Legius Syndrome

Categories: Genetic diseases, Rare diseases, Skin diseases, Fetal diseases, Neuronal diseases

Aliases & Classifications for Legius Syndrome

MalaCards integrated aliases for Legius Syndrome:

Name: Legius Syndrome 54 23 50 24 25 56 71 29 13
Neurofibromatosis Type 1-Like Syndrome 23 24 25
Nfls 24 25 71
Neurofibromatosis 1-Like Syndrome 56 71
Neurofibromatosis, Type 1-Like Syndrome 69
Neurofibromatosis Type 1 Like Syndrome 50
Cafe-Au-Lait Spots 42
Nf1-Like Syndrome 56


Orphanet epidemiological data:

legius syndrome
Inheritance: Autosomal dominant; Prevalence: 1-9/100000 (Worldwide); Age of onset: Childhood,Infancy,Neonatal; Age of death: normal life expectancy;


autosomal dominant

phenotypic overlap with neurofibromatosis 1 (nf1, )
some patients do not have dysmorphic features


legius syndrome:
Inheritance autosomal dominant inheritance


Penetrance The vast majority of individuals with spred1 pathogenic variants have café au lait macules and/or freckling; however, the age of pigment penetrance is not established. only two individuals (a 60-year-old male and a 2-year-old child), each with a presumed spred1 pathogenic variant, were reported not to have café au lait macules or freckling [brems et al 2007, messiaen et al 2009]...


External Ids:

OMIM 54 611431
Orphanet 56 ORPHA137605
MESH via Orphanet 43 C548032
UMLS via Orphanet 70 C1969623
ICD10 via Orphanet 34 Q85.0
MedGen 40 C1969623
MeSH 42 D019080

Summaries for Legius Syndrome

NIH Rare Diseases : 50 the following summary is from orphanet, a european reference portal for information on rare diseases and orphan drugs.orpha number: 137605disease definitionlegius syndrome, also known as nf1-like syndrome, is a rare, genetic skin pigmentation disorder characterized by multiple café-au-lait macules with or without axillary or inguinal freckling.epidemiologythe prevalence of legius syndrome is not known. fewer than 200 cases have been reported to date. prevalence may be higher than expected due to misdiagnosis of cases as neurofibromatosis type 1 (nf1, see this term). the incidence of nf1 is reported to be 1/3000, and about 2% of patients fulfilling diagnostic criteria for nf1 are found to have the genetic mutation underlying legius syndrome (spred1).clinical descriptionthe clinical presentation of legius syndrome is very similar to that of nf1. patients typically present with multiple café-au-lait spots sometimes associated with intertriginous freckling, but lack lisch nodules, optic pathway gliomas, bone abnormalities, neurofibromas or other tumor manifestations. the number of café-au-lait macules tends to increase with age during childhood. other less common manifestations include short stature, macrocephaly, noonan-like facies, pectus excavatum/carinatum, lipomas, hypopigmented macules, vascular lesions, learning disabilities, attention deficit/hyperactivity disorder (adhd), and developmental delay.etiologylegius syndrome is caused by heterozygous inactivating mutations in the spred1 gene (15q14), involved in regulation of the ras-mapk signal transduction pathway. nearly 100 different mutations in this gene have been identified. the proportion of cases related to de novo mutations is not yet known. no genotype-phenotype correlations have been found.diagnostic methodsabout 50% of patients with legius syndrome fulfill the diagnostic criteria for nf1, but they have a far milder phenotype compared to nf1 patients. diagnosis based solely on the presence of clinical features is difficult, given the overlap with other disorders characterized by multiple café-au-lait spots. the presence of characteristic clinical signs in parents of affected individuals is supportive of diagnosis. however, molecular genetic testing is required to confirm the diagnosis and testing is available on a clinical basis.differential diagnosislegius syndrome is differentiated from nf1 by the absence of the non-pigmentary clinical manifestations seen in this disorder (i.e. lisch nodules, neurofibromas, optic glioma, bone abnormalities). correct diagnosis is essential because of the differences in prognosis and long-term monitoring between legius syndrome and nf1. other disorders to consider include noonan syndrome, noonan syndrome with lentigines (leopard syndrome), and mccune-albright syndrome (see these terms).antenatal diagnosisprenatal diagnosis is possible and requires prior identification of the disease-causing mutation in the family.genetic counselinglegius syndrome follows an autosomal dominant pattern of inheritance. genetic counseling should be provided to affected and treatmentdrug therapy should be considered for the behavioral manifestations of the disorder (adhd). physical, speech, and occupational therapy is recommended for those with developmental delay and educational support for those with learning difficulties.prognosisgiven the current knowledge of disease manifestations and complications, the prognosis for patients with legius syndrome is considered to be very good.visit the orphanet disease page for more resources. last updated: 7/2/2014

