Pathogenic
synonymous (splice-disrupting)
Coded as synonymous but disrupts splicing and causes exon skipping, predicted to truncate the protein; a synonymous annotation alone would miss its effect.
Show evidence (1 reference)
PMID:30071673 SUPPORT REVIEW SYNTHESIS Human Clinical
"a splice-variant (c.148-3_148-2delCA) and a synonymous variant (c.552G>A) both causing exon skipping"
Records that the synonymous allele acts through exon skipping.
p.Ser65Arg (c.195T>G)
missense
Novel missense allele found in trans with the splice variant c.148-3_148-2delCA in a single proband; it altered VEGFC processing in vitro. Its contribution on its own is not established, so no clinical significance is asserted here.
Show evidence (1 reference)
PMID:32592340 SUPPORT Human Clinical
"Two VEGF-C variations were found in the proband, a novel p.(Ser65Arg) and a pathogenic c.148-3_148-2delCA, of paternal and maternal origin, respectively."
Reports the missense allele and its in-trans configuration.
💊

Medical Actions

1
Compression therapy
Action: compression therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is compression therapy (NCIT:C157735). NCIT:C157735 is a clinical intervention from the NCI Thesaurus. Ontology label: Compression Therapy NCIT:C157735
Platform: Device
No disease-specific therapy exists and no VEGFC-specific treatment study has been reported. Care follows general primary-lymphedema practice: volume reduction with low-stretch bandaging, then long-term maintenance with compression garments, exercise and a normal body weight, with patient education to prevent cellulitis.
Mechanism Target:
MODULATES Predominantly lower limb lymphedema — External compression limits interstitial fluid accumulation in the affected limbs without correcting the lymphatic defect.
Show evidence (3 references)
PMID:35817543 SUPPORT REVIEW SYNTHESIS Other
"Unfortunately, the treatments for lymphedema are limited to compression bandages and massages."
Review statement that compression and massage are the available treatments for lymphedema, including the genetic primary forms discussed in the review; no VEGFC-specific treatment study exists.
PMID:33407666 SUPPORT REVIEW SYNTHESIS Other
"Treatment aims to prevent those complications, reduce the volume with low-stretch bandages, then stabilize it over the long term by exercises and wearing a compression garment."
National consensus care protocol for primary lymphedema recommending bandaging and compression garments; applied here by extrapolation to this genetic form.
PMID:33502936 SUPPORT REVIEW SYNTHESIS Other
"Most patients with primary lymphedema are satisfactorily managed with compression regimens, exercise, and maintenance of a normal body weight."
Review supporting compression-based conservative management of primary lymphedema in general.
🔬

Diagnosis

2
Molecular genetic testing of VEGFC and FLT4
In a patient with congenital Milroy-like lower-limb lymphedema, both FLT4 (VEGFR3) and VEGFC are tested, usually within a primary-lymphedema gene panel or by exome sequencing. VEGFC is examined in particular when no FLT4 variant is found. Patient RNA analysis can confirm the effect of a suspected splice variant.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A heterozygous (rarely biallelic) loss-of-function VEGFC variant that segregates with lymphedema confirms the diagnosis.
Show evidence (3 references)
PMID:24744435 SUPPORT Human Clinical
"genetic analysis of VEGFC would be useful in diagnosing patients that present with Milroy features but have no mutation in VEGFR-3"
Recommends VEGFC testing in FLT4-negative Milroy-like patients.
PMID:30071673 SUPPORT Human Clinical
"The proband had previously been screened for mutations in VEGFR3 (exons 17–26, covering the tyrosine kinase domain) and found to be negative."
Illustrates the FLT4-first, then VEGFC, testing sequence.
PMID:30071673 SUPPORT Human Clinical
"Sequencing of the wild type and mutant bands extracted from the agarose gel confirmed that exon 2 is spliced out during the transcription of the mutant allele of the proband and her mother"
Patient cDNA analysis established the splicing consequence of an intronic VEGFC variant.
Lymphoscintigraphy
Lower-limb lymphoscintigraphy confirms lymphatic dysfunction. In VEGFC cases it shows reduced but present groin uptake with tortuous, rerouted tracts, whereas FLT4-related Milroy disease typically shows no uptake in the main tracts or groin. Abnormal drainage can be seen in carriers with little or no clinical swelling.
lymphoscintigraphy NCIT:C67262 NCI Thesaurus (NCIT)
Results: Reduced inguinal uptake with tortuous tracts and rerouting around the feet, ankles and lower legs.
Show evidence (3 references)
PMID:33407666 SUPPORT REVIEW SYNTHESIS Other
"Limb lymphoscintigraphy is useful to confirm the diagnosis."
National care protocol for primary lymphedema recommending lymphoscintigraphy for diagnostic confirmation.
PMID:30071673 SUPPORT Human Clinical
"In summary, the cases with VEGFC mutations where lymphoscintigraphy has been performed all show some uptake in the groin at a reduced rate."
Characteristic lymphoscintigraphic finding in VEGFC cases.
PMID:30071673 SUPPORT Human Clinical
"Therefore, lymphoscintigraphy could prove a useful tool to differentiate between the two primary lymphedema phenotypes."
Supports using lymphoscintigraphy to distinguish VEGFC disease from Milroy disease.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population prevalence estimate exists. By 2018, 23 VEGFC variant carriers from five families had been reported; a further biallelic case was reported in 2020. VEGFC variants were absent from a 116-patient Italian primary lymphedema cohort screened by gene panel.
Show evidence (2 references)
PMID:30071673 SUPPORT Human Clinical
"Of the 23 individuals (11 male and 12 female) from 5 families (including the family described here) reported to date, we see marked inter-familial and intra-familial variation (Table 1)."
Literature case count supporting the ultra-rare classification.
PMID:29906362 SUPPORT Human Clinical
"No alterations were identified in SOX18, VEGFC, and CCBE1 genes."
VEGFC variants are a rare cause of primary lymphedema; none were found in a 116-patient cohort.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Congenital Primary Lymphedema of Gordon:

Milroy disease Not Yet Curated MONDO:0007919
Overlapping Features FLT4 (VEGFR3)-related congenital primary lymphedema presents with the same external phenotype of congenital bilateral pedal lymphedema. VEGFC testing is indicated in Milroy-like patients without an FLT4 variant. Lymphoscintigraphy may help separate them: Milroy disease shows no uptake in the main lymphatic tracts or groin, whereas VEGFC cases show reduced groin uptake along tortuous, rerouted tracts.
Show evidence (2 references)
PMID:24744435 SUPPORT Human Clinical
"The clinical presentation, similar to Milroy disease, indicates an overlapping of the external phenotype of both diseases, suggesting that genetic analysis of VEGFC would be useful in diagnosing patients that present with Milroy features but have no mutation in VEGFR-3."
Establishes clinical overlap with Milroy disease and the role of genetic testing in distinguishing them.
PMID:30071673 SUPPORT Human Clinical
"This contrasts with the lymphoscintigrams seen in Milroy disease, which show no uptake within the main lymphatic tracts and groin area after 2 h."
Identifies a lymphoscintigraphic difference between the two disorders.
🐁

Animal Models

2
Vegfc heterozygous mouse
Species
Mouse
Genotype
Vegfc+/-
Publication
PMID:14634646
Pathograph links
Dermal Lymphatic Vessel Hypoplasia recapitulates fidelity: high observes: tissue Heterozygous loss of Vegfc reproduces the human genotype and produces cutaneous lymphatic hypoplasia with lymphedema.
Limitations: Mouse dermal lymphatic anatomy and the hind-paw distribution of edema differ from human lower-limb lymphedema.
Show evidence (1 reference)
PMID:14634646 SUPPORT Model Organism
"The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema."
Supports the heterozygous mouse as a model of the dermal lymphatic hypoplasia node.
Chy-3 mouse (Vegfc-containing deletion, hemizygous)
Species
Mouse
Genotype
Heterozygous chromosomal deletion including Vegfc (Chy-3)
Publication
PMID:17584866
Pathograph links
Impaired Lower Limb Lymphatic Drainage recapitulates fidelity: moderate observes: tissue Chy-3 mice show failed dermal-to-deep lymphatic transport in the lower limbs with hind-paw lymphedema, mirroring the lower-limb predilection of the human disorder.
Limitations: The deletion removes genes other than Vegfc, and the mice also develop chylous ascites, which is not a feature of the human disorder.
Show evidence (1 reference)
PMID:17584866 SUPPORT Model Organism
"These findings further delineate the lymphatic phenotype of Chy-3 mice, identify a collateral lymph drainage pathway previously undescribed in other genetic models of lymphedema, and demonstrate a predilection for lymphatic abnormalities of the lower limbs."
Supports the model's relevance to lower-limb lymphatic drainage failure.
{ }

