Legius Syndrome

Genetic MONDO:0012669 Pathograph 7 Show in embeddings browser RASopathy

Legius syndrome (LGSS; formerly "neurofibromatosis type 1-like syndrome", NFLS) is an autosomal dominant RASopathy caused by heterozygous germline loss-of-function variants in SPRED1. SPRED1 encodes a Sprouty-related, EVH1 domain-containing negative regulator of RAS-MAPK signaling whose principal function is to recruit neurofibromin — the RAS-GTPase-activating protein encoded by NF1 — to activated RAS at the plasma membrane. Loss of SPRED1 therefore phenocopies the pigmentary arm of neurofibromatosis type 1: multiple bilateral café-au-lait macules with or without axillary/inguinal freckling, macrocephaly, lipomas, and a mild neurocognitive profile of learning disability, ADHD, and developmental delay. Critically, and unlike NF1, Legius syndrome is not associated with neurofibromas, Lisch nodules, symptomatic optic pathway gliomas, or the characteristic NF1 osseous lesions, which is why it is classified as a RASopathy rather than a form of neurofibromatosis. Because the two conditions are clinically indistinguishable in early childhood when only pigmentary findings are present, molecular confirmation of a SPRED1 variant is the defining diagnostic criterion in the 2021 international consensus revision.

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1
Mappings
1
Definitions
1
Inheritance
6
Pathophys.
14
Phenotypes
2
Gaps
7
Pathograph
1
Genes
3
Medical Actions
2
Differentials
1
References
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0012669 Legius syndrome
skos:exactMatch MONDO
Primary disease term for this entry. MONDO:0012669 is anchored to SPRED1 (RO:0004003 HGNC:20249) and cross-references OMIM:611431 and Orphanet:137605, matching the gene and entity curated here.
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Definitions

1
2021 international consensus diagnostic criteria for Legius syndrome
The International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC) established the first formal diagnostic criteria for Legius syndrome in 2021. Unlike the NF1 criteria, which can be met clinically, the Legius syndrome criteria require molecular confirmation: a heterozygous pathogenic SPRED1 variant at a ~50% variant allele fraction in apparently normal tissue, together with six or more bilaterally distributed café-au-lait macules and no NF1-related diagnostic criteria other than axillary or inguinal freckling. A child of an affected parent needs only one of these. Fewer than six café-au-lait macules does not exclude the diagnosis.
DIAGNOSTIC_CRITERIA Clinical and molecular diagnosis of non-mosaic Legius syndrome. Separate criteria exist for mosaic Legius syndrome, which is very rare.
Inclusion criteria
  • Six or more bilaterally distributed cafe-au-lait macules Six or more café-au-lait macules with a bilateral distribution. Fewer than six does not exclude the diagnosis.
  • Heterozygous pathogenic SPRED1 variant at ~50% variant allele fraction A heterozygous pathogenic variant in SPRED1 with a variant allele fraction of 50% in apparently normal tissue such as white blood cells. This molecular criterion is required and is what distinguishes the Legius syndrome criteria from the clinically satisfiable NF1 criteria.
Exclusion criteria
  • Any NF1-related diagnostic criterion other than skinfold freckling Presence of any other NF1 diagnostic criterion — neurofibromas, Lisch nodules or choroidal abnormalities, optic pathway glioma, or a distinctive NF1 osseous lesion — excludes Legius syndrome. Axillary or inguinal freckling is the sole permitted exception.
Show evidence (2 references)
PMID:34012067 SUPPORT Human Clinical
"A: The diagnostic criteria for Legius syndrome are met in an individual who does not have a parent diagnosed with Legius syndrome if the following CRITERIA are present:"
Introduces the consensus diagnostic criteria table for Legius syndrome.
PMID:34012067 SUPPORT Human Clinical
"A heterozygous pathogenic variant in SPRED1 with a variant allele fraction of 50% in apparently normal tissue such as white blood cells"
States the required molecular criterion that distinguishes the Legius syndrome criteria from the clinically satisfiable NF1 criteria.
Notes: The consensus group explicitly considered and rejected classifying Legius syndrome as an NF1 subtype, on the grounds that in the absence of neurofibromas it is inappropriate to consider it a type of neurofibromatosis.
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Inheritance

1
Autosomal Dominant HP:0000006
Legius syndrome is inherited in an autosomal dominant manner. Unlike many ultra-rare RASopathies, most affected individuals have an affected parent rather than a de novo variant, and each child of an affected individual has a 50% recurrence risk.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:20945555 SUPPORT Human Clinical
"Legius syndrome is inherited in an autosomal dominant manner. Many individuals diagnosed with Legius syndrome have an affected parent."
GeneReviews states the autosomal dominant inheritance pattern and the predominance of inherited rather than de novo variants.
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Discussions and Knowledge Gaps

2
Is the tumor risk in Legius syndrome truly at population baseline, or does the absence of tumors in published cohorts reflect limited sample size and incomplete adult follow-up?
KNOWLEDGE GAP OPEN gap_legius_residual_tumor_risk
Attached to
pathophysiology#RAS-MAPK Pathway Hyperactivation
The clinical management of Legius syndrome — developmental rather than oncologic surveillance — rests on the claim that SPRED1 loss does not confer the tumor predisposition of NF1. The strongest supporting observation is nonetheless a zero count in a modest cohort: 0 of 42 SPRED1-positive individuals, with a 95% confidence interval extending to 7%. A tumor risk anywhere below that upper bound is statistically compatible with the data, and the cohorts are weighted toward children, so adult-onset risk is especially poorly constrained. Because SPRED1 and NF1 converge on the same RAS-inactivation step, a mechanistic prior for some residual risk is not unreasonable, and resolving this determines whether any oncologic surveillance is warranted.
Proposed experiments
Genomic-ascertainment cohort of adult SPRED1 variant carriers
exp_legius_population_scale_cancer_risk_ascertainment
Identify carriers of pathogenic and likely pathogenic germline SPRED1 variants in large unselected biobank/health-system genomic datasets rather than in neurofibromatosis clinics, and compare age-stratified adult cancer incidence against non-carrier controls. Genomic rather than clinical ascertainment removes the referral bias that inflates the apparent specificity of the pigmentary phenotype, and biobank scale provides the person-years needed to tighten the upper confidence bound well below 7%.
Show evidence (1 reference)
PMID:19920235 SUPPORT Human Clinical
"None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas."
Supports the absence of NF1 tumor manifestations, but the reported confidence interval bounds the residual risk only loosely at 7%, which is what leaves this question open.
Does the hippocampal LTP/LTD disequilibrium seen in Spred1-null mice account for the learning disability and ADHD observed in humans with heterozygous SPRED1 loss of function?
HUMAN MODEL MISMATCH OPEN gap_legius_human_model_cognitive_mechanism
Attached to
pathophysiology#Hippocampal Synaptic Plasticity Impairment
The mechanistic account of the neurocognitive phenotype rests entirely on a mouse model, and two gaps separate it from the human disease. First is a dosage mismatch: the electrophysiology and behavioral deficits are reported in homozygous Spred1(-/-) animals, whereas humans with Legius syndrome are heterozygous. Second, no human study has demonstrated a corresponding hippocampal plasticity or ERK-signaling abnormality, so the inference from rodent CA1 physiology to human learning disability remains an extrapolation rather than a demonstrated mechanism. This matters therapeutically, because MEK-inhibitor-based cognitive rescue strategies proposed for RASopathies presuppose that the human deficit is ERK-driven in the same way.
Proposed experiments
Heterozygous Spred1 model plus matched human cognitive-electrophysiological phenotyping
exp_legius_heterozygous_model_and_human_cognitive_phenotyping
Repeat the CA1 LTP/LTD and Morris water maze characterization in Spred1(+/-) animals to test whether the phenotype survives at the dosage that models human disease, and pair this with a prospective human cohort combining standardized neuropsychological testing, ADHD assessment, and non-invasive plasticity readouts in SPRED1 carriers versus NF1-matched and unaffected controls.
Show evidence (1 reference)
PMID:19118178 SUPPORT Model Organism
"We investigated hippocampus-dependent learning and memory as well as synaptic plasticity in Spred1(-/-) mice, an animal model of this newly discovered human syndrome."
The mechanism is established in homozygous null mice, whereas human Legius syndrome results from heterozygous loss of function.
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Pathophysiology

