LMPHM1
MCID: LYM144
MIFTS: 47

Lymphatic Malformation 1 (LMPHM1)

Categories: Cardiovascular diseases, Fetal diseases, Gastrointestinal diseases, Genetic diseases, Immune diseases, Neuronal diseases, Rare diseases, Reproductive diseases, Skin diseases

Aliases & Classifications for Lymphatic Malformation 1

MalaCards integrated aliases for Lymphatic Malformation 1:

Name: Lymphatic Malformation 1 57 74
Milroy Disease 57 24 53 25 59 74
Hereditary Lymphedema Type I 53 25 59 29 6
Nonne-Milroy Lymphedema 57 53 25 59 74
Primary Congenital Lymphedema 57 53 74
Congenital Primary Lymphedema 53 59
Milroy's Disease 53 25
Lmphm1 57 74
Pcl 57 74
Lymphedema, Hereditary, Ia, Formerly; Lmph1a, Formerly 57
Lymphedema, Hereditary, Type I, Formerly 57
Lymphedema, Hereditary, Ia, Formerly 57
Primary Congenital Lymphedema; Pcl 57
Congenital Hereditary Lymphedema 53
Congenital Familial Lymphedema 25
Hereditary Lymphedema, Type I 24
Lymphedema Hereditary Type Ia 74
Milroy Congenital Lymphedema 24
Lymphedema, Hereditary, 1a 74
Lymphedema, Early-Onset 57
Hereditary Lymphedema 1 53
Early Onset Lymphedema 53
Lymphedema Early-Onset 74
Hereditary Lymphedema 53
Nonne-Milroy Syndrome 53
Nonne-Milroy Disease 53
Lmph1a, Formerly 57
Nonne's Syndrome 53
Lmph1a 74

Characteristics:

Orphanet epidemiological data:

59
milroy disease
Inheritance: Autosomal dominant; Age of onset: Infancy,Neonatal;

OMIM:

57
Inheritance:
autosomal dominant

Miscellaneous:
onset usually at birth
later onset may occur
variable expression and severity
more prevalent in females
spontaneous resorption (rare)
lymphedema that presents at puberty is called meige disease ()


HPO:

32
lymphatic malformation 1:
Inheritance autosomal dominant inheritance
Onset and clinical course congenital onset


GeneReviews:

24
Penetrance Approximately 85%-90% of individuals who have a pathogenic variant in flt4 develop lower-limb lymphedema by age three years; conversely, 10%-15% of individuals with an flt4 pathogenic variant are clinically unaffected.

Classifications:



External Ids:

MeSH 44 D008209
ICD10 via Orphanet 34 Q82.0
UMLS via Orphanet 73 C1704423
Orphanet 59 ORPHA79452
MedGen 42 C1704423

Summaries for Lymphatic Malformation 1

Genetics Home Reference : 25 Milroy disease is a condition that affects the normal function of the lymphatic system. The lymphatic system produces and transports fluids and immune cells throughout the body. Impaired transport with accumulation of lymph fluid can cause swelling (lymphedema). Individuals with Milroy disease typically have lymphedema in their lower legs and feet at birth or develop it in infancy. The lymphedema typically occurs on both sides of the body and may worsen over time. Milroy disease is associated with other features in addition to lymphedema. Males with Milroy disease are sometimes born with an accumulation of fluid in the scrotum (hydrocele). Males and females may have upslanting toenails, deep creases in the toes, wart-like growths (papillomas), and prominent leg veins. Some individuals develop non-contagious skin infections called cellulitis that can damage the thin tubes that carry lymph fluid (lymphatic vessels). Episodes of cellulitis can cause further swelling in the lower limbs.