MalaCards based summary : Legius Syndrome, also known as neurofibromatosis type 1-like syndrome, is related to watson syndrome and cafe-au-lait spots, multiple, and has symptoms including ptosis, micrognathia and hypertelorism. An important gene associated with Legius Syndrome is SPRED1 (Sprouty Related EVH1 Domain Containing 1), and among its related pathways/superpathways are Cytokine Signaling in Immune system and Negative regulation of FGFR1 signaling. Affiliated tissues include skin, testes and bone, and related phenotypes are craniofacial and limbs/digits/tail

UniProtKB/Swiss-Prot : 71 Neurofibromatosis 1-like syndrome: A disorder characterized mainly by cafe au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1, axillary freckling, and macrocephaly. Additional clinical manifestations include Noonan-like facial dysmorphism, lipomas, learning disabilities and attention deficit-hyperactivity.

Genetics Home Reference : 25 Legius syndrome is a condition characterized by changes in skin coloring (pigmentation). Almost all affected individuals have multiple café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Another pigmentation change, freckles in the armpits and groin, may occur in some affected individuals.

OMIM : 54
Legius syndrome is an autosomal dominant disorder that shows some similarities to neurofibromatosis type I (NF1; 162200), which is caused by mutation in the neurofibromin gene (613113); however, Legius syndrome is less severe. Individuals with Legius syndrome typically have multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. Legius syndrome is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. The SPRED1 gene encodes a negative regulator of the RAS-MAPK pathway, similar to neurofibromin, and thus may be considered a RASopathy (review by Brems et al., 2012). (611431)

Wikipedia : 72 Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots. It was... more...