6
Germline SPRED1 Loss of Function
Legius syndrome is caused by heterozygous germline loss-of-function variants in SPRED1, a member of the SPROUTY/SPRED family of proteins that act as negative regulators of the RAS-RAF interaction and downstream MAPK signaling. This was the first human disease attributed to the SPRY/SPRED gene family and placed the disorder within the RASopathy group of RAS-MAPK pathway disorders.
SPRED1 hgnc:20249 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPRED1 (hgnc:20249). hgnc:20249 is a gene from the HUGO Gene Nomenclature Committee.
negative regulation of Ras protein signal transduction GO:0046580 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of Ras protein signal transduction (GO:0046580). GO:0046580 is a biological process from the Gene Ontology.
Downstream
Impaired Neurofibromin Recruitment to Activated RAS Loss of functional SPRED1 removes the adaptor that delivers neurofibromin to RAS at the plasma membrane.
Show evidence (2 references)
PMID:17704776 SUPPORT Human Clinical
"We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling."
The founding report establishing germline SPRED1 loss of function as the cause of the disorder and its role as a RAS-MAPK negative regulator.
PMID:11493923 SUPPORT In Vitro
"Like Sprouty, Spred inhibited growth-factor-mediated activation of MAP kinase."
Original functional characterization of Spred proteins as suppressors of growth-factor-driven MAPK activation, the activity lost in Legius syndrome.
Impaired Neurofibromin Recruitment to Activated RAS
SPRED1 suppresses RAS-ERK signaling not by acting on RAS directly but by serving as a membrane-targeting adaptor for neurofibromin, the RAS-GAP encoded by NF1. The SPRED1 EVH1 domain binds short N- and C-terminal helical extensions flanking the GAP-related domain (GRD) of neurofibromin — regions dispensable for GAP catalysis and absent from p120GAP, which explains the selectivity of SPRED1 for neurofibromin among RasGAPs. Pathogenic EVH1-domain missense variants found in Legius syndrome reduce GRD binding affinity and correspondingly abolish the ERK-suppressing activity of SPRED1, providing a direct molecular link between genotype and pathway dysregulation. Structural work confirms that SPRED1-mediated membrane targeting allows neurofibromin to engage activated KRAS simultaneously.
SPRED1 hgnc:20249 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPRED1 (hgnc:20249). hgnc:20249 is a gene from the HUGO Gene Nomenclature Committee. NF1 hgnc:7765 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NF1 (hgnc:7765). hgnc:7765 is a gene from the HUGO Gene Nomenclature Committee.
GTPase activator activity GO:0005096 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased GTPase activator activity (GO:0005096). GO:0005096 is a molecular function from the Gene Ontology.
Downstream
RAS-MAPK Pathway Hyperactivation Without membrane-recruited neurofibromin, RAS-GTP is inefficiently hydrolyzed and flux through the RAF-MEK-ERK cascade is sustained.
Show evidence (6 references)
PMID:22751498 SUPPORT In Vitro
"We show that Spred1 binding induces the plasma membrane localization of NF1, which subsequently down-regulates Ras-GTP levels."
Direct demonstration that SPRED1 acts as a membrane-targeting adaptor for neurofibromin, which is the claim this node makes; the EVH1-GRD interaction and structural papers establish the binding interface but not the membrane localization itself.
PMID:22751498 SUPPORT In Vitro
"This novel mechanism for the regulation of neurofibromin provides a molecular bridge for understanding the overlapping pathophysiology of NF1 and Legius syndrome."
Establishes this node as the shared molecular step that explains why SPRED1 loss and NF1 loss produce overlapping pathophysiology.
PMID:26635368 SUPPORT In Vitro
"we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin"
Maps the SPRED1-neurofibromin interface whose disruption underlies Legius syndrome.
+ 3 more references
RAS-MAPK Pathway Hyperactivation
Like the other RASopathies, Legius syndrome results from germline dysregulation of the RAS-MAPK (RAS/ERK) signal transduction cascade. The shared pathway lesion places the disorder in the same phenotypically overlapping family as neurofibromatosis type 1, Noonan syndrome, Costello syndrome, and cardiofaciocutaneous syndrome, and accounts for the macrocephaly, pigmentary, and neurocognitive features shared across the group. In Legius syndrome the dysregulation is comparatively mild and does not reach the threshold required for neurofibroma or other NF1 tumor formation.
positive regulation of MAPK cascade GO:0043410 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of MAPK cascade (GO:0043410). GO:0043410 is a biological process from the Gene Ontology.
Downstream
Biallelic SPRED1 Inactivation in Melanocytes Pathway dysregulation becomes phenotypically manifest in skin only where a somatic second hit removes the remaining SPRED1 allele.
Hippocampal Synaptic Plasticity Impairment Sustained ERK activation in hippocampal circuits perturbs the balance of long-term potentiation and depression.
Show evidence (1 reference)
PMID:17704776 SUPPORT Human Clinical
"This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway."
Places Legius syndrome within the RAS-MAPK (RASopathy) group sharing this final common mechanism.
Biallelic SPRED1 Inactivation in Melanocytes
Melanocytes isolated from a café-au-lait macule of an affected individual carried, in addition to the germline SPRED1 variant, an acquired somatic mutation in the wild-type SPRED1 allele. Café-au-lait macule formation in Legius syndrome therefore follows a two-hit, mosaic-somatic logic in the melanocyte lineage, mirroring the second-hit requirement described for NF1 pigmentary lesions, rather than arising from germline haploinsufficiency alone.
melanocyte CL:0000148 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves melanocyte (CL:0000148). CL:0000148 is a cell type from the Cell Ontology.
SPRED1 hgnc:20249 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPRED1 (hgnc:20249). hgnc:20249 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Cafe-au-lait Macule Formation Clonal patches of SPRED1-null melanocytes produce the hyperpigmented macules that define the clinical phenotype.
Show evidence (1 reference)
PMID:17704776 SUPPORT Human Clinical
"indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome"
States the biallelic-inactivation requirement for the pigmentary lesion.
Cafe-au-lait Macule Formation
The cardinal and often sole objective finding of Legius syndrome: multiple, bilaterally distributed café-au-lait macules, with or without skinfold (axillary or inguinal) freckling, clinically indistinguishable from those of neurofibromatosis type 1. Because the pigmentary phenotype is shared, roughly half of individuals with a SPRED1 variant satisfy the older NIH clinical criteria for NF1 despite having a different natural history — the observation that drove the 2021 consensus revision to make a molecular SPRED1 result a required diagnostic criterion.
melanocyte CL:0000148 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves melanocyte (CL:0000148). CL:0000148 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:34012067 SUPPORT Human Clinical
"LGSS, inherited in an autosomal dominant pattern, is characterized by multiple CALMs similar to NF1 with or without skinfold freckling, caused by heterozygous PVs in SPRED1, located on chromosome 15."
Consensus statement describing the defining pigmentary phenotype and its genetic basis.
Hippocampal Synaptic Plasticity Impairment
Spred1-null mice show impaired performance in the Morris water maze and visual-discrimination T-maze with normal basic neuromotor and sensory abilities, together with defects in short- and long-term hippocampal synaptic plasticity including a disequilibrium between long-term potentiation and long-term depression in CA1. Increased ERK phosphorylation is measurable in Spred1-null slices after LTP induction, linking the plasticity defect to Ras/ERK hyperactivation. This is the candidate substrate for the learning disability, ADHD, and developmental delay reported in affected individuals, but the translational step from mouse hippocampal physiology to the human cognitive phenotype has not been directly demonstrated (see the HUMAN_MODEL_MISMATCH discussion).
SPRED1 hgnc:20249 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPRED1 (hgnc:20249). hgnc:20249 is a gene from the HUGO Gene Nomenclature Committee.
long-term synaptic potentiation GO:0060291 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal long-term synaptic potentiation (GO:0060291). GO:0060291 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:19118178 SUPPORT Model Organism
"Electrophysiological recordings on brain slices from these animals identified defects in short- and long-term synaptic hippocampal plasticity, including a disequilibrium between long-term potentiation (LTP) and long-term depression in CA1 region."
Documents the hippocampal plasticity defect in the Spred1-null mouse model.
PMID:19118178 SUPPORT Model Organism
"Spred1(-/-) mice show decreased learning and memory performance in the Morris water maze and visual-discrimination T-maze, but normal basic neuromotor and sensory abilities."
Shows a selective learning and memory deficit rather than a general sensorimotor impairment in the model.
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Pathograph