MalaCards based summary : Lymphatic Malformation 1, also known as milroy disease, is related to congenital lymphedema and hereditary lymphedema. An important gene associated with Lymphatic Malformation 1 is FLT4 (Fms Related Tyrosine Kinase 4), and among its related pathways/superpathways are VEGF Pathway (Qiagen) and RhoGDI Pathway. Affiliated tissues include skin, testis and endothelial, and related phenotypes are hyperkeratosis and varicose veins

NIH Rare Diseases : 53 Milroy disease is a lymphatic disease that causes swelling (lymphedema) in the lower legs and feet. Lymphedema is usually present at birth or develops in infancy. It typically occurs on both sides of the body and can worsen over time. Other symptoms may include accumulation of fluid in the scrotum in males (hydrocele), upslanting toenails, deep creases in the toes, wart-like growths, prominent leg veins, and/or cellulitis. Milroy disease is sometimes caused by changes (mutations) in the FLT4 gene and is inherited in an autosomal dominant manner. In many cases, the cause remains unknown. Treatment may include lymphedema therapy to improve function and alleviate symptoms.

OMIM : 57 Primary lymphedema is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. Onset is usually at birth or in early childhood but can occur later, and the severity is variable (summary by Gordon et al., 2013 and Balboa-Beltran et al., 2014). (153100)

UniProtKB/Swiss-Prot : 74 Lymphatic malformation 1: A form of primary lymphedema, a disease characterized by swelling of body parts due to developmental anomalies and functional defects of the lymphatic system. Patients with lymphedema may suffer from recurrent local infections. LMPHM1 is an autosomal dominant form with variable expression and severity. Onset is usually at birth or in early childhood but can occur later. Affected individuals manifest lymphedema, predominantly in the lower limbs, and hypoplasia of lymphatic vessels. Additional features are hemangioma and nail dysplasia or papillomatosis.

GeneReviews: NBK1239

Related Diseases for Lymphatic Malformation 1

Diseases in the Lymphatic Malformations family:

Lymphatic Malformation 1 Lymphatic Malformation 5
Lymphatic Malformation 2 Lymphatic Malformation 3
Lymphatic Malformation 4 Lymphatic Malformation 6
Lymphatic Malformation 7 Rare Lymphatic Malformation

Diseases related to Lymphatic Malformation 1 via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 173)
# Related Disease Score Top Affiliating Genes
1 congenital lymphedema 32.2 VEGFC FLT4
2 hereditary lymphedema 32.2 VEGFC FLT4
3 lymphedema 29.6 VEGFC GJC2 FLT4
4 lymphangioma 29.6 VEGFC FLT4
5 lymphangiosarcoma 29.6 VEGFC FLT4
6 lung cancer susceptibility 3 29.5 VEGFC FLT4
7 hereditary lymphedema ii 12.7
8 hereditary lymphedema ic 12.5
9 hereditary lymphedema id 12.5
10 hereditary lymphedema ia 12.5
11 hereditary lymphedema ib 12.5
12 obsolete: congenital primary lymphedema 12.3
13 plasma cell leukemia 12.3
14 hereditary lymphedema i 12.1
15 lymphatic malformation 5 11.7
16 lymphedema-distichiasis syndrome 11.6
17 yellow nail syndrome 11.2
18 lymphatic malformation 4 11.2
19 hydrops, lactic acidosis, and sideroblastic anemia 10.4
20 personality disorder 10.4
21 glioblastoma multiforme 10.3
22 glioblastoma 10.3
23 glioma 10.3
24 glial tumor 10.3
25 collagenopathy type 2 alpha 1 10.3
26 cellulitis 10.3
27 chudley-mccullough syndrome 10.2
28 post-traumatic stress disorder 10.2
29 acute stress disorder 10.2
30 spinal cord injury 10.2
31 primary lymphedema 10.2
32 antisocial personality disorder 10.2
33 avoidant personality disorder 10.2
34 severe combined immunodeficiency 10.2
35 papilloma 10.1
36 elephantiasis 10.1
37 hydrocele 10.1
38 colorectal cancer 10.1
39 hepatocellular carcinoma 10.1
40 gastric cancer 10.1
41 desmoid tumor 10.0
42 nephrotic syndrome 10.0
43 diarrhea 10.0
44 malignant fibroxanthoma 10.0
45 thrombocytosis 10.0
46 histiocytoma 10.0
47 fibrous histiocytoma 10.0
48 septic arthritis 10.0
49 arthritis 10.0
50 undifferentiated pleomorphic sarcoma 10.0