Source YAML

click to show 
name: Congenital Primary Lymphedema of Gordon
creation_date: "2026-10-08T00:00:00Z"
description: >-
  Congenital primary lymphedema of Gordon (hereditary lymphedema type ID, LMPH1D)
  is a rare autosomal dominant Milroy-like primary lymphedema caused by
  heterozygous loss-of-function variants in VEGFC, which encodes vascular
  endothelial growth factor C, the principal ligand of the lymphatic receptor
  VEGFR3 (FLT4). Truncating, frameshift and splice-altering VEGFC alleles yield
  a protein lacking an intact VEGF homology domain that is poorly secreted and
  biologically inactive, so the disease mechanism is haploinsufficiency rather
  than dominant-negative interference. Reduced VEGFC-VEGFR3 signaling leads to
  hypoplasia and dysfunction of the dermal lymphatic network of the lower limbs.
  Affected individuals usually present at or soon after birth with painless
  bilateral pedal or below-knee lymphedema, often with prominent wide-calibre
  veins over the shins and feet, upslanting dysplastic toenails and, in some
  males, hydrocele. Penetrance is incomplete and expressivity varies within and
  between families. Lymphoscintigraphy shows tortuous lymphatic tracts with
  rerouting and reduced inguinal uptake, a pattern that differs from the
  absent main-tract uptake typical of FLT4-related Milroy disease. Management is
  supportive, centred on compression.
category: Mendelian
parents:
- lymphatic malformation
synonyms:
- VEGFC-related congenital primary lymphedema
- hereditary lymphedema type ID
- lymphedema, hereditary, ID
- LMPH1D
- Milroy-like primary lymphedema
disease_term:
  preferred_term: congenital primary lymphedema of Gordon
  term:
    id: MONDO:0035500
    label: congenital primary lymphedema of Gordon
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Heterozygous VEGFC variants co-segregate with lymphedema across multiple
    generations in the reported families. Penetrance is incomplete: some
    variant carriers have no clinical swelling or only occasional ankle
    swelling, although lymphoscintigraphy can still show abnormal drainage in
    clinically unaffected carriers. Severity varies within families. A single
    proband carrying biallelic VEGFC variants (one inherited from each parent)
    has also been reported.
  evidence:
  - reference: PMID:23410910
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant cosegregated with the affected status in the family.
    explanation: >-
      Co-segregation of the heterozygous VEGFC frameshift variant with
      lymphedema in the founding family supports dominant transmission.
  - reference: PMID:24744435
    reference_title: A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation segregates with the phenotype in the family according to a
      dominant model with full penetrance.
    explanation: >-
      An independent family with a VEGFC stop variant shows dominant
      segregation. This particular family happened to be fully penetrant;
      across all reported families penetrance is incomplete (see the next
      item).
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were also reports of reduced penetrance since six individuals
      carrying a VEGFC mutation had no clinical signs of primary lymphedema (n =
      4) or reported occasional swelling (n = 2) of feet and ankles.
    explanation: >-
      Pooled across the five families reported to that date, six variant
      carriers were clinically unaffected or minimally affected, establishing
      incomplete penetrance.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The extent of the lymphedema varies within the family with the mother of
      the proband being very mildly affected and the grandfather moderately
      affected.
    explanation: >-
      Documents variable expressivity among carriers of the same VEGFC allele.
pathophysiology:
- name: VEGFC Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Heterozygous frameshift, nonsense and splice-site VEGFC variants are all
    predicted to truncate the protein so that it lacks a complete VEGF homology
    domain, which is required to activate VEGFR3. The c.571_572insTT protein is
    stable but poorly secreted. In a zebrafish floorplate overexpression assay
    the mutant proteins lose the ability to induce vessel sprouting, and
    co-expression with wild-type VEGFC does not suppress wild-type activity,
    so the mutant allele acts by loss of function (haploinsufficiency) rather
    than as a dominant negative. VEGFC is secreted as an inactive precursor
    that becomes an active VEGFR3 ligand only after proteolytic processing by
    the ADAMTS3-CCBE1 complex. The biallelic p.Ser65Arg allele, reported in one
    patient, altered this processing in vitro.
  genes:
  - preferred_term: VEGFC
    term:
      id: hgnc:12682
      label: VEGFC
  molecular_functions:
  - preferred_term: vascular endothelial growth factor receptor 3 binding
    modifier: DECREASED
    term:
      id: GO:0043185
      label: vascular endothelial growth factor receptor 3 binding
  evidence:
  - reference: PMID:23410910
    reference_title: "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."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, when overexpressing the human c.571_572insTT variant in the
      floorplate, no sprouting of vessels was observed, indicating that the base
      changes have a marked effect on the activity of VEGFC.
    explanation: >-
      In vivo zebrafish assay showing that the patient frameshift allele has
      lost VEGFC biological activity.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Therefore, we conclude that the vegfc-intron 2–3 c.325+5G>A variant does
      not result in a protein with dominant negative properties but most likely
      leads to a haplo-insufficient phenotype.
    explanation: >-
      Co-expression of mutant and wild-type Vegfc in zebrafish excludes a
      dominant-negative effect, supporting haploinsufficiency.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All reported mutations are predicted to form a truncated protein, which is
      deemed to be dysfunctional.
    explanation: >-
      Summarizes that every VEGFC allele reported in this disorder is
      truncating.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      The work of Gordon et al. showed that, although the truncated mutant
      protein c.571_572insTT is stable, it is not secreted efficiently
    explanation: >-
      Restates the cell-culture finding from the founding report that the
      frameshift protein is retained rather than secreted, so less ligand
      reaches the extracellular space.
  - reference: PMID:27159393
    reference_title: Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we have developed and used biochemical and cellular tools to
      demonstrate that an ADAMTS3-CCBE1 complex can form independently of
      VEGFR3 and is required to convert VEGFC, but not VEGFD, into an active
      ligand.
    explanation: >-
      Establishes that VEGFC must be proteolytically activated to signal, the
      step that the p.Ser65Arg allele perturbs.
  - reference: PMID:32592340
    reference_title: Investigation on the role of biallelic variants in VEGF-C found in a patient affected by Milroy-like lymphedema.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional characterization of the p.(Ser65Arg) variation in vitro showed
      alterations in VEGF-C processing.
    explanation: >-
      A patient missense allele impairs VEGFC maturation in vitro.
  downstream:
  - target: Reduced VEGFR3 Signaling in Lymphatic Endothelium
    causal_link_type: DIRECT
    description: >-
      A truncated VEGFC lacking the VEGF homology domain cannot activate
      VEGFR3, halving the available ligand dose.
    evidence:
    - reference: PMID:30071673
      reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The other four truncated proteins (Figure 2D) also lack a complete VHD,
        which is most likely going to affect the phosphorylation of VEGFR3.
      explanation: >-
        Links loss of the VEGF homology domain in the mutant proteins to reduced
        VEGFR3 activation; this is an inference by the authors rather than a
        direct measurement.
- name: Reduced VEGFR3 Signaling in Lymphatic Endothelium
  biological_scale: CELLULAR
  description: >-
    VEGFC is the paracrine factor that drives sprouting, migration and
    proliferation of lymphatic endothelial cells through VEGFR3. With only one
    functional VEGFC allele, VEGFR3 signaling in lymphatic endothelium is
    insufficient for normal lymphatic development, the same pathway that is
    disrupted by kinase-dead FLT4 variants in Milroy disease.
  cell_types:
  - preferred_term: lymphatic endothelial cell
    term:
      id: CL:0002138
      label: endothelial cell of lymphatic vessel
  biological_processes:
  - preferred_term: vascular endothelial growth factor receptor-3 signaling pathway
    modifier: DECREASED
    term:
      id: GO:0036325
      label: vascular endothelial growth factor receptor-3 signaling pathway
  evidence:
  - reference: PMID:14634646
    reference_title: Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results indicate that VEGF-C is the paracrine factor essential for
      lymphangiogenesis, and show that both Vegfc alleles are required for normal
      lymphatic development.
    explanation: >-
      Mouse genetics show that both Vegfc alleles are needed, establishing a
      dosage-sensitive VEGFC-VEGFR3 axis.
  - reference: PMID:35817543
    reference_title: Molecular Mechanisms Driving Lymphedema and Other Lymphatic Anomalies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      VEGF-C/VEGFR3 signaling is necessary for every step of lymphatic vascular
      development and maintenance.
    explanation: >-
      Review synthesis placing VEGFC-VEGFR3 signaling at the centre of
      lymphatic development and maintenance.
  downstream:
  - target: Dermal Lymphatic Vessel Hypoplasia
    causal_link_type: DIRECT
    description: >-
      Insufficient VEGFR3 activation reduces sprouting and growth of the dermal
      lymphatic plexus.
    evidence:
    - reference: PMID:35817543
      reference_title: Molecular Mechanisms Driving Lymphedema and Other Lymphatic Anomalies.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Thus, it is reasonable to suspect a reduction in the number of LECs as
        one of the disease-initiating defects in patients with mutations in
        VEGFR3, VEGFC, CCBE1, ADAMTS3, and GATA2.
      explanation: >-
        Connects reduced VEGFC signaling to a deficit of lymphatic endothelial
        cells; stated as a reasoned hypothesis by the review authors.
- name: Dermal Lymphatic Vessel Hypoplasia
  biological_scale: TISSUE
  description: >-
    Vegfc heterozygous mice and Chy-3 mice, which are hemizygous for a deletion
    including Vegfc, develop a hypoplastic dermal lymphatic network with
    lymphedema of the hind limbs, while the blood vasculature is unaffected.
    Drainage from the superficial dermal lymphatics to the deep lymphatics of
    the lower limbs fails, matching the lower-limb predilection of the human
    disease.
  biological_processes:
  - preferred_term: lymphangiogenesis
    modifier: DECREASED
    term:
      id: GO:0001946
      label: lymphangiogenesis
  evidence:
  - reference: PMID:14634646
    reference_title: Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The lack of lymphatic vessels resulted in prenatal death due to fluid
      accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic
      hypoplasia and lymphedema.
    explanation: >-
      Vegfc heterozygous mice, the genetic counterpart of the human disorder,
      develop cutaneous lymphatic hypoplasia.
  - reference: PMID:17584866
    reference_title: Chy-3 mice are Vegfc haploinsufficient and exhibit defective dermal superficial to deep lymphatic transition and dermal lymphatic hypoplasia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Visual lymphangiography and immunofluorescence staining showed a
      hypoplastic dermal lymphatic network, whereas the blood vasculature
      appeared unaffected.
    explanation: >-
      An independent Vegfc-haploinsufficient mouse model shows dermal
      lymphatic hypoplasia with sparing of blood vessels.
  downstream:
  - target: Impaired Lower Limb Lymphatic Drainage
    causal_link_type: DIRECT
    description: >-
      A hypoplastic dermal lymphatic network cannot carry lymph from the
      superficial dermis of the lower limbs to the deep truncal lymphatics.
    evidence:
    - reference: PMID:17584866
      reference_title: Chy-3 mice are Vegfc haploinsufficient and exhibit defective dermal superficial to deep lymphatic transition and dermal lymphatic hypoplasia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Lymphatic tracer was not transported from the dermal to the deep truncal
        lymphatic system in the lower limbs, even though the deep lymphatic
        vessels and nodes were present and patent.
      explanation: >-
        Shows that the dermal lymphatic defect impairs lower-limb lymph
        transport in a Vegfc-haploinsufficient model.
  - target: Abnormal lymphatic tracts on lymphoscintigraphy
    causal_link_type: DIRECT
    description: >-
      The structurally abnormal lymphatic network is visualized clinically as
      tortuous, rerouted tracts on lymphoscintigraphy.
    evidence:
    - reference: PMID:30071673
      reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The tracer is following tortuous tracts with rerouting around feet,
        ankles, and lower legs, which indicates that the tracer is not following
        the normal tracts to the groin area seen in healthy controls.
      explanation: >-
        The abnormal tracer route in VEGFC patients is the imaging readout of
        the abnormal lymphatic network; the link to dermal hypoplasia rests on
        the mouse models.
- name: Impaired Lower Limb Lymphatic Drainage
  biological_scale: TISSUE
  description: >-
    In patients, lymphoscintigraphy shows reduced tracer uptake at the groin
    with tortuous tracts and rerouting around the feet, ankles and lower legs,
    indicating dysfunctional initial lymphatics. Interstitial fluid that is not
    cleared accumulates as lymphedema of the feet and lower legs.
  evidence:
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, the cases with VEGFC mutations where lymphoscintigraphy has
      been performed all show some uptake in the groin at a reduced rate.
    explanation: >-
      Reduced inguinal uptake in every imaged VEGFC case documents impaired
      lower-limb lymph drainage in patients.
  downstream:
  - target: Predominantly lower limb lymphedema
    causal_link_type: DIRECT
    description: >-
      Failure to clear interstitial fluid from the lower limbs produces pedal
      and below-knee lymphedema.
  - target: Hydrocele testis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hydrocele is reported in a subset of affected males, as in Milroy
      disease, and is attributed to defective lymphatic drainage; the specific
      genital lymphatic defect has not been characterized in VEGFC patients.
  - target: Edema of the dorsum of hands
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Transient neonatal hand edema has been reported in one proband, implying
      that the drainage defect can extend beyond the lower limbs.
  - target: Cellulitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Lymph stasis predisposes to skin infection in primary lymphedema
      generally; this edge is extrapolated and has not been documented in
      VEGFC patients.
  - target: Upslanting toenail
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Upslanting dysplastic toenails result from chronic edema of the nail bed.
    evidence:
    - reference: PMID:30071673
      reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There was bilateral pitting edema in both feet and the right lower leg
        (Figure 1I–K) with mildly dysplastic and upslanting toenails (due to
        edema of the nail bed).
      explanation: >-
        The authors attribute the toenail dysplasia to edema of the nail bed.
phenotypes:
- name: Predominantly lower limb lymphedema
  category: Cardiovascular
  diagnostic: true
  frequency: FREQUENT
  description: >-
    Painless bilateral lymphedema of the feet that frequently extends below the
    knee, usually present at birth or within the first year. Across 23 reported
    variant carriers from five families, 17 (74%) had swelling, most often
    bilateral below-knee lymphedema; 70% of those with a recorded age of onset
    presented congenitally.
  phenotype_term:
    preferred_term: Predominantly lower limb lymphedema
    term:
      id: HP:0003550
      label: Predominantly lower limb lymphedema
  evidence:
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For example, 17 of the 23 individuals (74%) have some forms of swelling in
      which most had bilateral below-knee lymphedema (n = 12) but some cases had
      isolated ankle and foot lymphedema (n = 5).
    explanation: >-
      Pooled frequency (74%) of lower-limb lymphedema among VEGFC variant
      carriers maps to the FREQUENT band.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of individuals (70%, nine of the 13 where the age of onset has
      been recorded) presented with congenital (<1 year) primary lymphedema.
    explanation: >-
      Supports congenital onset of the lymphedema in most affected individuals.
  - reference: PMID:24744435
    reference_title: A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a newborn patient with an external phenotype consistent with
      Milroy disease and a truncating mutation (p.R210X) in the VEGFC gene
      detected by exome sequence analysis.
    explanation: >-
      A newborn presentation with Milroy-like congenital lymphedema in an
      independent VEGFC family.
- name: Abnormal lymphatic tracts on lymphoscintigraphy
  category: Cardiovascular
  diagnostic: true
  description: >-
    Lymphoscintigraphy shows tortuous lymphatic tracts with rerouting of tracer
    around the feet, ankles and lower legs and reduced inguinal uptake. Abnormal
    tracts can be seen in carriers with little or no clinical swelling.
  phenotype_term:
    preferred_term: Tortuous lower limb lymphatic tracts
    term:
      id: HP:0100766
      label: Abnormal lymphatic vessel morphology
  evidence:
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tracer is following tortuous tracts with rerouting around feet,
      ankles, and lower legs, which indicates that the tracer is not following
      the normal tracts to the groin area seen in healthy controls.
    explanation: >-
      Describes the characteristic abnormal lymphatic tracts on imaging in
      VEGFC cases.
- name: Prominent superficial veins
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Prominent, wide-calibre veins over the shins and on the dorsa of the feet
    are a characteristic sign; among nine reported individuals in whom this was
    recorded, five (55%) had them. The mechanism linking VEGFC deficiency to the
    venous sign has not been established.
  phenotype_term:
    preferred_term: Prominent superficial veins
    term:
      id: HP:0001015
      label: Prominent superficial veins
  evidence:
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital primary lymphedema of Gordon typically presents, like Milroy
      disease, with congenital, pedal lymphedema with prominent, wide caliber