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

14
Ear 1
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing loss, annotated with Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20945555 SUPPORT INDIRECT Human Clinical
"referral to otolaryngologist for those with identified hearing loss"
GeneReviews directs otolaryngology referral for hearing loss in Legius syndrome. Recorded as INDIRECT because the sentence prescribes management for affected individuals rather than reporting how often hearing loss occurs.
Eye 1
Lisch Nodules (Explicitly Absent) HP:0009737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Lisch nodules (HP:0009737). HP:0009737 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (1 reference)
PMID:34012067 SUPPORT Human Clinical
"No individuals with LGSS have developed Lisch nodules, neurofibromas, or other complications of NF1."
The consensus statement records the absence of Lisch nodules in Legius syndrome.
Head and Neck 1
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17704776 SUPPORT Human Clinical
"consist of multiple café-au-lait spots, axillary freckling and macrocephaly"
Macrocephaly is described among the cardinal clinical features in the founding human description of the disorder.
PMID:26635368 SUPPORT In Vitro
"a phenotype known as Legius syndrome, which consists of symptoms of multiple café-au-lait macules, axillary freckling, learning disabilities, and macrocephaly"
Framing sentence from the introduction of this biochemical study, listing macrocephaly among the core features. Graded by the cited publication's own evidence type, consistent with the five other citations of this paper in this entry; the human clinical source for the phenotype is PMID:17704776 above.
Integument 4
Multiple Cafe-au-lait Macules Multiple cafe-au-lait spots HP:0007565 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple cafe-au-lait spots (HP:0007565). HP:0007565 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17704776 SUPPORT Human Clinical
"The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly."
Multiple café-au-lait macules are listed among the defining clinical features in the founding description.
Axillary Freckling HP:0000997 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axillary freckling (HP:0000997). HP:0000997 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17704776 SUPPORT Human Clinical
"multiple café-au-lait spots, axillary freckling and macrocephaly"
Axillary freckling is a defining clinical feature of the disorder.
Inguinal Freckling HP:0030052 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal freckling (HP:0030052). HP:0030052 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34012067 SUPPORT Human Clinical
"Six or more café-au-lait macules (Supplementary Fig. 12) bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling"
The consensus criteria explicitly admit axillary or inguinal freckling as compatible with Legius syndrome.
Neurofibroma (Explicitly Absent) HP:0001067 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Neurofibroma (HP:0001067). HP:0001067 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (2 references)
PMID:19920235 SUPPORT Human Clinical
"None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas."
Directly documents the absence of neurofibromas and other NF1 tumor manifestations in the SPRED1-positive cohort.
PMID:34012067 SUPPORT Human Clinical
"No individuals with LGSS have developed Lisch nodules, neurofibromas, or other complications of NF1."
The consensus group confirms the absence of neurofibromas and Lisch nodules in Legius syndrome.
Musculoskeletal 3
Lipoma HP:0012032 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lipoma (HP:0012032). HP:0012032 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20945555 SUPPORT Human Clinical
"Additional clinical manifestations commonly reported include intertriginous freckling, lipomas, macrocephaly"
Lipomas are listed among the commonly reported manifestations.
Pectus Excavatum HP:0000767 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20945555 SUPPORT INDIRECT Human Clinical
"treatment of pectus excavatum and scoliosis per orthopedist"
GeneReviews directs orthopedic treatment of pectus excavatum in Legius syndrome. Recorded as INDIRECT because the sentence prescribes management rather than reporting the finding's occurrence or frequency, from which occurrence follows by one inference step.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20945555 SUPPORT INDIRECT Human Clinical
"assess for pigmentary lesions, lipomas, scoliosis, and new-onset seizures at each visit"
GeneReviews places scoliosis under routine surveillance in Legius syndrome. Recorded as INDIRECT because a surveillance recommendation implies rather than reports the finding's occurrence.
Nervous System 4
Specific Learning Disability HP:0001328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Specific learning disability (HP:0001328). HP:0001328 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20945555 SUPPORT Human Clinical
"Additional clinical manifestations commonly reported include intertriginous freckling, lipomas, macrocephaly, and learning disabilities, attention-deficit/hyperactivity disorder (ADHD), and developmental delays."
GeneReviews lists learning disability among the commonly reported manifestations.
PMID:19366998 SUPPORT Human Clinical
"Their NF1-like phenotype was characterised by a high prevalence of café-au-lait spots, freckling, learning disability, and an absence of neurofibromas and Lisch nodules in agreement with the original description."
Independent French replication cohort reporting learning disability at high prevalence in SPRED1-mutated families, so this phenotype does not rest on the GeneReviews summary alone.
Attention Deficit Hyperactivity Disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20945555 SUPPORT Human Clinical
"macrocephaly, and learning disabilities, attention-deficit/hyperactivity disorder (ADHD), and developmental delays"
ADHD is among the commonly reported manifestations in GeneReviews.
Developmental Delay Neurodevelopmental delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20945555 SUPPORT Human Clinical
"learning disabilities, attention-deficit/hyperactivity disorder (ADHD), and developmental delays"
Developmental delay is among the commonly reported manifestations. GeneReviews says "developmental delays" without asserting delay across all domains, so this binds HP:0012758 (delay in one or more developmental domains) rather than the global term.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20945555 SUPPORT INDIRECT Human Clinical
"standard treatment for seizures per experienced neurologist"
GeneReviews directs neurologic management of seizures in Legius syndrome. Recorded as INDIRECT because the sentence prescribes management rather than reporting seizure occurrence or frequency.
🧬

Genetic Associations

1
SPRED1 (Pathogenic Variants)
Gene: SPRED1 hgnc:20249 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPRED1 (hgnc:20249). hgnc:20249 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:19920235 SUPPORT Human Clinical
"In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands."
Documents the breadth of the SPRED1 mutational spectrum and the absence of a single recurrent variant.
PMID:34012067 SUPPORT Human Clinical
"Further studies have shown that SPRED1 PVs account for 1% of sporadic cases and 19% of familial cases with pigmentary features of NF1 (CALMs and freckling) only."
Quantifies the diagnostic yield of SPRED1 testing in individuals with isolated pigmentary NF1 features.
PMID:19366998 SUPPORT Human Clinical
"Germline loss-of-function mutations in the SPRED1 gene have recently been identified in patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1 (neurofibromin 1) mutation found, suggesting a neurofibromatosis type 1-like syndrome."
Independent replication in five French families confirming germline loss-of-function SPRED1 variants as the molecular cause in individuals meeting NF1 criteria without an NF1 variant.
💊

Medical Actions

3
Supportive and Multidisciplinary Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management is symptom-directed. Reported components include behavioral modification and/or pharmacologic therapy for ADHD; physical, speech, and occupational therapy for developmental delays; individualized education plans for learning disorders; dermatologic referral for lipoma management; orthopedic management of pectus excavatum and scoliosis; standard seizure management; and otolaryngology referral for hearing loss.
Show evidence (1 reference)
PMID:20945555 SUPPORT Human Clinical
"Treatment of manifestations: Consideration of behavioral modification and/or pharmacologic therapy for those with ADHD; physical, speech, and occupational therapy for those with identified developmental delays; individualized education plans for those with learning disorders; referral to..."
GeneReviews enumerates the symptom-directed management components for Legius syndrome.
Developmental and Behavioral Surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Recommended surveillance is developmental and dermatologic rather than oncologic — a direct consequence of the absent tumor predisposition. Monitor developmental progress, educational needs, and behavior at each visit; assess for pigmentary lesions, lipomas, scoliosis, and new-onset seizures at each visit; hearing evaluation as needed.
Show evidence (1 reference)
PMID:20945555 SUPPORT Human Clinical
"Surveillance: Monitor developmental progress, educational needs, and behavioral assessment at each visit; assess for pigmentary lesions, lipomas, scoliosis, and new-onset seizures at each visit; hearing evaluation as needed."
GeneReviews specifies the surveillance schedule, notably without tumor screening.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling is central, both for the 50% recurrence risk and because reclassifying a presumed NF1 diagnosis as Legius syndrome substantially changes prognosis and surveillance. Once the familial SPRED1 variant is known, prenatal and preimplantation genetic testing are possible.
Show evidence (2 references)
PMID:20945555 SUPPORT Human Clinical
"Each child of an individual with Legius syndrome caused by a germline SPRED1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Once the SPRED1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
GeneReviews states the recurrence risk and reproductive testing options that genetic counseling addresses.
PMID:19366998 SUPPORT Human Clinical
"NIH diagnostic criteria for NF1 must be revised in view of this newly characterised Legius syndrome in order to establish a specific genetic counselling."
States why separating Legius syndrome from NF1 matters for counseling, the argument that later produced the 2021 consensus criteria revision.
🔬