GeneReviews: NBK47312

Related Diseases for Legius Syndrome

Diseases related to Legius Syndrome via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 49)
id Related Disease Score Top Affiliating Genes
1 watson syndrome 33.9 NF1 PTPN11
2 cafe-au-lait spots, multiple 12.6
3 neurofibromatosis, type 1 11.2
4 noonan syndrome 1 10.8
5 borna disease 10.5 NF1 SPRED1
6 merkel cell carcinoma 10.4 SPRY1 SPRY2
7 progressive multifocal leukoencephalopathy 10.3 PTPN11 SPRED1
8 cervical serous adenocarcinoma 10.3 PTPN11 SPRED1
9 nephrolithiasis 10.3 NF1 PTPN11
10 radioulnar synostosis 10.2 NF1 PTPN11
11 skin epithelioid hemangioma 10.1 NF1 PTPN11 SPRED1
12 leopard syndrome 1 10.1 NF1 PTPN11 SPRED1
13 nephronophthisis 15 10.1 NF1 PTPN11 SPRED1
14 lateral sclerosis 9.9
15 neuronitis 9.8
16 encephalopathy 9.8
17 autosomal dominant deafness-onychodystrophy syndrome 9.8 NF1 PTPN11 SPRED1 SPRED2
18 piebaldism 9.8
19 choroiditis 9.8
20 large intestine adenocarcinoma 9.8 MSH2 MSH6
21 optic nerve sheath meningioma 9.8 MSH2 MSH6
22 benign fibrous mesothelioma 9.7 MSH2 MSH6
23 cataract 27, nuclear progressive 9.7 MSH2 MSH6
24 auditory neuropathy 9.7 MSH2 MSH6
25 substance abuse 9.7
26 retinitis 9.7
27 craniopharyngioma 9.7
28 neuropathy 9.7
29 glioma 9.7
30 hiv-1 9.7
31 head injury 9.7
32 subcortical arteriosclerotic encephalopathy 9.7
33 charcot-marie-tooth disease 9.7
34 hydrocephalus 9.7
35 tooth disease 9.7
36 normal pressure hydrocephalus 9.7
37 wissler's syndrome 9.6 MSH2 MSH6
38 benign ependymoma 9.6 MSH2 MSH6
39 hereditary nephrotic syndromes, autosomal dominant 9.6 MSH2 MSH6
40 optic papillitis 9.5 MSH2 MSH6
41 lymphoplasmacytic lymphoma 9.5 MSH2 MSH6 NF1
42 wolffian duct adenoma 9.5 MSH2 MSH6
43 y-linked disease 9.5 MSH2 MSH6 NF1
44 muir-torre syndrome 9.4 MSH2 MSH6
45 cellular myxoid liposarcoma 9.4 MSH2 MSH6
46 mismatch repair cancer syndrome 9.3 MSH2 MSH6
47 neurofibromatosis, familial spinal 9.2 MSH2 MSH6 NF1 SPRED1
48 verrucous papilloma 9.1 MSH2 MSH6
49 interstitial nephritis, karyomegalic 6.2 MSH2 MSH6 NF1 PTPN11 SPRED1 SPRED2

Graphical network of the top 20 diseases related to Legius Syndrome:

Diseases related to Legius Syndrome

Symptoms & Phenotypes for Legius Syndrome

Symptoms via clinical synopsis from OMIM:


Muscle Soft Tissue:

Head And Neck- Mouth:
short neck
high arched palate
deeply grooved philtrum
high peaks of upper lip vermilion border

Skin Nails & Hair- Skin:
cafe-au-lait spots
axillary freckling

Head And Neck- Ears:
low-set posteriorly rotated ears

Head And Neck- Face:
noonan-like facies in a minority of patients
triangular face with age

Neurologic- Behavioral Psychiatric Manifestations:
attention deficit-hyperactivity

Head And Neck- Eyes:
downslanting palpebral fissures
epicanthal folds

Neurologic- Central Nervous System:
learning difficulties
no neurofibromas

Skin Nails & Hair- Hair:
low posterior hairline

Head And Neck- Head:
macrocephaly (less common)

Chest- External Features:
pectus deformities (in some patients)

Clinical features from OMIM:


Human phenotypes related to Legius Syndrome:

32 (show all 19)
id Description HPO Frequency HPO Source Accession
1 ptosis 32 HP:0000508
2 micrognathia 32 HP:0000347
3 hypertelorism 32 HP:0000316
4 short neck 32 HP:0000470
5 macrocephaly 32 HP:0000256
6 triangular face 32 HP:0000325
7 downslanted palpebral fissures 32 HP:0000494
8 low-set, posteriorly rotated ears 32 HP:0000368
9 low posterior hairline 32 HP:0002162
10 epicanthus 32 HP:0000286
11 muscular hypotonia 32 HP:0001252
12 axillary freckling 32 HP:0000997
13 high, narrow palate 32 HP:0002705
14 attention deficit hyperactivity disorder 32 HP:0007018
15 neurofibromas 32 HP:0001067
16 multiple lipomas 32 HP:0001012
17 specific learning disability 32 HP:0001328
18 abnormality of the sternum 32 occasional (7.5%) HP:0000766
19 cafe-au-lait spot 32 HP:0000957