      veins over the shins and on the dorsa of the feet.
    explanation: >-
      States prominent veins as a typical presenting sign.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Not all the reports on VEGFC cases confirm the absence or presence of
      prominent veins but, in the nine individuals where a note has been made,
      five of those (55%) had such veins.
    explanation: >-
      Pooled frequency of 55% maps to the FREQUENT band.
- name: Upslanting toenail
  category: Integumentary
  description: >-
    Upslanting, dysplastic toenails, attributed to edema of the nail bed, often
    with deep interphalangeal creases of the toes (no HPO term exists for deep
    toe interphalangeal creases).
  phenotype_term:
    preferred_term: Upslanting toenail
    term:
      id: HP:0032344
      label: Upslanting toenail
  evidence:
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients have upslanting, dysplastic toenails and deep,
      interphalangeal creases of the toes.
    explanation: >-
      Lists upslanting dysplastic toenails among the typical features.
- name: Hydrocele testis
  category: Genitourinary
  frequency: OCCASIONAL
  description: >-
    Hydrocele was present in 3 of 11 (27%) reported affected males, a frequency
    comparable to the 37% reported in Milroy disease.
  phenotype_term:
    preferred_term: Hydrocele testis
    term:
      id: HP:0000034
      label: Hydrocele testis
  evidence:
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of other clinical signs, 27% (3/11) of the males presented with hydrocele.
    explanation: >-
      27% of males maps to the OCCASIONAL band.
- name: Edema of the dorsum of hands
  category: Cardiovascular
  description: >-
    Mild bilateral edema of the dorsa of the hands was noted postnatally in one
    proband and resolved spontaneously; the authors describe upper-limb
    involvement as unusual for this disorder.
  phenotype_term:
    preferred_term: Edema of the dorsum of hands
    term:
      id: HP:0007514
      label: Edema of the dorsum of hands
  evidence:
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Albeit mild, the proband also had lymphedema of the dorsi of both hands
      post-natally, which is a little unusual.
    explanation: >-
      Single-case report of transient hand lymphedema; frequency omitted.
- name: Cellulitis
  category: Infectious
  description: >-
    Cellulitis (erysipelas) is the main acute complication of primary
    lymphedema in general. It has not been reported in the published VEGFC
    families, so this phenotype is extrapolated from primary lymphedema as a
    whole and no frequency is given.
  phenotype_term:
    preferred_term: Cellulitis
    term:
      id: HP:0100658
      label: Cellulitis
  evidence:
  - reference: PMID:33407666
    reference_title: Primary lymphedema French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      The main acute lymphedema complication is cellulitis (erysipelas).
    explanation: >-
      National care protocol for primary lymphedema naming cellulitis as the
      main acute complication; applies to this disorder only by extrapolation.
genetic:
- name: VEGFC
  association: Heterozygous loss-of-function (truncating, frameshift, splice-site) variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: VEGFC
    term:
      id: hgnc:12682
      label: VEGFC
  evidence:
  - reference: PMID:23410910
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first time a mutation in one of the ligands of VEGFR3 has been
      reported to cause primary lymphedema.
    explanation: >-
      Founding report establishing VEGFC as a primary lymphedema gene.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we provide independent evidence that VEGFC mutations are
      causative of primary lymphedema of the type originally described by Gordon
      et al.
    explanation: >-
      Independent family confirming VEGFC causality for this specific entity.
  - reference: PMID:32592340
    reference_title: Investigation on the role of biallelic variants in VEGF-C found in a patient affected by Milroy-like lymphedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two VEGF-C variations were found in the proband, a novel p.(Ser65Arg) and a
      pathogenic c.148-3_148-2delCA, of paternal and maternal origin,
      respectively.
    explanation: >-
      A proband with congenital Milroy-like lymphedema carrying biallelic VEGFC
      variants, extending the allelic spectrum.
  variants:
  - name: c.571_572insTT
    type: frameshift
    clinical_significance: PATHOGENIC
    description: >-
      Exon 4 two-base insertion found in the founding three-generation family;
      the encoded protein lacks activity in the zebrafish sprouting assay.
    evidence:
    - reference: PMID:23410910
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Exome sequencing of 5 such patients was performed, and a novel frameshift
        variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1
        proband.
      explanation: >-
        Identifies the founding frameshift allele.
  - name: p.Arg210Ter (c.628C>T)
    type: nonsense
    clinical_significance: PATHOGENIC
    description: >-
      Exon 4 stop-gain variant segregating with lymphedema in a Spanish family.
    evidence:
    - reference: PMID:24744435
      reference_title: A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a newborn patient with an external phenotype consistent with
        Milroy disease and a truncating mutation (p.R210X) in the VEGFC gene
        detected by exome sequence analysis.
      explanation: >-
        Reports the nonsense allele.
  - name: c.361+5G>A
    type: splice site
    clinical_significance: PATHOGENIC
    description: >-
      Intron 2 donor splice-site variant causing exon 2 skipping, a frameshift
      and premature stop (p.Ala50ValfsTer18), removing the entire VEGF homology
      domain.
    evidence:
    - reference: PMID:30071673
      reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The mutation induced skipping of exon 2 of VEGFC resulting in a
        frameshift and the introduction of a premature stop codon
        (p.Ala50ValfsTer18).
      explanation: >-
        Patient cDNA analysis demonstrates the splicing consequence.
  - name: c.148-3_148-2delCA
    type: splice site
    clinical_significance: PATHOGENIC
    description: >-
      Acceptor splice-site deletion causing exon skipping, first reported in
      its own family (Fastre et al. 2018) and later found in trans with
      p.Ser65Arg in a biallelic proband.
    evidence:
    - reference: PMID:30071673
      reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        a splice-variant (c.148-3_148-2delCA) and a synonymous variant
        (c.552G>A) both causing exon skipping
      explanation: >-
        Summarizes the previously reported splice allele and its exon-skipping
        effect.
  - name: c.552G>A
    type: synonymous (splice-disrupting)
    clinical_significance: PATHOGENIC
    description: >-
      Coded as synonymous but disrupts splicing and causes exon skipping,
      predicted to truncate the protein; a synonymous annotation alone would
      miss its effect.
    evidence:
    - reference: PMID:30071673
      reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        a splice-variant (c.148-3_148-2delCA) and a synonymous variant
        (c.552G>A) both causing exon skipping
      explanation: >-
        Records that the synonymous allele acts through exon skipping.
  - name: p.Ser65Arg (c.195T>G)
    type: missense
    description: >-
      Novel missense allele found in trans with the splice variant
      c.148-3_148-2delCA in a single proband; it altered VEGFC processing in
      vitro. Its contribution on its own is not established, so no clinical
      significance is asserted here.
    evidence:
    - reference: PMID:32592340
      reference_title: Investigation on the role of biallelic variants in VEGF-C found in a patient affected by Milroy-like lymphedema.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two VEGF-C variations were found in the proband, a novel p.(Ser65Arg) and
        a pathogenic c.148-3_148-2delCA, of paternal and maternal origin,
        respectively.
      explanation: >-
        Reports the missense allele and its in-trans configuration.
diagnosis:
- name: Molecular genetic testing of VEGFC and FLT4
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    In a patient with congenital Milroy-like lower-limb lymphedema, both FLT4
    (VEGFR3) and VEGFC are tested, usually within a primary-lymphedema gene
    panel or by exome sequencing. VEGFC is examined in particular when no FLT4
    variant is found. Patient RNA analysis can confirm the effect of a
    suspected splice variant.
  results: >-
    A heterozygous (rarely biallelic) loss-of-function VEGFC variant that
    segregates with lymphedema confirms the diagnosis.
  evidence:
  - reference: PMID:24744435
    reference_title: A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genetic analysis of VEGFC would be useful in diagnosing patients that
      present with Milroy features but have no mutation in VEGFR-3
    explanation: >-
      Recommends VEGFC testing in FLT4-negative Milroy-like patients.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband had previously been screened for mutations in VEGFR3 (exons
      17–26, covering the tyrosine kinase domain) and found to be negative.
    explanation: >-
      Illustrates the FLT4-first, then VEGFC, testing sequence.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of the wild type and mutant bands extracted from the agarose
      gel confirmed that exon 2 is spliced out during the transcription of the
      mutant allele of the proband and her mother
    explanation: >-
      Patient cDNA analysis established the splicing consequence of an intronic
      VEGFC variant.
- name: Lymphoscintigraphy
  diagnosis_term:
    preferred_term: lymphoscintigraphy
    term:
      id: NCIT:C67262
      label: Lymphoscintigraphy
  description: >-
    Lower-limb lymphoscintigraphy confirms lymphatic dysfunction. In VEGFC cases
    it shows reduced but present groin uptake with tortuous, rerouted tracts,
    whereas FLT4-related Milroy disease typically shows no uptake in the main
    tracts or groin. Abnormal drainage can be seen in carriers with little or
    no clinical swelling.
  results: >-
    Reduced inguinal uptake with tortuous tracts and rerouting around the feet,
    ankles and lower legs.
  evidence:
  - reference: PMID:33407666
    reference_title: Primary lymphedema French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Limb lymphoscintigraphy is useful to confirm the diagnosis.
    explanation: >-
      National care protocol for primary lymphedema recommending
      lymphoscintigraphy for diagnostic confirmation.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, the cases with VEGFC mutations where lymphoscintigraphy has
      been performed all show some uptake in the groin at a reduced rate.
    explanation: >-
      Characteristic lymphoscintigraphic finding in VEGFC cases.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, lymphoscintigraphy could prove a useful tool to differentiate
      between the two primary lymphedema phenotypes.
    explanation: >-
      Supports using lymphoscintigraphy to distinguish VEGFC disease from
      Milroy disease.
treatments:
- name: Compression therapy
  description: >-
    No disease-specific therapy exists and no VEGFC-specific treatment study
    has been reported. Care follows general primary-lymphedema practice:
    volume reduction with low-stretch bandaging, then long-term maintenance
    with compression garments, exercise and a normal body weight, with patient
    education to prevent cellulitis.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: compression therapy
    term:
      id: NCIT:C157735
      label: Compression Therapy
  target_mechanisms:
  - target: Predominantly lower limb lymphedema
    treatment_effect: MODULATES
    description: >-
      External compression limits interstitial fluid accumulation in the
      affected limbs without correcting the lymphatic defect.
  evidence:
  - reference: PMID:35817543
    reference_title: Molecular Mechanisms Driving Lymphedema and Other Lymphatic Anomalies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Unfortunately, the treatments for lymphedema are limited to compression
      bandages and massages.
    explanation: >-
      Review statement that compression and massage are the available
      treatments for lymphedema, including the genetic primary forms discussed
      in the review; no VEGFC-specific treatment study exists.
  - reference: PMID:33407666
    reference_title: Primary lymphedema French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Treatment aims to prevent those complications, reduce the volume with
      low-stretch bandages, then stabilize it over the long term by exercises
      and wearing a compression garment.
    explanation: >-
      National consensus care protocol for primary lymphedema recommending
      bandaging and compression garments; applied here by extrapolation to
      this genetic form.
  - reference: PMID:33502936
    reference_title: "Primary Lymphedema: Update on Genetic Basis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Most patients with primary lymphedema are satisfactorily managed with
      compression regimens, exercise, and maintenance of a normal body weight.
    explanation: >-
      Review supporting compression-based conservative management of primary
      lymphedema in general.
animal_models:
- name: Vegfc heterozygous mouse
  species: Mouse
  genotype: Vegfc+/-
  publication: PMID:14634646
  modeled_mechanisms:
  - target: Dermal Lymphatic Vessel Hypoplasia
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Heterozygous loss of Vegfc reproduces the human genotype and produces
      cutaneous lymphatic hypoplasia with lymphedema.
    limitations: >-
      Mouse dermal lymphatic anatomy and the hind-paw distribution of edema
      differ from human lower-limb lymphedema.
    evidence:
    - reference: PMID:14634646
      reference_title: Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The lack of lymphatic vessels resulted in prenatal death due to fluid
        accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic
        hypoplasia and lymphedema.
      explanation: >-
        Supports the heterozygous mouse as a model of the dermal lymphatic
        hypoplasia node.
- name: Chy-3 mouse (Vegfc-containing deletion, hemizygous)
  species: Mouse
  genotype: Heterozygous chromosomal deletion including Vegfc (Chy-3)
  publication: PMID:17584866
  modeled_mechanisms:
  - target: Impaired Lower Limb Lymphatic Drainage
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Chy-3 mice show failed dermal-to-deep lymphatic transport in the lower
      limbs with hind-paw lymphedema, mirroring the lower-limb predilection of
      the human disorder.
    limitations: >-
      The deletion removes genes other than Vegfc, and the mice also develop
      chylous ascites, which is not a feature of the human disorder.
    evidence:
    - reference: PMID:17584866
      reference_title: Chy-3 mice are Vegfc haploinsufficient and exhibit defective dermal superficial to deep lymphatic transition and dermal lymphatic hypoplasia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These findings further delineate the lymphatic phenotype of Chy-3 mice,
        identify a collateral lymph drainage pathway previously undescribed in
        other genetic models of lymphedema, and demonstrate a predilection for
        lymphatic abnormalities of the lower limbs.
      explanation: >-
        Supports the model's relevance to lower-limb lymphatic drainage failure.
differential_diagnoses:
- name: Milroy disease
  disease_term:
    preferred_term: Milroy disease
    term:
      id: MONDO:0007919
      label: lymphatic malformation 1
  description: >-
    FLT4 (VEGFR3)-related congenital primary lymphedema presents with the same
    external phenotype of congenital bilateral pedal lymphedema. VEGFC testing
    is indicated in Milroy-like patients without an FLT4 variant.
    Lymphoscintigraphy may help separate them: Milroy disease shows no uptake in
    the main lymphatic tracts or groin, whereas VEGFC cases show reduced groin
    uptake along tortuous, rerouted tracts.
  evidence:
  - reference: PMID:24744435
    reference_title: A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical presentation, similar to Milroy disease, indicates an
      overlapping of the external phenotype of both diseases, suggesting that
      genetic analysis of VEGFC would be useful in diagnosing patients that
      present with Milroy features but have no mutation in VEGFR-3.
    explanation: >-
      Establishes clinical overlap with Milroy disease and the role of genetic
      testing in distinguishing them.
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This contrasts with the lymphoscintigrams seen in Milroy disease, which
      show no uptake within the main lymphatic tracts and groin area after 2 h.
    explanation: >-
      Identifies a lymphoscintigraphic difference between the two disorders.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists. By 2018, 23 VEGFC variant carriers
    from five families had been reported; a further biallelic case was reported
    in 2020. VEGFC variants were absent from a 116-patient Italian primary
    lymphedema cohort screened by gene panel.
  evidence:
  - reference: PMID:30071673
    reference_title: A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 23 individuals (11 male and 12 female) from 5 families (including
      the family described here) reported to date, we see marked inter-familial
      and intra-familial variation (Table 1).
    explanation: >-
      Literature case count supporting the ultra-rare classification.
  - reference: PMID:29906362
    reference_title: Genetic Screening in a Large Cohort of Italian Patients Affected by Primary Lymphedema Using a Next Generation Sequencing (NGS) Approach.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No alterations were identified in SOX18, VEGFC, and CCBE1 genes.
    explanation: >-
      VEGFC variants are a rare cause of primary lymphedema; none were found in
      a 116-patient cohort.
notes: >-
  Lump/split: MONDO:0035500 is a leaf term under lymphatic malformation and is
  defined by its causal gene (VEGFC), so it is curated as a standalone entry.
  FLT4-related Milroy disease (lymphatic malformation 1) shares the clinical
  presentation and the VEGFC-VEGFR3 pathway but is a separate gene-defined
  disorder; it is listed as a differential diagnosis, not a subtype. No dismech
  entry for Milroy disease existed at curation time. The Fastre et al. 2018
  splice-site report (PMID:29542815) is a letter with no PubMed abstract and was
  not quoted, but its two splice alleles are recorded from the summary in
  PMID:30071673. No ClinGen gene-disease validity assertion for VEGFC was
  found. No GeneReviews chapter covers this disorder. Treatment content and
  the cellulitis phenotype are extrapolated from general primary-lymphedema guidance;
  VEGF-C gene-transfer products (Lymfactin) have been trialled only in
  secondary lymphedema and are not recorded as treatments here.
clinical_trials: []
datasets: []
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Congenital_Primary_Lymphedema_Of_Gordon · 2026-10-08T15:41:52Z · View source