Diagnosis

1
Clinical criteria with SPRED1 molecular confirmation
In an individual without an affected parent, the international consensus criteria require six or more bilaterally distributed café-au-lait macules, no other NF1 diagnostic features apart from axillary or inguinal freckling, and a heterozygous pathogenic SPRED1 variant in apparently normal tissue. Molecular confirmation is especially important because pigmentary findings alone overlap strongly with neurofibromatosis type 1.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:34012067 SUPPORT Human Clinical
"Six or more café-au-lait macules (Supplementary Fig. 12) bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling"
States the consensus pigmentary and exclusion criteria used together with identification of a heterozygous pathogenic SPRED1 variant.
PMID:20945555 SUPPORT Human Clinical
"The diagnosis of Legius syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in SPRED1 identified by molecular genetic testing."
Sources the molecular-confirmation half of this diagnostic entry: the consensus criteria above establish the pigmentary and exclusion findings, and GeneReviews states that SPRED1 molecular genetic testing is what establishes the diagnosis in a proband with those findings.
📊

Prevalence

1
Worldwide
Birth Prevalence 1.3–2.2 per 100,000 1–9 per 1,000,000 (births)
Consensus estimate of 1/46,000-1/75,000 live births (approximately 1.3-2.2 per 100,000), roughly 20-fold rarer than NF1 (1/2,000-1/3,000). Corresponds to about 4% of individuals followed in a neurofibromatosis clinic.
Show evidence (1 reference)
PMID:34012067 SUPPORT Human Clinical
"The condition is less frequent than NF1 with an estimated birth prevalence of 1/46,000–1/75,000 (4% of individuals followed at a neurofibromatosis clinic)"
Provides the consensus birth-prevalence estimate normalized here to cases per 100,000.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Legius Syndrome:

Neurofibromatosis type 1 MONDO:0018975
Overlapping Features The principal differential and the reason the disorder was originally named "NF1-like syndrome". The two are clinically indistinguishable in early childhood when only pigmentary findings are present, and about half of SPRED1-positive individuals satisfy the older NIH clinical criteria for NF1. Read the other way round, 1.9% (95% CI 1.2%-2.9%) of individuals carrying a clinical NF1 diagnosis by the NIH criteria in fact have Legius syndrome — the diagnostic yield of SPRED1 testing in that ascertained population, which is not a population prevalence and is recorded here rather than in `prevalence:`.
Distinguishing Features
  • Legius syndrome lacks neurofibromas (cutaneous and plexiform), Lisch nodules, symptomatic optic pathway gliomas, and the distinctive NF1 osseous lesions.
  • The causal gene differs — SPRED1 rather than NF1 — although both converge on failure of neurofibromin-mediated RAS inactivation.
  • Legius syndrome is roughly 20-fold rarer (birth prevalence ~1/46,000-1/75,000 versus ~1/2,000-1/3,000 for NF1).
Show evidence (3 references)
PMID:19920235 SUPPORT Human Clinical
"Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%; 95% confidence interval ... 32%-64%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history."
Quantifies the clinical overlap that makes NF1 the principal differential diagnosis.
PMID:19920235 SUPPORT Human Clinical
"In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS."
Quantifies the fraction of clinically diagnosed NF1 that is actually Legius syndrome, that is, the diagnostic yield of SPRED1 testing in the NF1-criteria population.
PMID:19920235 SUPPORT Human Clinical
"Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1."
States the tumor-risk contrast that distinguishes Legius syndrome from NF1.
Constitutional mismatch repair deficiency syndrome
Overlapping Features CMMRD can present in childhood with multiple café-au-lait macules and skinfold freckling mimicking NF1 or Legius syndrome, but carries a severe early-onset cancer predisposition, so it must be excluded before pigmentary findings are attributed to a RASopathy.
Distinguishing Features
  • CMMRD carries a high early-onset malignancy risk (brain, hematologic, gastrointestinal) absent in Legius syndrome.
  • Biallelic germline mismatch repair gene variants rather than a heterozygous SPRED1 variant.
Show evidence (1 reference)
PMID:34012067 SUPPORT Human Clinical
"If only café-au-lait macules and freckling are present, the diagnosis is most likely mosaic neurofibromatosis type 1 but rarely might be mosaic Legius syndrome or constitutional mismatch repair deficiency (CMMRD) syndrome."
The consensus criteria list CMMRD among the conditions to consider when only pigmentary findings are present.
{ }