Graphical network of the top 20 diseases related to Lymphatic Malformation 1:



Diseases related to Lymphatic Malformation 1

Symptoms & Phenotypes for Lymphatic Malformation 1

Human phenotypes related to Lymphatic Malformation 1:

59 32 (show all 27)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hyperkeratosis 59 32 frequent (33%) Frequent (79-30%) HP:0000962
2 varicose veins 59 32 frequent (33%) Frequent (79-30%) HP:0002619
3 cellulitis 59 32 very rare (1%) Frequent (79-30%) HP:0100658
4 ankle swelling 59 32 frequent (33%) Frequent (79-30%) HP:0001785
5 toenail dysplasia 59 32 frequent (33%) Frequent (79-30%) HP:0100797
6 hydrocele testis 59 32 very rare (1%) Frequent (79-30%) HP:0000034
7 predominantly lower limb lymphedema 59 32 very rare (1%) Frequent (79-30%) HP:0003550
8 pedal edema 32 frequent (33%) HP:0010741
9 behavioral abnormality 59 32 occasional (7.5%) Occasional (29-5%) HP:0000708
10 epicanthus 59 32 occasional (7.5%) Occasional (29-5%) HP:0000286
11 specific learning disability 59 32 occasional (7.5%) Occasional (29-5%) HP:0001328
12 neoplasm of the skin 59 32 occasional (7.5%) Occasional (29-5%) HP:0008069
13 lichenification 59 32 occasional (7.5%) Occasional (29-5%) HP:0100725
14 angiosarcoma 59 32 occasional (7.5%) Occasional (29-5%) HP:0200058
15 abnormal facial shape 59 32 very rare (1%) Very rare (<4-1%) HP:0001999
16 erysipelas 59 32 very rare (1%) Very rare (<4-1%) HP:0001055
17 papilloma 32 very rare (1%) HP:0012740
18 prominent superficial veins 32 very rare (1%) HP:0001015
19 urethral stricture 32 very rare (1%) HP:0012227
20 hypoplasia of lymphatic vessels 32 very rare (1%) HP:0003759
21 nonimmune hydrops fetalis 32 very rare (1%) HP:0001790
22 upslanting toenail 32 very rare (1%) HP:0032344
23 lymphedema 59 Very frequent (99-80%)
24 hemangioma 32 HP:0001028
25 edema of the lower limbs 59 Frequent (79-30%)
26 abnormal venous morphology 59 Frequent (79-30%)
27 hyperkeratosis over edematous areas 32 HP:0007448

Symptoms via clinical synopsis from OMIM:

57
Cardiovascular Vascular:
hemangioma

Genitourinary External Genitalia Male:
hydrocele

Muscle Soft Tissue:
lymphedema, predominantly in the lower limbs
lymphography shows hypoplasia of lymphatic vessels

Skin Nails Hair Skin:
hemangioma
hyperkeratosis over edematous areas
papillomatosis over edematous areas

Skin Nails Hair Nails:
upturned toenails

Prenatal Manifestations Amniotic Fluid:
non-immune fetal hydrops (rare)

Clinical features from OMIM:

153100

Drugs & Therapeutics for Lymphatic Malformation 1

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Phase I/II Combinational Investigational New Drug Application: Imaging Lymphatic Function in Normal Subjects and in Persons With Lymphatic Disorders Enrolling by invitation NCT00833599 NIRFLI with ICG

Search NIH Clinical Center for Lymphatic Malformation 1

Genetic Tests for Lymphatic Malformation 1

Genetic tests related to Lymphatic Malformation 1:

# Genetic test Affiliating Genes
1 Hereditary Lymphedema Type I 29 FLT4

Anatomical Context for Lymphatic Malformation 1

MalaCards organs/tissues related to Lymphatic Malformation 1:

41
Skin, Testis, Endothelial, Tongue

Publications for Lymphatic Malformation 1

Articles related to Lymphatic Malformation 1:

(show top 50) (show all 87)
# Title Authors PMID Year
1
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. 38 4 8 71
23410910 2013
2
Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations. 38 4 8 71
16965327 2006
3
Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphoedema. 4 8 71
12960217 2003
4
Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. 4 8 71
10835628 2000
5
Hereditary lymphedema: evidence for linkage and genetic heterogeneity. 4 8 71
9817924 1998
6
A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. 38 8 71
24744435 2014
7
Recessive primary congenital lymphoedema caused by a VEGFR3 mutation. 38 8 71
19289394 2009
8
Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3. 38 8 71
16924388 2006
9
Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. 38 4 8
19002718 2009
10
Milroy disease and the VEGFR-3 mutation phenotype. 38 4 8
15689446 2005
11
Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. 38 4 71
10856194 2000
12
Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families. 4 8
11170072 2001
13
Milroy Disease 38 71
20301417 2006
14
Mapping of primary congenital lymphedema to the 5q35.3 region. 38 8
9973292 1999
15
FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update. 38 4
23074044 2013
16
Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography. 8
22831870 2012
17
Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. 71
21266381 2011
18
GJC2 missense mutations cause human lymphedema. 71
20537300 2010
19
Three children with Milroy disease and de novo mutations in VEGFR3. 38 4
17250670 2007
20
Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. 38 4
12740761 2003
21
Prenatal diagnosis of Milroy's primary congenital lymphedema. 38 4
12224079 2002
22
Autosomal recessive lymphedema? 8
3735758 1986
23
Congenital lymphedema in two siblings. 8
4010046 1985
24
Congenital hereditary lymphedema in the pig. 8
642582 1978
25
The pathogenesis of congenital hereditary lymphedema in the pig. 8
642583 1978
26
CONGENITAL HEREDITARY LYMPHOEDEMA. 8
14295660 1965
27
PLEURAL EFFUSION IN CHRONIC HEREDITARY LYMPHEDEMA (NONNE, MILROY, MEIGE'S DISEASE). REPORT OF TWO CASES. 8
14115303 1964
28
Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. 4
24281367 2014
29
The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. 4
23621851 2013
30
Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. 4
22284827 2012
31
Yellow nail syndrome: analysis of 41 consecutive patients. 4
18403655 2008
32
Yellow nail syndrome: not a genetic disorder? Eleven new cases and a review of the literature. 4
17459037 2007
33
Hydrops fetalis: an unusual prenatal presentation of hereditary congenital lymphedema. 4
16231305 2005
34
Turner's syndrome. 4
15371580 2004
35
Turner syndrome in childhood and adolescence. 4
12464229 2002
36
A model for gene therapy of human hereditary lymphedema. 4
11592985 2001
37
Prenatal diagnosis of Nonne-Milroy lymphedema. 4
11547763 2001
38
VEGFR3 gene structure, regulatory region, and sequence polymorphisms. 4
11292664 2001
39
Surgical treatment of Milroy disease. 38
31165487 2019
40
Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot. 38
30582441 2019
41
Immunohistochemical Evaluation of Histological Change in a Chinese Milroy Disease Family With Venous and Skin Abnormities. 38
30941160 2019
42
A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon. 38
30071673 2018
43
A novel mutation in the conserved sequence of vascular endothelial growth factor receptor 3 leads to primary lymphoedema. 38
29896974 2018
44
From fish embryos to human patients: lymphangiogenesis in development and disease. 38
29800868 2018
45
Modified enteromesenteric bridging operation for primary lymphedema. 38
30337509 2018
46
Bipolar Radiofrequency Ablation (Coblation) of External Auditory Canal Lymphatic Malformation and Other Soft Stenoses. 38
29078703 2017
47
[Primary lymphedema due to Milroy disease]. 38
26818397 2017
48
Atypical retiform hemangioendothelioma arising in a patient with Milroy disease: a case report and review of the literature. 38
27730656 2017
49
[Primary congenital lymphedema: Milroy disease: the first case observed in the Department of Pediatrics at the University Hospital Yalgado Ouedraogo, Ouagadougou]. 38
28748022 2017
50
Milroy Disease or Primary Congenital Lymphedema Associated With Invasive Squamous Cell Carcinoma. 38
27374380 2016