New entry for MONDO:0035500 (VEGFC-related congenital primary lymphedema), anchored on the MONDO label and its RO:0004003 causal gene hgnc:12682 VEGFC. Lump/split: a standalone gene-defined Disease. FLT4-related Milroy disease (MONDO:0007919) is a differential diagnosis, not a subtype; the KB has no Milroy entry. Sources. First curated from PubMed: the founding family (PMID:23410910), a stop-gain family (PMID:24744435), a splice-site family whose full text pools phenotypes across five families (PMID:30071673), a biallelic case (PMID:32592340), the Vegfc+/- and Chy-3 mouse models (PMID:14634646, PMID:17584866), a lymphatic-anomaly review (PMID:35817543) and an Italian panel cohort with no VEGFC findings (PMID:29906362). A falcon deep-research report (research/Congenital_Primary_Lymphedema_Of_Gordon-deep-research-falcon.md) was then generated: 11/11 references resolved, with no off-topic or unresolved references. Its only term-validation flag is a template artifact, the MONDO ID labelled 'if available'. just preflight-dr could not run: it requires the ~1.3 GB local MONDO build, which was not downloaded because disk space was limited. Named-entity confusion was checked by hand instead. The report is about VEGFC/Gordon throughout (VEGFC 50 mentions, FLT4 6, only as the Milroy differential), and every source it cites is a VEGFC or general-lymphedema paper. Reconciled from the report, all quoted from fetched caches: the secretion defect of the c.571_572insTT protein, quoted from the PMID:30071673 full text and marked quote_role BACKGROUND; ADAMTS3-CCBE1 proteolytic activation of VEGFC (PMID:27159393); the p.Ser65Arg variant and its processing defect (PMID:32592340); and two primary-lymphedema management sources for compression therapy (PMID:33407666 French national protocol, PMID:33502936). Not taken from the report: generic primary-lymphedema complications such as cellulitis and fibroadipose change, which are not documented in VEGFC cases, and the Lymfactin trials, which tested secondary lymphedema only. Fastre et al. 2018 (PMID:29542815) is a letter with no abstract and was not cited. Pathophysiology is a four-node chain: VEGFC haploinsufficiency -> reduced VEGFR3 signaling -> dermal lymphatic hypoplasia -> impaired lower-limb drainage. It is wired to the lymphedema, hydrocele, hand edema, toenail and lymphoscintigraphy phenotypes. Prominent superficial veins are left unconnected because no mechanism has been reported. Frequencies come from the pooled counts in PMID:30071673. There is no ClinGen CGGV record and no GeneReviews chapter (check-genereviews --online: NO_CHAPTER). Validated with just validate, validate-terms, count-verified-snippets (44/44), check-duplicate-keys, check-entity-refs, check-causal-targets, check-enum-values, check-snippet-length, check-title-snippets, check-gene-activity-grounding (against origin/main), compliance-connectivity, check-coarse-phenotypes and validate-disorders.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 49 citations 2026-10-08T16:21:41.471513