Source YAML

click to show 
name: Legius Syndrome
creation_date: "2026-07-13T00:00:00Z"
description: >-
  Legius syndrome (LGSS; formerly "neurofibromatosis type 1-like syndrome", NFLS)
  is an autosomal dominant RASopathy caused by heterozygous germline
  loss-of-function variants in SPRED1. SPRED1 encodes a Sprouty-related, EVH1
  domain-containing negative regulator of RAS-MAPK signaling whose principal
  function is to recruit neurofibromin — the RAS-GTPase-activating protein encoded
  by NF1 — to activated RAS at the plasma membrane. Loss of SPRED1 therefore
  phenocopies the pigmentary arm of neurofibromatosis type 1: multiple bilateral
  café-au-lait macules with or without axillary/inguinal freckling, macrocephaly,
  lipomas, and a mild neurocognitive profile of learning disability, ADHD, and
  developmental delay. Critically, and unlike NF1, Legius syndrome is not
  associated with neurofibromas, Lisch nodules, symptomatic optic pathway gliomas,
  or the characteristic NF1 osseous lesions, which is why it is classified as a
  RASopathy rather than a form of neurofibromatosis. Because the two conditions
  are clinically indistinguishable in early childhood when only pigmentary
  findings are present, molecular confirmation of a SPRED1 variant is the
  defining diagnostic criterion in the 2021 international consensus revision.
category: Genetic
parents:
- RASopathy
synonyms:
- NF1-like syndrome
- neurofibromatosis type 1-like syndrome
- NFLS
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012669
      label: Legius syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary disease term for this entry. MONDO:0012669 is anchored to SPRED1
      (RO:0004003 HGNC:20249) and cross-references OMIM:611431 and
      Orphanet:137605, matching the gene and entity curated here.
disease_term:
  preferred_term: Legius syndrome
  description: >-
    An autosomal dominant RASopathy caused by heterozygous germline
    loss-of-function variants in SPRED1, producing the pigmentary features of
    neurofibromatosis type 1 without its tumor manifestations.
  term:
    id: MONDO:0012669
    label: Legius syndrome
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:34012067
      reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        LGSS, inherited in an autosomal dominant pattern, is characterized by
        multiple CALMs similar to NF1 with or without skinfold freckling, caused by
        heterozygous PVs in SPRED1, located on chromosome 15.
      explanation: >-
        Supports classification as an inherited (germline, autosomal dominant)
        RAS-MAPK pathway genetic disorder.
pathophysiology:
- name: Germline SPRED1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Legius syndrome is caused by heterozygous germline loss-of-function variants
    in SPRED1, a member of the SPROUTY/SPRED family of proteins that act as
    negative regulators of the RAS-RAF interaction and downstream MAPK signaling.
    This was the first human disease attributed to the SPRY/SPRED gene family and
    placed the disorder within the RASopathy group of RAS-MAPK pathway disorders.
  genes:
  - preferred_term: SPRED1
    term:
      id: hgnc:20249
      label: SPRED1
  biological_processes:
  - preferred_term: negative regulation of Ras protein signal transduction
    term:
      id: GO:0046580
      label: negative regulation of Ras protein signal transduction
    modifier: DECREASED
  downstream:
  - target: Impaired Neurofibromin Recruitment to Activated RAS
    description: >-
      Loss of functional SPRED1 removes the adaptor that delivers neurofibromin
      to RAS at the plasma membrane.
    evidence:
    - reference: PMID:26635368
      reference_title: "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."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway
        by recruiting neurofibromin to Ras through the EVH1-GRD interaction
      explanation: >-
        Establishes neurofibromin recruitment as the mechanism by which SPRED1
        suppresses RAS-ERK signaling, and therefore the step lost when SPRED1
        function is lost.
  evidence:
  - reference: PMID:17704776
    reference_title: "Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report germline loss-of-function mutations in SPRED1 in a newly
      identified autosomal dominant human disorder. SPRED1 is a member of the
      SPROUTY/SPRED family of proteins that act as negative regulators of
      RAS->RAF interaction and mitogen-activated protein kinase (MAPK)
      signaling.
    explanation: >-
      The founding report establishing germline SPRED1 loss of function as the
      cause of the disorder and its role as a RAS-MAPK negative regulator.
  - reference: PMID:11493923
    reference_title: "Spred is a Sprouty-related suppressor of Ras signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Like Sprouty, Spred inhibited growth-factor-mediated activation of MAP
      kinase.
    explanation: >-
      Original functional characterization of Spred proteins as suppressors of
      growth-factor-driven MAPK activation, the activity lost in Legius syndrome.
- name: Impaired Neurofibromin Recruitment to Activated RAS
  biological_scale: MOLECULAR
  description: >-
    SPRED1 suppresses RAS-ERK signaling not by acting on RAS directly but by
    serving as a membrane-targeting adaptor for neurofibromin, the RAS-GAP
    encoded by NF1. The SPRED1 EVH1 domain binds short N- and C-terminal helical
    extensions flanking the GAP-related domain (GRD) of neurofibromin — regions
    dispensable for GAP catalysis and absent from p120GAP, which explains the
    selectivity of SPRED1 for neurofibromin among RasGAPs. Pathogenic EVH1-domain
    missense variants found in Legius syndrome reduce GRD binding affinity and
    correspondingly abolish the ERK-suppressing activity of SPRED1, providing a
    direct molecular link between genotype and pathway dysregulation. Structural
    work confirms that SPRED1-mediated membrane targeting allows neurofibromin to
    engage activated KRAS simultaneously.
  genes:
  - preferred_term: SPRED1
    term:
      id: hgnc:20249
      label: SPRED1
  - preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  molecular_functions:
  - preferred_term: GTPase activator activity
    term:
      id: GO:0005096
      label: GTPase activator activity
    modifier: DECREASED
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: >-
      Without membrane-recruited neurofibromin, RAS-GTP is inefficiently
      hydrolyzed and flux through the RAF-MEK-ERK cascade is sustained.
    evidence:
    - reference: PMID:26635368
      reference_title: "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."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        EVH1 domain mutations with reduced binding to the GRD also disrupted the
        ERK suppression activity of SPRED1.
      explanation: >-
        Directly couples loss of the SPRED1-neurofibromin interaction to failure
        of ERK suppression.
    - reference: PMID:22751498
      reference_title: "A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here we show that neurofibromin, the NF1 gene product, is a
        Spred1-interacting protein that is necessary for Spred1's inhibitory
        function.
      explanation: >-
        Neurofibromin is required for SPRED1 to suppress the pathway, so failure
        to recruit it leaves RAS-MAPK signaling unrestrained.
  evidence:
  - reference: PMID:22751498
    reference_title: "A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that Spred1 binding induces the plasma membrane localization of
      NF1, which subsequently down-regulates Ras-GTP levels.
    explanation: >-
      Direct demonstration that SPRED1 acts as a membrane-targeting adaptor for
      neurofibromin, which is the claim this node makes; the EVH1-GRD
      interaction and structural papers establish the binding interface but not
      the membrane localization itself.
  - reference: PMID:22751498
    reference_title: "A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This novel mechanism for the regulation of neurofibromin provides a
      molecular bridge for understanding the overlapping pathophysiology of NF1
      and Legius syndrome.
    explanation: >-
      Establishes this node as the shared molecular step that explains why
      SPRED1 loss and NF1 loss produce overlapping pathophysiology.
  - reference: PMID:26635368
    reference_title: "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."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino
      acids and the C-terminal 20 amino acids of the GTPase-activating protein
      (GAP)-related domain (GRD) of neurofibromin
    explanation: >-
      Maps the SPRED1-neurofibromin interface whose disruption underlies Legius
      syndrome.
  - reference: PMID:26635368
    reference_title: "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."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius
      syndrome reduced the binding affinity between the EVH1 domain and the GRD
    explanation: >-
      Shows that Legius-associated EVH1 missense variants act by weakening
      neurofibromin binding.
  - reference: PMID:32697994
    reference_title: "Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The structure provides insight into how the membrane targeting of
      neurofibromin by SPRED1 allows simultaneous interaction with activated
      KRAS.
    explanation: >-
      Structural confirmation that SPRED1 positions neurofibromin at the membrane
      to act on active RAS.
  - reference: PMID:32697994
    reference_title: "Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of the neurofibromin-SPRED1 interface provides a rationale for
      mutations observed in Legius syndrome and suggests why SPRED1 can bind to
      neurofibromin but no other RasGAPs.
    explanation: >-
      Explains both the pathogenicity of interface variants and the selectivity
      of SPRED1 for neurofibromin rather than other RasGAPs.
- name: RAS-MAPK Pathway Hyperactivation
  biological_scale: CELLULAR
  description: >-
    Like the other RASopathies, Legius syndrome results from germline
    dysregulation of the RAS-MAPK (RAS/ERK) signal transduction cascade. The
    shared pathway lesion places the disorder in the same phenotypically
    overlapping family as neurofibromatosis type 1, Noonan syndrome, Costello
    syndrome, and cardiofaciocutaneous syndrome, and accounts for the
    macrocephaly, pigmentary, and neurocognitive features shared across the
    group. In Legius syndrome the dysregulation is comparatively mild and does
    not reach the threshold required for neurofibroma or other NF1 tumor
    formation.
  biological_processes:
  - preferred_term: positive regulation of MAPK cascade
    term:
      id: GO:0043410
      label: positive regulation of MAPK cascade
    modifier: INCREASED
  downstream:
  - target: Biallelic SPRED1 Inactivation in Melanocytes
    description: >-
      Pathway dysregulation becomes phenotypically manifest in skin only where a
      somatic second hit removes the remaining SPRED1 allele.
    evidence:
    - reference: PMID:17704776
      reference_title: "Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        indicating that complete SPRED1 inactivation is needed to generate a
        café-au-lait spot in this syndrome
      explanation: >-
        Establishes that the pigmentary lesion requires biallelic, not
        heterozygous, SPRED1 loss.
  - target: Hippocampal Synaptic Plasticity Impairment
    description: >-
      Sustained ERK activation in hippocampal circuits perturbs the balance of
      long-term potentiation and depression.
    evidence:
    - reference: PMID:19118178
      reference_title: "Spred1 is required for synaptic plasticity and hippocampus-dependent learning."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This indicates that deficits in hippocampus-dependent learning and