Variations for Lymphatic Malformation 1

ClinVar genetic disease variations for Lymphatic Malformation 1:

6
# Gene Variation Type Significance SNP ID GRCh37 Pos GRCh38 Pos
1 FLT4 NM_182925.5(FLT4): c.2569G> A (p.Gly857Arg) single nucleotide variant Pathogenic rs267606818 5:180046743-180046743 5:180619743-180619743
2 FLT4 NM_182925.5(FLT4): c.3122G> C (p.Arg1041Pro) single nucleotide variant Pathogenic rs121909650 5:180043464-180043464 5:180616464-180616464
3 FLT4 NM_182925.5(FLT4): c.3131T> C (p.Leu1044Pro) single nucleotide variant Pathogenic rs121909651 5:180043455-180043455 5:180616455-180616455
4 FLT4 NM_182925.5(FLT4): c.3341C> T (p.Pro1114Leu) single nucleotide variant Pathogenic rs121909652 5:180040101-180040101 5:180613101-180613101
5 FLT4 NM_182925.5(FLT4): c.3104A> G (p.His1035Arg) single nucleotide variant Pathogenic rs121909653 5:180043482-180043482 5:180616482-180616482
6 FLT4 NM_182925.5(FLT4): c.2632G> A (p.Val878Met) single nucleotide variant Pathogenic rs121909654 5:180046680-180046680 5:180619680-180619680
7 FLT4 NM_182925.5(FLT4): c.3257T> C (p.Ile1086Thr) single nucleotide variant Pathogenic rs121909655 5:180041142-180041142 5:180614142-180614142
8 FLT4 NM_182925.5(FLT4): c.3316G> A (p.Glu1106Lys) single nucleotide variant Pathogenic rs121909656 5:180041083-180041083 5:180614083-180614083
9 FLT4 NM_182925.5(FLT4): c.3320_3322TCT[1] (p.Phe1108del) short repeat Pathogenic rs587776833 5:180041074-180041076 5:180614074-180614076
10 FLT4 NM_182925.5(FLT4): c.2563G> A (p.Ala855Thr) single nucleotide variant Pathogenic rs121909657 5:180046749-180046749 5:180619749-180619749

UniProtKB/Swiss-Prot genetic disease variations for Lymphatic Malformation 1:

74 (show all 11)
# Symbol AA change Variation ID SNP ID
1 FLT4 p.Gly857Arg VAR_018409 rs267606818
2 FLT4 p.His1035Arg VAR_018412 rs121909653
3 FLT4 p.Arg1041Pro VAR_018413 rs121909650
4 FLT4 p.Leu1044Pro VAR_018414 rs121909651
5 FLT4 p.Pro1114Leu VAR_018415 rs121909652
6 FLT4 p.Ala855Thr VAR_074044 rs121909657
7 FLT4 p.Val878Met VAR_074045 rs121909654
8 FLT4 p.Gln1020Leu VAR_074046
9 FLT4 p.Ile1086Thr VAR_074048 rs121909655
10 FLT4 p.Glu1106Lys VAR_074049 rs121909656
11 FLT4 p.Ser1235Cys VAR_074051

Expression for Lymphatic Malformation 1

Search GEO for disease gene expression data for Lymphatic Malformation 1.

Pathways for Lymphatic Malformation 1

GO Terms for Lymphatic Malformation 1

Biological processes related to Lymphatic Malformation 1 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 angiogenesis GO:0001525 9.37 VEGFC FLT4
2 positive regulation of protein phosphorylation GO:0001934 9.32 VEGFC FLT4
3 positive regulation of endothelial cell proliferation GO:0001938 9.26 VEGFC FLT4
4 vascular endothelial growth factor receptor signaling pathway GO:0048010 9.16 VEGFC FLT4
5 sprouting angiogenesis GO:0002040 8.96 VEGFC FLT4
6 vascular endothelial growth factor signaling pathway GO:0038084 8.62 VEGFC FLT4

Sources for Lymphatic Malformation 1

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
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32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
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49 NCI
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54 NINDS
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57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 TGDB
71 Tocris
72 UMLS
73 UMLS via Orphanet
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