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Congenital Primary Lymphedema of Gordon
  • MONDO ID: MONDO:0035500 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Congenital Primary Lymphedema of Gordon covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

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  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Congenital primary lymphedema of Gordon: disease-characteristics report

Evidence scope. This entry concerns VEGFC-associated hereditary lymphedema ID, not the clinically similar FLT4-associated Milroy disease. The most informative disease-specific synthesis examined 23 variant carriers in five families through 2018; a further biallelic-VEGFC family was described in 2020. Those small, selected pedigrees cannot establish population prevalence, lifetime penetrance, or treatment efficacy. The 2023–2024 publications located principally advance lymphatic biology or treatment of other forms of lymphedema; their findings are identified as such below. (nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite pages 8-10, mukenge2020investigationonthe pages 1-2, moleri2023lymphaticdefectsin pages 1-2)

1. Disease information

Congenital primary lymphedema of Gordon is an inherited impairment of lymphatic development and drainage caused by reduced vascular endothelial growth factor C (VEGF-C) function. Its predominant manifestation is congenital or early-onset swelling of the feet and lower legs; it is often termed Milroy-like lymphedema because its appearance overlaps with Milroy disease, although the implicated gene differs. Identifiers supported by the retrieved literature are OMIM phenotype 615907, also called lymphedema, hereditary, ID, and ORPHA:79452. MONDO:0035500 is the identifier supplied for this entry but was not independently verified in the retrieved sources. The causative gene is VEGFC (OMIM gene 601528); classic Milroy disease is associated with FLT4/VEGFR3 and OMIM phenotype 153100. No disease-specific ICD-10, ICD-11, or MeSH identifier was verified; a generic lymphedema code must not be represented as a syndrome-specific identifier. Evidence comes from published pedigrees and aggregated disease-level literature, not an individual’s electronic health record. (nadarajah2018anovelsplicesite pages 1-3, martinalmedina2021developmentandphysiological pages 37-40, balboabeltran2014anovelstop pages 1-2)