        synaptic plasticity induced by SPRED1 deficiency are related to
        hyperactivation of the Ras/ERK pathway.
      explanation: >-
        Links Ras/ERK hyperactivation to the synaptic plasticity defect in the
        Spred1-null mouse model.
  evidence:
  - reference: PMID:17704776
    reference_title: "Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This disorder is yet another member of the recently characterized group of
      phenotypically overlapping syndromes caused by mutations in the genes
      encoding key components of the RAS-MAPK pathway.
    explanation: >-
      Places Legius syndrome within the RAS-MAPK (RASopathy) group sharing this
      final common mechanism.
- name: Biallelic SPRED1 Inactivation in Melanocytes
  biological_scale: CELLULAR
  description: >-
    Melanocytes isolated from a café-au-lait macule of an affected individual
    carried, in addition to the germline SPRED1 variant, an acquired somatic
    mutation in the wild-type SPRED1 allele. Café-au-lait macule formation in
    Legius syndrome therefore follows a two-hit, mosaic-somatic logic in the
    melanocyte lineage, mirroring the second-hit requirement described for NF1
    pigmentary lesions, rather than arising from germline haploinsufficiency
    alone.
  genes:
  - preferred_term: SPRED1
    term:
      id: hgnc:20249
      label: SPRED1
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  downstream:
  - target: Cafe-au-lait Macule Formation
    description: >-
      Clonal patches of SPRED1-null melanocytes produce the hyperpigmented
      macules that define the clinical phenotype.
    evidence:
    - reference: PMID:17704776
      reference_title: "Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Melanocytes from a café-au-lait spot showed, in addition to the germline
        SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1
        allele
      explanation: >-
        Documents the somatic second hit in lesional melanocytes as the proximate
        cause of the macule.
  evidence:
  - reference: PMID:17704776
    reference_title: "Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      indicating that complete SPRED1 inactivation is needed to generate a
      café-au-lait spot in this syndrome
    explanation: >-
      States the biallelic-inactivation requirement for the pigmentary lesion.
- name: Cafe-au-lait Macule Formation
  biological_scale: TISSUE
  description: >-
    The cardinal and often sole objective finding of Legius syndrome: multiple,
    bilaterally distributed café-au-lait macules, with or without skinfold
    (axillary or inguinal) freckling, clinically indistinguishable from those of
    neurofibromatosis type 1. Because the pigmentary phenotype is shared, roughly
    half of individuals with a SPRED1 variant satisfy the older NIH clinical
    criteria for NF1 despite having a different natural history — the observation
    that drove the 2021 consensus revision to make a molecular SPRED1 result a
    required diagnostic criterion.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LGSS, inherited in an autosomal dominant pattern, is characterized by
      multiple CALMs similar to NF1 with or without skinfold freckling, caused by
      heterozygous PVs in SPRED1, located on chromosome 15.
    explanation: >-
      Consensus statement describing the defining pigmentary phenotype and its
      genetic basis.
- name: Hippocampal Synaptic Plasticity Impairment
  biological_scale: CELLULAR
  description: >-
    Spred1-null mice show impaired performance in the Morris water maze and
    visual-discrimination T-maze with normal basic neuromotor and sensory
    abilities, together with defects in short- and long-term hippocampal synaptic
    plasticity including a disequilibrium between long-term potentiation and
    long-term depression in CA1. Increased ERK phosphorylation is measurable in
    Spred1-null slices after LTP induction, linking the plasticity defect to
    Ras/ERK hyperactivation. This is the candidate substrate for the learning
    disability, ADHD, and developmental delay reported in affected individuals,
    but the translational step from mouse hippocampal physiology to the human
    cognitive phenotype has not been directly demonstrated (see the
    HUMAN_MODEL_MISMATCH discussion).
  genes:
  - preferred_term: SPRED1
    term:
      id: hgnc:20249
      label: SPRED1
  biological_processes:
  - preferred_term: long-term synaptic potentiation
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19118178
    reference_title: "Spred1 is required for synaptic plasticity and hippocampus-dependent learning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Electrophysiological recordings on brain slices from these animals
      identified defects in short- and long-term synaptic hippocampal
      plasticity, including a disequilibrium between long-term potentiation (LTP)
      and long-term depression in CA1 region.
    explanation: >-
      Documents the hippocampal plasticity defect in the Spred1-null mouse model.
  - reference: PMID:19118178
    reference_title: "Spred1 is required for synaptic plasticity and hippocampus-dependent learning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Spred1(-/-) mice show decreased learning and memory performance in the
      Morris water maze and visual-discrimination T-maze, but normal basic
      neuromotor and sensory abilities.
    explanation: >-
      Shows a selective learning and memory deficit rather than a general
      sensorimotor impairment in the model.
phenotypes:
- name: Multiple Cafe-au-lait Macules
  description: >-
    Six or more bilaterally distributed café-au-lait macules are the cardinal
    finding and the anchor of the Legius syndrome diagnostic criteria. Fewer than
    six macules does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Multiple cafe-au-lait spots
    term:
      id: HP:0007565
      label: Multiple cafe-au-lait spots
  evidence:
  - reference: PMID:17704776
    reference_title: "Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features of the reported disorder resemble those of
      neurofibromatosis type 1 and consist of multiple café-au-lait spots,
      axillary freckling and macrocephaly.
    explanation: >-
      Multiple café-au-lait macules are listed among the defining clinical
      features in the founding description.
- name: Axillary Freckling
  description: >-
    Skinfold freckling in the axillary region, the only NF1-related feature
    permitted alongside café-au-lait macules under the Legius syndrome diagnostic
    criteria.
  phenotype_term:
    preferred_term: Axillary freckling
    term:
      id: HP:0000997
      label: Axillary freckling
  evidence:
  - reference: PMID:17704776
    reference_title: "Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      multiple café-au-lait spots, axillary freckling and macrocephaly
    explanation: Axillary freckling is a defining clinical feature of the disorder.
- name: Inguinal Freckling
  description: >-
    Inguinal skinfold freckling; like axillary freckling, it is compatible with a
    Legius syndrome diagnosis and does not by itself indicate NF1.
  phenotype_term:
    preferred_term: Inguinal freckling
    term:
      id: HP:0030052
      label: Inguinal freckling
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six or more café-au-lait macules (Supplementary Fig. 12) bilaterally
      distributed and no other NF1-related diagnostic criteria except for
      axillary or inguinal freckling
    explanation: >-
      The consensus criteria explicitly admit axillary or inguinal freckling as
      compatible with Legius syndrome.
- name: Macrocephaly
  description: >-
    Macrocephaly is a consistently reported feature, shared with NF1 and with
    other RASopathies.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:17704776
    reference_title: "Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      consist of multiple café-au-lait spots, axillary freckling and
      macrocephaly
    explanation: >-
      Macrocephaly is described among the cardinal clinical features in the
      founding human description of the disorder.
  - reference: PMID:26635368
    reference_title: "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."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a phenotype known as Legius syndrome, which consists of symptoms of
      multiple café-au-lait macules, axillary freckling, learning disabilities,
      and macrocephaly
    explanation: >-
      Framing sentence from the introduction of this biochemical study, listing
      macrocephaly among the core features. Graded by the cited publication's own
      evidence type, consistent with the five other citations of this paper in
      this entry; the human clinical source for the phenotype is PMID:17704776
      above.
- name: Specific Learning Disability
  description: >-
    Learning disabilities are commonly reported and, with ADHD and developmental
    delay, constitute the neurocognitive arm of the phenotype.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional clinical manifestations commonly reported include
      intertriginous freckling, lipomas, macrocephaly, and learning
      disabilities, attention-deficit/hyperactivity disorder (ADHD), and
      developmental delays.
    explanation: >-
      GeneReviews lists learning disability among the commonly reported
      manifestations.
  - reference: PMID:19366998
    reference_title: "SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their NF1-like phenotype was characterised by a high prevalence of
      café-au-lait spots, freckling, learning disability, and an absence of
      neurofibromas and Lisch nodules in agreement with the original
      description.
    explanation: >-
      Independent French replication cohort reporting learning disability at
      high prevalence in SPRED1-mutated families, so this phenotype does not
      rest on the GeneReviews summary alone.
- name: Attention Deficit Hyperactivity Disorder
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      macrocephaly, and learning disabilities, attention-deficit/hyperactivity
      disorder (ADHD), and developmental delays
    explanation: ADHD is among the commonly reported manifestations in GeneReviews.
- name: Developmental Delay
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      learning disabilities, attention-deficit/hyperactivity disorder (ADHD),
      and developmental delays
    explanation: >-
      Developmental delay is among the commonly reported manifestations.
      GeneReviews says "developmental delays" without asserting delay across
      all domains, so this binds HP:0012758 (delay in one or more
      developmental domains) rather than the global term.
- name: Lipoma
  description: >-
    Lipomas are a commonly reported soft-tissue finding and may require
    dermatologic referral for management.
  phenotype_term:
    preferred_term: Lipoma
    term:
      id: HP:0012032
      label: Lipoma
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional clinical manifestations commonly reported include
      intertriginous freckling, lipomas, macrocephaly
    explanation: Lipomas are listed among the commonly reported manifestations.
- name: Pectus Excavatum
  description: >-
    A skeletal finding named in the GeneReviews management section as requiring
    orthopedic treatment in Legius syndrome.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: treatment of pectus excavatum and scoliosis per orthopedist
    explanation: >-
      GeneReviews directs orthopedic treatment of pectus excavatum in Legius
      syndrome. Recorded as INDIRECT because the sentence prescribes management