MGI Mouse Phenotypes related to Legius Syndrome:

id Description MGI Source Accession Score Top Affiliating Genes
1 craniofacial MP:0005382 9.65 PTPN11 SPRED1 SPRY2 SPRY4 NF1
2 limbs/digits/tail MP:0005371 9.63 NF1 PTPN11 SPRED1 SPRED2 SPRY2 SPRY4
3 neoplasm MP:0002006 9.43 MSH2 MSH6 NF1 PTPN11 SPRY1 SPRY2
4 respiratory system MP:0005388 9.02 NF1 PTPN11 SPRED1 SPRY2 SPRY4

Drugs & Therapeutics for Legius Syndrome

Interventional clinical trials:

id Name Status NCT ID Phase Drugs
1 Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1) Active, not recruiting NCT00111384

Search NIH Clinical Center for Legius Syndrome

Cochrane evidence based reviews: cafe-au-lait spots

Genetic Tests for Legius Syndrome

Genetic tests related to Legius Syndrome:

id Genetic test Affiliating Genes
1 Legius Syndrome 29 24 SPRED1

Anatomical Context for Legius Syndrome

MalaCards organs/tissues related to Legius Syndrome:

Skin, Testes, Bone

Publications for Legius Syndrome

Articles related to Legius Syndrome:

(show all 24)
id Title Authors Year
The first Slovak Legius syndrome patient carrying the SPRED1 gene mutation. ( 28150585 )
The absence that makes the difference: choroidal abnormalities in Legius syndrome. ( 28747691 )
Legius syndrome: A case report. ( 28378438 )
Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1. ( 26635368 )
Legius Syndrome: two novel mutations in the SPRED1 gene. ( 27081556 )
Family with Legius syndrome (neurofibromatosis type 1-like syndrome). ( 25981987 )
Legius syndrome: case report and review of literature. ( 25883013 )
SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia. ( 24469042 )
Legius Syndrome, an Update.Molecular Pathology of Mutations in SPRED1. ( 24334617 )
Review and update of SPRED1 mutations causing Legius syndrome. ( 22753041 )
CafAc-au-lait macules and intertriginous freckling in piebaldism: clinical overlap with neurofibromatosis type 1 and Legius syndrome. ( 22438235 )
A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. ( 22751498 )
Observations on intelligence and behavior in 15 patients with Legius syndrome. ( 21495177 )
The SPRED1 Variants Repository for Legius Syndrome. ( 22384355 )
Identification of five novel SPRED1 germline mutations in Legius syndrome. ( 21649642 )
Legius syndrome in fourteen families. ( 21089071 )
Novel human pathological mutations. Gene symbol: SPRED1. Disease: Legius syndrome. ( 20108385 )
Novel human pathological mutations. Gene symbol: SPRED1. Disease: Legius syndrome. ( 20108386 )
Novel human pathological mutations. Gene symbol: SPRED1. Disease: Legius syndrome. ( 20108421 )
Novel human pathological mutations. Gene symbol: SPRED1. Disease: Legius syndrome. ( 20108422 )
Novel human pathological mutations. Gene symbol: SPRED1. Disease: Legius syndrome. ( 20108420 )
Pigmentary findings in neurofibromatosis type 1-like syndrome (Legius syndrome): potential diagnostic dilemmas. ( 19920242 )
SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. ( 19443465 )
Legius Syndrome ( 20945555 )

Variations for Legius Syndrome

UniProtKB/Swiss-Prot genetic disease variations for Legius Syndrome:

id Symbol AA change Variation ID SNP ID
1 SPRED1 p.Trp31Cys VAR_064827
2 SPRED1 p.Val44Asp VAR_064828 rs121434318

ClinVar genetic disease variations for Legius Syndrome:

6 (show all 15)
id Gene Variation Type Significance SNP ID Assembly Location
1 SPRED1 NM_152594.2(SPRED1): c.349C> T (p.Arg117Ter) single nucleotide variant Pathogenic rs121434312 GRCh37 Chromosome 15, 38614583: 38614583
2 SPRED1 NM_152594.2(SPRED1): c.70C> T (p.Arg24Ter) single nucleotide variant Pathogenic rs121434313 GRCh37 Chromosome 15, 38591611: 38591611
3 SPRED1 SPRED1, IVS5DS, G-A, +1 single nucleotide variant Pathogenic
4 SPRED1 NM_152594.2(SPRED1): c.643C> T (p.Gln215Ter) single nucleotide variant Pathogenic rs121434314 GRCh37 Chromosome 15, 38641683: 38641683
5 SPRED1 NM_152594.2(SPRED1): c.190C> T (p.Arg64Ter) single nucleotide variant Pathogenic rs121434315 GRCh37 Chromosome 15, 38591731: 38591731
6 SPRED1 NM_152594.2(SPRED1): c.637C> T (p.Gln213Ter) single nucleotide variant Pathogenic rs121434316 GRCh37 Chromosome 15, 38641677: 38641677
7 SPRED1 NM_152594.2(SPRED1): c.784A> T (p.Arg262Ter) single nucleotide variant Pathogenic rs121434317 GRCh37 Chromosome 15, 38643314: 38643314
8 SPRED1 NM_152594.2(SPRED1): c.131T> A (p.Val44Asp) single nucleotide variant Pathogenic rs121434318 GRCh37 Chromosome 15, 38591672: 38591672
9 SPRED1 SPRED1, 2-BP DEL, 1045AG deletion Pathogenic
10 NF1 NM_000267.3(NF1): c.2041C> T (p.Arg681Ter) single nucleotide variant Pathogenic rs768638173 GRCh38 Chromosome 17, 31226474: 31226474
11 SPRED1 NM_152594.2(SPRED1): c.796_797delAT (p.Met266Valfs) deletion Pathogenic rs864622410 GRCh37 Chromosome 15, 38643326: 38643327
12 SPRED1 NM_152594.2(SPRED1): c.1151_1152delAG (p.Glu384Glyfs) deletion Pathogenic rs878855228 GRCh37 Chromosome 15, 38643681: 38643682
13 SPRED1 NM_152594.2(SPRED1): c.973C> T (p.Arg325Ter) single nucleotide variant Pathogenic rs1057518683 GRCh37 Chromosome 15, 38643503: 38643503
14 SPRED1 NC_000015.10: g.(?_38299373)_(38357249_?)del deletion Pathogenic GRCh37 Chromosome 15, 38591574: 38649450
15 SPRED1 NM_152594.2(SPRED1): c.421C> T (p.Gln141Ter) single nucleotide variant Pathogenic rs1060502505 GRCh38 Chromosome 15, 38324807: 38324807

Copy number variations for Legius Syndrome from CNVD:

id CNVD ID Chromosom Start End Type Gene Symbol CNVD Disease
1 91538 15 31400000 37900000 Copy number SPRED1 Legius syndrome

Expression for Legius Syndrome

Search GEO for disease gene expression data for Legius Syndrome.

Pathways for Legius Syndrome

Pathways related to Legius Syndrome according to GeneCards Suite gene sharing:

(show all 11)
id Super pathways Score Top Affiliating Genes
Show member pathways
Show member pathways
Show member pathways
Show member pathways
5 11.73 MSH2 MSH6 NF1
6 11.65 SPRED1 SPRY1 SPRY2
Show member pathways
8 11.17 PTPN11 SPRY2
9 11.14 MSH2 MSH6
10 10.96 NF1 PTPN11 SPRY1 SPRY2
11 10.9 MSH2 MSH6

GO Terms for Legius Syndrome

Cellular components related to Legius Syndrome according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 MutSalpha complex GO:0032301 8.62 MSH2 MSH6

Biological processes related to Legius Syndrome according to GeneCards Suite gene sharing:

(show all 27)
id Name GO ID Score Top Affiliating Genes
1 multicellular organism development GO:0007275 9.8 SPRED1 SPRED2 SPRED3 SPRY1 SPRY2 SPRY3
2 fibroblast growth factor receptor signaling pathway GO:0008543 9.71 PTPN11 SPRED1 SPRED2
3 negative regulation of ERK1 and ERK2 cascade GO:0070373 9.65 SPRY1 SPRY2 SPRY4
4 intrinsic apoptotic signaling pathway in response to DNA damage GO:0008630 9.63 MSH2 MSH6
5 negative regulation of GTPase activity GO:0034260 9.63 SPRY1 SPRY2
6 mismatch repair GO:0006298 9.62 MSH2 MSH6
7 metanephros development GO:0001656 9.62 NF1 SPRY1
8 negative regulation of epidermal growth factor receptor signaling pathway GO:0042059 9.61 SPRY1 SPRY2
9 inactivation of MAPK activity GO:0000188 9.61 SPRED1 SPRED2
10 establishment of mitotic spindle orientation GO:0000132 9.59 SPRY1 SPRY2
11 somatic hypermutation of immunoglobulin genes GO:0016446 9.58 MSH2 MSH6
12 isotype switching GO:0045190 9.58 MSH2 MSH6
13 negative regulation of fibroblast growth factor receptor signaling pathway GO:0040037 9.57 SPRY1 SPRY2
14 determination of adult lifespan GO:0008340 9.56 MSH2 MSH6
15 positive regulation of DNA damage response, signal transduction by p53 class mediator GO:0043517 9.55 SPRED1 SPRED2
16 negative regulation of DNA recombination GO:0045910 9.52 MSH2 MSH6
17 positive regulation of helicase activity GO:0051096 9.51 MSH2 MSH6
18 negative regulation of Ras protein signal transduction GO:0046580 9.5 NF1 SPRY1 SPRY2
19 bud elongation involved in lung branching GO:0060449 9.49 SPRY1 SPRY2
20 maintenance of DNA repeat elements GO:0043570 9.46 MSH2 MSH6
21 somatic recombination of immunoglobulin gene segments GO:0016447 9.43 MSH2 MSH6
22 negative regulation of neurotrophin TRK receptor signaling pathway GO:0051387 9.4 SPRY1 SPRY2
23 regulation of protein deacetylation GO:0090311 9.37 SPRED1 SPRED2
24 negative regulation of peptidyl-threonine phosphorylation GO:0010801 9.33 SPRED1 SPRED2 SPRY2
25 negative regulation of MAPK cascade GO:0043409 9.3 NF1
26 negative regulation of MAP kinase activity GO:0043407 9.26 NF1 SPRY1 SPRY2 SPRY4
27 regulation of signal transduction GO:0009966 9.17 SPRED1 SPRED2 SPRED3 SPRY1 SPRY2 SPRY3

Molecular functions related to Legius Syndrome according to GeneCards Suite gene sharing:

(show all 11)
id Name GO ID Score Top Affiliating Genes
1 protein kinase binding GO:0019901 9.78 MSH2 SPRED1 SPRED2 SPRY2
2 ADP binding GO:0043531 9.49 MSH2 MSH6
3 four-way junction DNA binding GO:0000400 9.46 MSH2 MSH6
4 mismatched DNA binding GO:0030983 9.43 MSH2 MSH6
5 MutLalpha complex binding GO:0032405 9.4 MSH2 MSH6
6 oxidized purine DNA binding GO:0032357 9.37 MSH2 MSH6
7 guanine/thymine mispair binding GO:0032137 9.32 MSH2 MSH6
8 single guanine insertion binding GO:0032142 9.26 MSH2 MSH6
9 stem cell factor receptor binding GO:0005173 9.16 SPRED1 SPRED2
10 single thymine insertion binding GO:0032143 8.96 MSH2 MSH6
11 protein serine/threonine kinase inhibitor activity GO:0030291 8.8 SPRED1 SPRED2 SPRY2

Sources for Legius Syndrome

9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
28 GO
29 GTR
32 HPO
33 ICD10
34 ICD10 via Orphanet
38 LifeMap
40 MedGen
42 MeSH
43 MESH via Orphanet
44 MGI
46 NCI
47 NCIt
52 Novoseek
55 OMIM via Orphanet
59 PubMed
66 SNOMED-CT via Orphanet
68 Tocris
70 UMLS via Orphanet
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