2. Etiology and risk or protective factors

The established initiating cause is a germline VEGFC variant that impairs VEGF-C activity, generally heterozygous and consistent with autosomal-dominant transmission. Protein-truncating or splice-disrupting alleles predominate among the first five families. Family history increases the probability of carrying an allele but its absence does not exclude disease because manifestations may be subtle. No environmental exposure, pathogen, toxin, occupation, diet, or behavior has been shown to cause this Mendelian disorder; obesity may worsen primary lymphedema generally, not establish a VEGFC-specific gene–environment interaction. Normal body weight, activity, compression, and skin care are strategies to reduce manifestations or complications, not genetic protection against inheriting the condition. No protective human VEGFC allele or validated human severity-modifier gene was established. Mouse/fish experiments suggest possible compensation by VEGF-D and interaction with developmental regulators, but this should not be entered as proven protective human genetics. (nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite pages 8-10, nadarajah2018anovelsplicesite pages 11-13, sudduth2022primarylymphedemaupdate pages 1-2, moleri2023lymphaticdefectsin pages 1-2)

3. Phenotypes and frequencies

The best available denominator is 23 reported variant carriers from five families in 2018, not an unbiased cohort. They included 11 males and 12 females. The authors reported swelling in 17/23 (74%): 12 had bilateral below-knee disease and five had swelling limited to feet/ankles. Of 13 people with a recorded onset, 9/13 (approximately 70%) developed edema during the first year. Among the 11 males, 3/11 (27%) had hydrocele. Prominent ankle/foot veins were documented in 5/9 (55%) with this feature assessed. Four carriers had no clinical lymphedema and two reported only occasional swelling, demonstrating incomplete or variable clinical expression; these fractions should not be used as definitive penetrance estimates. (nadarajah2018anovelsplicesite pages 8-10, nadarajah2018anovelsplicesite pages 10-11, nadarajah2018anovelsplicesite media a542dc67)

Manifestation and type Characterization; suggested HPO annotation
Lower-limb and dorsal-foot lymphedema; clinical sign Usually evident at birth; bilateral or asymmetric, mild through substantial, sometimes pitting early and persistent into childhood. Suggest Lymphedema, Edema of the lower limbs, and Edema of the dorsum of feet; confirm current HPO term IDs before ingestion.
Prominent superficial/varicose veins; clinical sign Seen in assessed carriers; suggest Varicose veins or Prominent veins.
Hydrocele; clinical sign Occasional in males; suggest Hydrocele.
Upslanting or dysplastic toenails and deep toe creases; physical signs Present in some pedigrees, not quantified across all carriers; suggest Abnormal toenail morphology and Deep plantar creases, subject to ontology-label validation.
Reduced lymphatic tracer uptake, tortuous channels, or rerouting; imaging abnormality Demonstrated in assessed families, including some minimally symptomatic carriers; annotate as abnormal lymphoscintigraphy rather than a routine serum laboratory biomarker.

The proposed HPO labels are mapping suggestions, not verified HPO accession numbers. A 2018 child also had transient bilateral hand edema; her subtle facial findings should not automatically become defining syndrome features. Foot swelling can affect footwear, movement, skin integrity, and well-being, but syndrome-specific EQ-5D, SF-36, PROMIS, or phenotype-stratified quality-of-life scores were not located. In one 2014 family, running or walking aggravated an affected father’s edema while he reported no handicap; this illustrates individual variability rather than a population estimate. (nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite pages 3-5, balboabeltran2014anovelstop pages 2-3, vignes2021primarylymphedemafrench pages 1-2)

4. Genetic and molecular information

The principal gene is ** VEGFC — vascular endothelial growth factor C, encoding a secreted lymphangiogenic ligand; FLT4 encodes its receptor VEGFR3 and causes a different hereditary-lymphedema diagnosis when pathogenic. The Ensembl VEGFC target is ENSG00000150630. An independently verified HGNC numeric identifier, per-variant ClinVar accession or ACMG classification, and exact current gnomAD allele frequencies were not** obtained: published authors’ assessments of pathogenicity should not be relabeled as independently verified ClinVar classifications. All five original family changes were interpreted as germline disease-associated variants. (OpenTargets Search: -VEGFC, nadarajah2018anovelsplicesite pages 1-3)

Reported VEGFC variant Molecular effect and evidence
NM_005429: c.571_572insTT; p.Pro191Leufs*10 Exon-4 frameshift, first described by Gordon et al. in 2013; mutant protein detected intracellularly but not effectively secreted; failed a zebrafish sprouting assay.
c.628C>T; p.Arg210Ter Exon-4 stop-gain in a 2014 three-generation family; original report prints c.C628T/p.R210X.
c.148-3_148-2delCA; reported p.Ala50_Thr184del Splice-disrupting allele reported in a subsequent family; associated RNA change reported as r.148_552del.
c.552G>A; reported p.Ser121Ilefs*3 Synonymous at the DNA-coding level but splice disrupting; reported r.362_552del. A synonymous annotation alone would miss the functional effect.
NM_005429.2:c.361+5G>A; p.Ala50ValfsTer18 2018 donor-region allele; patient RNA showed r.148_361del, consistent with exon-2 skipping. A homologous zebrafish construct lost sprouting activity without demonstrable dominant-negative activity.
NM_005429.5:c.195T>G; p.Ser65Arg Reported in 2020, in trans with c.148-3_148-2delCA in a more severely affected child. Cell studies found reduced ADAMTS3 interaction and VEGF-C processing. Its contribution is supported by that family and assays, not proof that it causes the classic phenotype alone.

The first five rows correspond to five families, not five patients; the 2020 biallelic case should not be included in the 2018 denominator. The 2018 paper inconsistently prints c.361+5A>G in parts of its discussion, whereas its abstract, sequencing results, and family table report c.361+5G>A; use the latter provisionally and validate against the reference transcript before database ingestion. Likewise, its protein/RNA descriptions for earlier splice variants should be normalized against a current transcript. Precise population allele counts were not substantiated. No syndrome-specific pathogenic chromosomal rearrangement, somatic driver, founder allele, anticipation, germline mosaicism, epigenetic lesion, or confirmed human modifier gene was demonstrated; one proband’s karyotype and chromosomal microarray were normal. (lymphedema2013clinicaltranslationalresearch pages 2-4, balboabeltran2014anovelstop pages 2-3, nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite pages 3-5, nadarajah2018anovelsplicesite pages 10-11, mukenge2020investigationonthe pages 5-8, mukenge2020investigationonthe pages 1-2)

5. Environmental information

Congenital Gordon lymphedema is not infectious, transmissible, or caused by filarial parasites. Skin infection can instead complicate impaired lymph drainage; cancer treatment, trauma, venous disease, and filariasis are important alternative causes of swelling, not explanations for a segregating pathogenic VEGFC allele. Weight and physical activity may affect symptom burden across primary lymphedema, but disease-specific effects of smoking, alcohol, pollutants, radiation, toxins, or a particular diet have not been established. (vignes2021primarylymphedemafrench pages 1-2, sudduth2022primarylymphedemaupdate pages 1-2, nadarajah2018anovelsplicesite pages 1-3)

6. Mechanism and pathophysiology

Ordered causal chain — the words inferred and demonstrated distinguish interpretation from direct experiment:

  1. Germline VEGFC loss-of-function or splice disruption leads to an abnormal VEGF-C precursor or reduced effective VEGF-C availability; disrupted splicing is demonstrated in patient RNA for c.361+5G>A, and inefficient secretion is demonstrated in transfected cells for c.571_572insTT. (nadarajah2018anovelsplicesite pages 3-5, lymphedema2013clinicaltranslationalresearch pages 2-4)
  2. Loss or impaired maturation of extracellular VEGF-C leads to less active ligand available to bind VEGFR3/FLT4 on lymphatic endothelial cells. This is inferred for affected human tissues from protein structure, patient-associated functional assays, and established ligand-processing biology. Normal pro-VEGF-C processing involves FURIN-mediated C-terminal cleavage and CCBE1–ADAMTS3-dependent activation at the N-terminus. (nadarajah2018anovelsplicesite pages 1-3, bui2016proteolyticactivationdefines pages 1-2, martinalmedina2021developmentandphysiological pages 37-40)
  3. Reduced ligand–receptor signaling leads to weaker VEGFR3-driven lymphatic endothelial proliferation, survival, migration, and sprouting. Branch: VEGFR3 ordinarily signals through RAS–RAF–MEK–ERK/MAPK and PI3K–AKT, with downstream mTOR/eNOS effects; diminished activation of these specific branches in Gordon patient lymphatic cells has not been directly quantified. (kuonqui2023dysregulationoflymphatic pages 1-3, lymphedema2013clinicaltranslationalresearch pages 2-4)
  4. Insufficient developmental sprouting leads to a hypoplastic or inefficient lymphatic network: Vegfc-null mice retain specified PROX1-positive venous precursors but fail their egress/migration; analogous failure of mutant patient-derived VEGF-C constructs to drive sprouting was demonstrated in zebrafish overexpression assays. Extrapolation from these models to the precise human vessel lesion is inferred. (martinalmedina2021developmentandphysiological pages 37-40, nadarajah2018anovelsplicesite pages 5-8, nadarajah2018anovelsplicesite pages 8-10)
  5. Impaired lymphatic uptake and transport results in reduced or asymmetric lymphoscintigraphic tracer clearance, tortuous tracts and rerouting, demonstrated in human pedigrees, including mildly affected carriers. (lymphedema2013clinicaltranslationalresearch pages 2-4, nadarajah2018anovelsplicesite pages 3-5, nadarajah2018anovelsplicesite pages 8-10)
  6. Persistent interstitial lymph retention leads to pedal/lower-leg edema; branch: prolonged stasis can lead to skin thickening, fibroadipose change and cellulitis, as established for primary lymphedema generally, but their incidence and immune/metabolic signatures in genetically confirmed Gordon cases remain unknown. (lymphedema2013clinicaltranslationalresearch pages 1-2, vignes2021primarylymphedemafrench pages 1-2, vignes2021primarylymphedemafrench pages 7-8)