      rather than reporting the finding's occurrence or frequency, from which
      occurrence follows by one inference step.
- name: Scoliosis
  description: >-
    A skeletal finding named in the GeneReviews management section for
    orthopedic treatment and listed for surveillance at each visit.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      assess for pigmentary lesions, lipomas, scoliosis, and new-onset seizures
      at each visit
    explanation: >-
      GeneReviews places scoliosis under routine surveillance in Legius
      syndrome. Recorded as INDIRECT because a surveillance recommendation
      implies rather than reports the finding's occurrence.
- name: Seizures
  description: >-
    Seizures are managed by an experienced neurologist and new-onset seizures
    are assessed at each visit under the GeneReviews surveillance schedule.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: standard treatment for seizures per experienced neurologist
    explanation: >-
      GeneReviews directs neurologic management of seizures in Legius syndrome.
      Recorded as INDIRECT because the sentence prescribes management rather
      than reporting seizure occurrence or frequency.
- name: Hearing Impairment
  description: >-
    Hearing loss prompts otolaryngology referral, with hearing evaluation as
    needed under the GeneReviews surveillance schedule.
  phenotype_term:
    preferred_term: Hearing loss
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      referral to otolaryngologist for those with identified hearing loss
    explanation: >-
      GeneReviews directs otolaryngology referral for hearing loss in Legius
      syndrome. Recorded as INDIRECT because the sentence prescribes management
      for affected individuals rather than reporting how often hearing loss
      occurs.
- name: Neurofibroma (Explicitly Absent)
  description: >-
    The defining negative feature separating Legius syndrome from NF1, recorded
    here as an explicitly absent phenotype. In the largest genotype-phenotype
    cohort, none of 42 SPRED1-positive individuals had discrete cutaneous or
    plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic
    pathway gliomas. This absence is the reason the 2021 consensus group declined
    to classify the disorder as a subtype of neurofibromatosis.
  phenotype_term:
    preferred_term: Neurofibroma
    term:
      id: HP:0001067
      label: Neurofibroma
    modifier: ABSENT
  evidence:
  - reference: PMID:19920235
    reference_title: "Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete
      cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or
      symptomatic optic pathway gliomas.
    explanation: >-
      Directly documents the absence of neurofibromas and other NF1 tumor
      manifestations in the SPRED1-positive cohort.
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No individuals with LGSS have developed Lisch nodules, neurofibromas, or
      other complications of NF1.
    explanation: >-
      The consensus group confirms the absence of neurofibromas and Lisch nodules
      in Legius syndrome.
- name: Lisch Nodules (Explicitly Absent)
  description: >-
    Iris Lisch nodules, a diagnostic criterion for NF1, have not been reported in
    Legius syndrome. Recorded as an explicitly absent phenotype because their
    presence in a child with pigmentary findings argues for NF1 rather than
    Legius syndrome.
  phenotype_term:
    preferred_term: Lisch nodules
    term:
      id: HP:0009737
      label: Lisch nodules
    modifier: ABSENT
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No individuals with LGSS have developed Lisch nodules, neurofibromas, or
      other complications of NF1.
    explanation: >-
      The consensus statement records the absence of Lisch nodules in Legius
      syndrome.
genetic:
- name: SPRED1
  gene_term:
    preferred_term: SPRED1
    term:
      id: hgnc:20249
      label: SPRED1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    Heterozygous loss-of-function variants in SPRED1 (chromosome 15) cause Legius
    syndrome. The mutational spectrum is broad — 34 distinct SPRED1 variants were
    identified across 43 probands in the defining anonymous cohort — so there is
    no single recurrent variant, in contrast to the single recurrent SHOC2
    p.Ser2Gly variant of NS/LAH. Pathogenic missense variants cluster in the EVH1
    domain and act by weakening the neurofibromin GRD interaction. SPRED1 variants
    account for approximately 1% of sporadic and 19% of familial cases presenting
    with pigmentary features of NF1 only.
  evidence:
  - reference: PMID:19920235
    reference_title: "Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations
      in 43 probands were identified: 27 pathogenic mutations in 34 probands and
      7 probable nonpathogenic missense mutations in 9 probands.
    explanation: >-
      Documents the breadth of the SPRED1 mutational spectrum and the absence of a
      single recurrent variant.
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further studies have shown that SPRED1 PVs account for 1% of sporadic cases
      and 19% of familial cases with pigmentary features of NF1 (CALMs and
      freckling) only.
    explanation: >-
      Quantifies the diagnostic yield of SPRED1 testing in individuals with
      isolated pigmentary NF1 features.
  - reference: PMID:19366998
    reference_title: "SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Germline loss-of-function mutations in the SPRED1 gene have recently been
      identified in patients fulfilling the National Institutes of Health (NIH)
      diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1
      (neurofibromin 1) mutation found, suggesting a neurofibromatosis type
      1-like syndrome.
    explanation: >-
      Independent replication in five French families confirming germline
      loss-of-function SPRED1 variants as the molecular cause in individuals
      meeting NF1 criteria without an NF1 variant.
inheritance:
- name: Autosomal Dominant
  description: >-
    Legius syndrome is inherited in an autosomal dominant manner. Unlike many
    ultra-rare RASopathies, most affected individuals have an affected parent
    rather than a de novo variant, and each child of an affected individual has a
    50% recurrence risk.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Legius syndrome is inherited in an autosomal dominant manner. Many
      individuals diagnosed with Legius syndrome have an affected parent.
    explanation: >-
      GeneReviews states the autosomal dominant inheritance pattern and the
      predominance of inherited rather than de novo variants.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 1.3
  rate_high: 2.2
  notes: >-
    Consensus estimate of 1/46,000-1/75,000 live births (approximately 1.3-2.2 per
    100,000), roughly 20-fold rarer than NF1 (1/2,000-1/3,000). Corresponds to
    about 4% of individuals followed in a neurofibromatosis clinic.
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition is less frequent than NF1 with an estimated birth prevalence
      of 1/46,000–1/75,000 (4% of individuals followed at a neurofibromatosis
      clinic)
    explanation: >-
      Provides the consensus birth-prevalence estimate normalized here to cases
      per 100,000.
definitions:
- name: 2021 international consensus diagnostic criteria for Legius syndrome
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The International Consensus Group on Neurofibromatosis Diagnostic Criteria
    (I-NF-DC) established the first formal diagnostic criteria for Legius
    syndrome in 2021. Unlike the NF1 criteria, which can be met clinically, the
    Legius syndrome criteria require molecular confirmation: a heterozygous
    pathogenic SPRED1 variant at a ~50% variant allele fraction in apparently
    normal tissue, together with six or more bilaterally distributed café-au-lait
    macules and no NF1-related diagnostic criteria other than axillary or
    inguinal freckling. A child of an affected parent needs only one of these.
    Fewer than six café-au-lait macules does not exclude the diagnosis.
  scope: >-
    Clinical and molecular diagnosis of non-mosaic Legius syndrome. Separate
    criteria exist for mosaic Legius syndrome, which is very rare.
  inclusion_criteria:
  - preferred_term: Six or more bilaterally distributed cafe-au-lait macules
    term:
      id: HP:0007565
      label: Multiple cafe-au-lait spots
    description: >-
      Six or more café-au-lait macules with a bilateral distribution. Fewer than
      six does not exclude the diagnosis.
  - preferred_term: Heterozygous pathogenic SPRED1 variant at ~50% variant allele fraction
    description: >-
      A heterozygous pathogenic variant in SPRED1 with a variant allele fraction
      of 50% in apparently normal tissue such as white blood cells. This
      molecular criterion is required and is what distinguishes the Legius
      syndrome criteria from the clinically satisfiable NF1 criteria.
  exclusion_criteria:
  - preferred_term: Any NF1-related diagnostic criterion other than skinfold freckling
    description: >-
      Presence of any other NF1 diagnostic criterion — neurofibromas, Lisch
      nodules or choroidal abnormalities, optic pathway glioma, or a distinctive
      NF1 osseous lesion — excludes Legius syndrome. Axillary or inguinal
      freckling is the sole permitted exception.
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A: The diagnostic criteria for Legius syndrome are met in an individual who
      does not have a parent diagnosed with Legius syndrome if the following
      CRITERIA are present:
    explanation: Introduces the consensus diagnostic criteria table for Legius syndrome.
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A heterozygous pathogenic variant in SPRED1 with a variant allele fraction
      of 50% in apparently normal tissue such as white blood cells
    explanation: >-
      States the required molecular criterion that distinguishes the Legius
      syndrome criteria from the clinically satisfiable NF1 criteria.
  notes: >-
    The consensus group explicitly considered and rejected classifying Legius
    syndrome as an NF1 subtype, on the grounds that in the absence of
    neurofibromas it is inappropriate to consider it a type of neurofibromatosis.
diagnosis:
- name: Clinical criteria with SPRED1 molecular confirmation
  description: >-
    In an individual without an affected parent, the international consensus
    criteria require six or more bilaterally distributed café-au-lait macules,
    no other NF1 diagnostic features apart from axillary or inguinal freckling,
    and a heterozygous pathogenic SPRED1 variant in apparently normal tissue.
    Molecular confirmation is especially important because pigmentary findings
    alone overlap strongly with neurofibromatosis type 1.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six or more café-au-lait macules (Supplementary Fig. 12) bilaterally
      distributed and no other NF1-related diagnostic criteria except for
      axillary or inguinal freckling
    explanation: >-
      States the consensus pigmentary and exclusion criteria used together with
      identification of a heterozygous pathogenic SPRED1 variant.
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Legius syndrome is established in a proband with
      suggestive findings and a heterozygous pathogenic variant in SPRED1
      identified by molecular genetic testing.
    explanation: >-
      Sources the molecular-confirmation half of this diagnostic entry: the
      consensus criteria above establish the pigmentary and exclusion findings,
      and GeneReviews states that SPRED1 molecular genetic testing is what
      establishes the diagnosis in a proband with those findings.