The upstream lesion is reduced ligand function, not a demonstrated primary defect of VEGFR3 protein in these families. Coexpression assays did not demonstrate mutant-protein inhibition of wild-type VEGF-C; haploinsufficiency is the favored mechanism for the heterozygous truncating alleles. VEGF-D compensation remains a mechanistic hypothesis supported by other animal experiments, not a validated human rescue strategy. Suggested, accession-unverified annotations: GO biological processes lymphangiogenesis, lymphatic endothelial cell migration, VEGF receptor signaling pathway, and regulation of interstitial fluid homeostasis; GO cellular components extracellular region, endoplasmic reticulum/secretory pathway, and plasma membrane; CL cell types lymphatic endothelial cell, vascular endothelial cell, and, downstream, fibroblast and macrophage. No Gordon-patient-specific transcriptomic, proteomic, metabolomic, lipidomic, spatial, or single-cell signature, nor a disease-specific CRISPR-screen result, was located. (lymphedema2013clinicaltranslationalresearch pages 2-4, nadarajah2018anovelsplicesite pages 5-8, nadarajah2018anovelsplicesite pages 8-10, kuonqui2023dysregulationoflymphatic pages 1-3, vignes2021primarylymphedemafrench pages 1-2)

7. Anatomical structures affected

Primary sites: lymphatic vessels in skin and subcutaneous connective tissue of the feet, ankles, and distal lower limbs, commonly both sides but sometimes markedly asymmetric. Secondary sites: overlying skin, subcutaneous fat and, in occasional males, the scrotal fluid compartment associated with hydrocele. Mild hand involvement occurred in one child; systemic intestinal, pulmonary, neurological, or cardiac involvement is not an established defining feature of this entity. Relevant anatomy annotations, subject to UBERON identifier verification, are lymphatic vessel, skin of foot, lower limb, subcutaneous adipose tissue, and scrotum. At cell level, the receptor-bearing lymphatic endothelium is the key responding population; the affected VEGFC product normally acts as a secreted extracellular ligand. Skin fibrosis is downstream tissue remodeling, not evidence that fibroblasts carry a selective somatic lesion. (martinalmedina2021developmentandphysiological pages 37-40, nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite pages 3-5, bui2016proteolyticactivationdefines pages 1-2)

8. Temporal development

Onset is typically congenital, but infant, childhood, adolescent, and at least one adult presentation appear in the pedigrees; clinical onset can therefore lag behind the inherited lesion. The course is usually chronic and variably expressive: one 2013 family member’s pedal swelling improved in the third year, and another improved in childhood before worsening in adolescence; a 2018 child’s hand swelling resolved while foot swelling persisted at age four years eight months. Adult carriers can have subtle edema despite abnormal scans. General primary-lymphedema staging distinguishes stage 0 (abnormal transport without overt swelling), stage I (edema improves on elevation), stage II (persistent edema), and stage III (fibroadipose change), but these are general clinical stages, not a validated Gordon-specific progression sequence. No syndrome-specific progression rate, predictable remission frequency, or intervention window has been established. (lymphedema2013clinicaltranslationalresearch pages 1-2, nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite pages 3-5, nadarajah2018anovelsplicesite pages 8-10, sudduth2022primarylymphedemaupdate pages 1-2)

9. Inheritance and population

Pedigrees support autosomal-dominant inheritance with variable expressivity and incomplete clinical penetrance for heterozygous loss-of-function alleles. The later in-trans splice-plus-missense child suggests an additional biallelic, potentially dosage-sensitive presentation, not a reclassification of all families as recessive. A clinically unaffected carrier may nonetheless have abnormal lymphoscintigraphy; counseling should distinguish transmission of an allele from certainty of visible swelling. For a heterozygous affected parent, 50% transmission per pregnancy follows Mendelian segregation, while the probability and severity of clinical disease remain uncertain. The 2018 research collection contained 11 male and 12 female carriers, not a population-based sex ratio. No reliable Gordon-specific prevalence per 100,000, annual incidence, carrier frequency, founder effect, ethnic predilection, or geographic distribution was established. The frequently cited figure of approximately 1 in 100,000 children concerns all primary lymphedema, not Gordon disease. (nadarajah2018anovelsplicesite pages 8-10, nadarajah2018anovelsplicesite pages 10-11, mukenge2020investigationonthe pages 5-8, mukenge2020investigationonthe pages 1-2, sudduth2022primarylymphedemaupdate pages 1-2)

10. Diagnosis

Clinical pathway. Document onset, family history, foot/toe involvement, pitting, skin changes, limb circumference or volume, venous abnormalities, hydrocele, and associated findings suggesting another syndrome. A positive Stemmer sign supports lymphedema, but early pitting disease should not be rejected solely because longstanding fibrotic changes are absent. Evaluate alternative causes as indicated: venous Doppler for thrombosis/venous insufficiency, serum studies for systemic protein loss, and appropriate imaging for a compressive lesion. Lymphoscintigraphy confirms lymphatic dysfunction and characterizes bilateral uptake, tortuosity and rerouting; VEGFC cases often show residual but reduced flow, unlike the profound functional aplasia commonly described for classic FLT4 Milroy disease, although an individual VEGFC limb can also show functional aplasia. MRI lymphangiography or indocyanine-green imaging may help selected surgical/anatomical questions; no syndrome-specific blood, urine, biopsy, EEG, EMG, or ECG biomarker is established. (vignes2021primarylymphedemafrench pages 1-2, vignes2021primarylymphedemafrench pages 2-4, lymphedema2013clinicaltranslationalresearch pages 2-4, nadarajah2018anovelsplicesite pages 3-5, nadarajah2018anovelsplicesite pages 11-13)

Molecular pathway. Test both FLT4 and VEGFC in congenital Milroy-like edema; a primary-lymphedema panel can also evaluate phenotype-dependent alternatives including FOXC2, CCBE1, ADAMTS3, GATA2, KIF11, SOX18, GJC2, and PIEZO1. A known familial VEGFC allele permits targeted testing and segregation analysis. If panel testing is uninformative, exome or genome sequencing with copy-number and noncoding/splice evaluation may be considered by a genetics service; patient RNA analysis can directly establish whether a putative splice variant alters transcripts. Genome sequencing, microarray, karyotype, FISH, mitochondrial testing, and repeat-expansion tests are not established routine confirmatory tests for isolated VEGFC disease. When evaluating a novel allele, confirm transcript/HGVS, assess segregation and population frequency, apply contemporary ACMG/AMP criteria, and avoid assuming that any rare VEGFC missense variant is pathogenic. Distinguish FOXC2-associated distichiasis, KIF11-associated microcephaly/chorioretinopathy, SOX18-associated hypotrichosis/telangiectasia, syndromic generalized lymphatic dysplasias, venous edema, lipedema, and acquired lymphatic obstruction. Cascade evaluation can identify subtly affected relatives; no routine population newborn screen was identified. (lymphedema2013clinicaltranslationalresearch pages 1-2, nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite pages 3-5, mukenge2020investigationonthe pages 2-4, vignes2021primarylymphedemafrench pages 1-2)

11. Outcomes and prognosis

Syndrome-specific five-/ten-year survival, life expectancy, attributable mortality, validated prognostic biomarker, recovery probability, and patient-reported-outcome distribution are unknown. The published pedigrees demonstrate survival into adulthood and generally peripheral disease, but cannot prove normal population life expectancy. Clinical burden ranges from little apparent disability to persistent swelling, skin change or cellulitis; wider primary-lymphedema literature documents limitations in function and self-esteem and identifies higher BMI as an adverse morbidity correlate. Compression can control swelling, not correct the germline lesion; occasional spontaneous improvement does not establish a general cure rate. Monitor edema, function, skin infection and psychosocial effects rather than using a gene result alone to predict severity. (balboabeltran2014anovelstop pages 2-3, nadarajah2018anovelsplicesite pages 3-5, sudduth2022primarylymphedemaupdate pages 1-2, vignes2021primarylymphedemafrench pages 1-2)

12. Treatment and current applications

Established care is phenotype-directed and extrapolated from broader primary-lymphedema practice; no VEGFC-genotype-specific efficacy trial was found. Specialist assessment is followed, according to severity and age, by low-stretch bandaging/complete decongestive therapy, individualized compression garments, exercise, weight management, meticulous skin and nail care, and education about cellulitis. A French national protocol reports 30–60% volume reduction during an intensive phase across primary-lymphedema care; this is not a Gordon-specific response rate. Pediatric compression requires adjustment for growth and has no universal infant protocol. Manual lymphatic drainage has uncertain independent evidence in primary disease. Suggested NCIT concept labels, with identifiers requiring validation, are Compression Therapy, Physical Therapy, Exercise Therapy, Manual Lymphatic Drainage, and Patient Education. (vignes2021primarylymphedemafrench pages 5-7, vignes2021primarylymphedemafrench pages 7-8, sudduth2022primarylymphedemaupdate pages 1-2)

Complications and intervention. Prompt assessment and antibiotics are indicated for clinically diagnosed cellulitis; prophylactic penicillin may be considered under specialist guidance for recurrent episodes while treating skin entry sites. Antibiotics do not treat the VEGFC defect. Diuretics are not recommended for isolated lymphedema. Selected severe or refractory patients may be evaluated for lymphovenous bypass, lymph-node transfer, or reduction of established fibroadipose tissue; outcomes and optimal selection have not been measured specifically for Gordon disease. Potential NCIT concept labels requiring validation include Antibiotic Therapy, Lymphovenous Anastomosis, Lymph Node Transfer, and Liposuction. No established pharmacogenomic rule, enzyme replacement, approved gene therapy, RNA therapy, cell therapy, immunotherapy, or targeted drug exists for this syndrome. (vignes2021primarylymphedemafrench pages 7-8, vignes2021primarylymphedemafrench pages 5-7, sudduth2022primarylymphedemaupdate pages 1-2)

Experimental work must not be misapplied. The 2024 apelin–VEGF-C mRNA investigation concerned secondary lymphedema and proposed regenerative delivery, not treatment of inherited VEGFC deficiency. The VEGF-C adenoviral-vector product Lymfactin was studied with lymph-node transfer in post-breast-cancer secondary upper-limb lymphedema: phase II NCT03658967 enrolled 39 and is listed completed; phase I NCT02994771 enrolled 15 and is listed terminated, with the registry giving “Lack of efficacy” as its reason. Neither trial establishes efficacy or safety in children or patients with Gordon disease. (NCT03658967 chunk 1, NCT02994771 chunk 1)

13. Prevention

Primary prevention of the inherited allele: no vaccine, diet, environmental intervention, or medication prevents transmission. Reproductive genetic counseling can discuss the established familial allele, variable expression, prenatal testing, and preimplantation testing where appropriate and available; predictive testing of relatives should be individualized. Secondary prevention: inspect at-risk relatives for subtle pedal signs, offer familial-variant testing and specialist assessment where indicated, and initiate appropriate care before marked tissue remodeling. Tertiary prevention: compression where tolerated, activity/weight management, skin and toe-web care, prompt cellulitis treatment, and specialist consideration of prophylaxis after repeated infections. Routine childhood immunizations remain appropriate; they do not specifically prevent this genetic disorder. No established public-health screen or filariasis-control program specifically prevents Gordon disease. (nadarajah2018anovelsplicesite pages 8-10, vignes2021primarylymphedemafrench pages 7-8, vignes2021primarylymphedemafrench pages 5-7, vignes2021primarylymphedemafrench pages 1-2)

14. Other species and natural disease

The named clinical disorder is documented in humans (Homo sapiens, NCBI Taxon 9606). Orthologous Vegfc/vegfc is experimentally relevant in mouse (Mus musculus, 10090) and zebrafish (Danio rerio, 7955). Those experiments do not demonstrate a naturally occurring, breed-associated veterinary equivalent of the Gordon phenotype. No validated companion-animal breed or VBO annotation, naturally occurring cross-species transmission, zoonotic risk, or species-specific carrier frequency was located. NCBI ortholog Gene IDs should be verified before knowledge-base entry rather than inferred from a shared symbol. (martinalmedina2021developmentandphysiological pages 37-40, nadarajah2018anovelsplicesite pages 5-8, moleri2023lymphaticdefectsin pages 1-2)

15. Model organisms and research applications

Mouse genetics. Vegfc knockout embryos specify lymphatic precursors but fail normal sprouting, develop edema and die before birth; heterozygotes survive with edematous paws and dermal lymphatic hypoplasia. Chy-3 mice carry a deletion encompassing Vegfc, have reduced gene dosage, hypoplastic dermal lymphatics, abnormal superficial-to-deep transport, and additional findings such as chylous ascites. Do not confuse Chy-3 (Vegfc deletion) with Chy (Vegfr3 mutation). These models test dosage and lymphatic-network development but do not reproduce each human family’s exact allele or predict its individual clinical course. (martinalmedina2021developmentandphysiological pages 37-40, martinalmedina2021developmentandphysiological pages 40-42, martinalmedina2021developmentandphysiological pages 86-89)

Zebrafish and cell assays. Forced expression of normal human VEGF-C induced vessel hypersprouting, whereas the 2013 patient frameshift did not; 293T cells showed loss of mutant protein secretion. The 2018 homologous zebrafish splice construct similarly lost sprouting activity; coexpression with wild type supported absence of a dominant-negative effect. The 2020 patient-associated p.Ser65Arg allele reduced interaction/processing by ADAMTS3 in biochemical assays. A 2023 zebrafish sox18 model found that partial vegfc knockdown aggravated lymphatic defects and elevated sox7 could mask sox18 loss; this is pathway/modifier biology, not a study of Gordon patients or proof of a human modifier allele. Mouse resources include MGI/IMPC and zebrafish resources ZFIN, subject to verifying strain and allele records before entry. (lymphedema2013clinicaltranslationalresearch pages 2-4, nadarajah2018anovelsplicesite pages 5-8, mukenge2020investigationonthe pages 5-8, moleri2023lymphaticdefectsin pages 1-2)

Key primary sources, dates and exact abstract excerpts

  • Gordon K et al., Circulation Research, 15 March 2013, 112:956–960. DOI: 10.1161/CIRCRESAHA.113.300350. Abstract: “Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC ... was identified in 1 proband.” Human pedigree, cell secretion assay and zebrafish functional evidence. PMID not independently verified here. (lymphedema2013clinicaltranslationalresearch pages 1-2, lymphedema2013clinicaltranslationalresearch pages 2-4)
  • Balboa-Beltran E et al., Journal of Medical Genetics, online 17 April 2014, 51:475–478. DOI: 10.1136/jmedgenet-2013-102020. Abstract: “We report a newborn patient ... and a truncating mutation (p.R210X) in the VEGFC gene detected by exome sequence analysis.” Human family. PMID not independently verified here. (balboabeltran2014anovelstop pages 1-2, balboabeltran2014anovelstop pages 2-3)
  • Fastré E et al., Clinical Genetics, 2018, 94:179–181, “Splice-site mutations in VEGFC cause loss of function and Nonne-Milroy-like primary lymphedema.” Two earlier families and their variants are summarized in Nadarajah et al.; the original full text and its PMID were not independently verified here. (martinalmedina2021developmentandphysiological pages 86-89, nadarajah2018anovelsplicesite pages 10-11)
  • Nadarajah N et al., International Journal of Molecular Sciences, 1 August 2018, 19:2259. DOI: 10.3390/ijms19082259. Abstract: “The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18).” Human clinical/RNA data and zebrafish assay; Table 1 compiles the historical carrier denominator. PMID not independently verified here. (nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite media a542dc67)
  • Mukenge S et al., Molecular Genetics & Genomic Medicine, published 2020, DOI: 10.1002/mgg3.1389. Abstract: “Two VEGF-C variations were found in the proband, a novel p.(Ser65Arg) and a pathogenic c.148-3_148-2delCA ... Functional characterization ... showed alterations in VEGF-C processing.” Human family and in-vitro biochemistry. PMID not independently verified here. (mukenge2020investigationonthe pages 1-2)
  • Bui HM et al., Journal of Clinical Investigation, June 2016, 126:2167–2180. DOI: 10.1172/JCI83967. Abstract: an “ADAMTS3-CCBE1 complex ... is required to convert VEGFC, but not VEGFD, into an active ligand.” Mechanistic biochemistry and mouse genetics, not Gordon-patient measurements. (bui2016proteolyticactivationdefines pages 1-2)
  • Moleri S et al., Cells, 19 September 2023, 12:2309. DOI: 10.3390/cells12182309. Abstract: “Partial knockdown of vegfc exacerbates lymphatic defects in sox18 mutants.” Zebrafish pathway evidence, not disease-specific human evidence. (moleri2023lymphaticdefectsin pages 1-2)

Knowledge-base curation boundary: retain exact disease-specific observations and denominators separately from general-lymphedema guidance and animal-model inference. Verify MONDO cross-reference, ontology accession numbers, HGNC numeric ID, HGVS against the selected transcript, ClinVar assertions, current gnomAD frequencies, and PMID/NCIT identifiers before asserting them as database-validated fields. (nadarajah2018anovelsplicesite pages 1-3, nadarajah2018anovelsplicesite pages 10-11, vignes2021primarylymphedemafrench pages 1-2)

References

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Artifacts

## Context ID: pqac-00000064 Table 1 provides a summary of findings for 23 individuals across five families with VEGFC mutations, detailing their clinical prese

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 8
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 2
Resolved 1
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0035500 (2 mentions) - the report calls it "if available"; MONDO calls it congenital primary lymphedema of Gordon

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.