differential_diagnoses:
- name: Neurofibromatosis type 1
  disease_term:
    preferred_term: neurofibromatosis type 1
    term:
      id: MONDO:0018975
      label: neurofibromatosis type 1
  description: >-
    The principal differential and the reason the disorder was originally named
    "NF1-like syndrome". The two are clinically indistinguishable in early
    childhood when only pigmentary findings are present, and about half of
    SPRED1-positive individuals satisfy the older NIH clinical criteria for NF1.
    Read the other way round, 1.9% (95% CI 1.2%-2.9%) of individuals carrying a
    clinical NF1 diagnosis by the NIH criteria in fact have Legius syndrome —
    the diagnostic yield of SPRED1 testing in that ascertained population, which
    is not a population prevalence and is recorded here rather than in
    `prevalence:`.
  distinguishing_features:
  - Legius syndrome lacks neurofibromas (cutaneous and plexiform), Lisch nodules, symptomatic optic pathway gliomas, and the distinctive NF1 osseous lesions.
  - The causal gene differs — SPRED1 rather than NF1 — although both converge on failure of neurofibromin-mediated RAS inactivation.
  - Legius syndrome is roughly 20-fold rarer (birth prevalence ~1/46,000-1/75,000 versus ~1/2,000-1/3,000 for NF1).
  evidence:
  - reference: PMID:19920235
    reference_title: "Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%;
      95% confidence interval ... 32%-64%) fulfilled National Institutes of
      Health (NIH) NF1 diagnostic criteria based on the presence of more than 5
      CALMs with or without freckling or an NF1-compatible family history.
    explanation: >-
      Quantifies the clinical overlap that makes NF1 the principal differential
      diagnosis.
  - reference: PMID:19920235
    reference_title: "Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the
      clinical diagnosis of NF1 according to the NIH criteria had NFLS.
    explanation: >-
      Quantifies the fraction of clinically diagnosed NF1 that is actually Legius
      syndrome, that is, the diagnostic yield of SPRED1 testing in the
      NF1-criteria population.
  - reference: PMID:19920235
    reference_title: "Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among individuals in this study, NFLS was not associated with the
      peripheral and central nervous system tumors seen in NF1.
    explanation: >-
      States the tumor-risk contrast that distinguishes Legius syndrome from NF1.
- name: Constitutional mismatch repair deficiency syndrome
  description: >-
    CMMRD can present in childhood with multiple café-au-lait macules and
    skinfold freckling mimicking NF1 or Legius syndrome, but carries a severe
    early-onset cancer predisposition, so it must be excluded before pigmentary
    findings are attributed to a RASopathy.
  distinguishing_features:
  - CMMRD carries a high early-onset malignancy risk (brain, hematologic, gastrointestinal) absent in Legius syndrome.
  - Biallelic germline mismatch repair gene variants rather than a heterozygous SPRED1 variant.
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If only café-au-lait macules and freckling are present, the diagnosis is
      most likely mosaic neurofibromatosis type 1 but rarely might be mosaic
      Legius syndrome or constitutional mismatch repair deficiency (CMMRD)
      syndrome.
    explanation: >-
      The consensus criteria list CMMRD among the conditions to consider when only
      pigmentary findings are present.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    Management is symptom-directed. Reported components include behavioral
    modification and/or pharmacologic therapy for ADHD; physical, speech, and
    occupational therapy for developmental delays; individualized education plans
    for learning disorders; dermatologic referral for lipoma management;
    orthopedic management of pectus excavatum and scoliosis; standard seizure
    management; and otolaryngology referral for hearing loss.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of manifestations: Consideration of behavioral modification
      and/or pharmacologic therapy for those with ADHD; physical, speech, and
      occupational therapy for those with identified developmental delays;
      individualized education plans for those with learning disorders; referral
      to dermatologist as needed for lipoma management
    explanation: >-
      GeneReviews enumerates the symptom-directed management components for
      Legius syndrome.
- name: Developmental and Behavioral Surveillance
  description: >-
    Recommended surveillance is developmental and dermatologic rather than
    oncologic — a direct consequence of the absent tumor predisposition. Monitor
    developmental progress, educational needs, and behavior at each visit; assess
    for pigmentary lesions, lipomas, scoliosis, and new-onset seizures at each
    visit; hearing evaluation as needed.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Monitor developmental progress, educational needs, and
      behavioral assessment at each visit; assess for pigmentary lesions,
      lipomas, scoliosis, and new-onset seizures at each visit; hearing
      evaluation as needed.
    explanation: >-
      GeneReviews specifies the surveillance schedule, notably without tumor
      screening.
- name: Genetic Counseling
  description: >-
    Genetic counseling is central, both for the 50% recurrence risk and because
    reclassifying a presumed NF1 diagnosis as Legius syndrome substantially
    changes prognosis and surveillance. Once the familial SPRED1 variant is known,
    prenatal and preimplantation genetic testing are possible.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20945555
    reference_title: "Legius Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with Legius syndrome caused by a germline
      SPRED1 pathogenic variant has a 50% chance of inheriting the pathogenic
      variant. Once the SPRED1 pathogenic variant has been identified in an
      affected family member, prenatal and preimplantation genetic testing are
      possible.
    explanation: >-
      GeneReviews states the recurrence risk and reproductive testing options that
      genetic counseling addresses.
  - reference: PMID:19366998
    reference_title: "SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NIH diagnostic criteria for NF1 must be revised in view of this newly
      characterised Legius syndrome in order to establish a specific genetic
      counselling.
    explanation: >-
      States why separating Legius syndrome from NF1 matters for counseling, the
      argument that later produced the 2021 consensus criteria revision.
discussions:
- discussion_id: gap_legius_residual_tumor_risk
  prompt: >-
    Is the tumor risk in Legius syndrome truly at population baseline, or does the
    absence of tumors in published cohorts reflect limited sample size and
    incomplete adult follow-up?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#RAS-MAPK Pathway Hyperactivation
  rationale: >-
    The clinical management of Legius syndrome — developmental rather than
    oncologic surveillance — rests on the claim that SPRED1 loss does not confer
    the tumor predisposition of NF1. The strongest supporting observation is
    nonetheless a zero count in a modest cohort: 0 of 42 SPRED1-positive
    individuals, with a 95% confidence interval extending to 7%. A tumor risk
    anywhere below that upper bound is statistically compatible with the data,
    and the cohorts are weighted toward children, so adult-onset risk is
    especially poorly constrained. Because SPRED1 and NF1 converge on the same
    RAS-inactivation step, a mechanistic prior for some residual risk is not
    unreasonable, and resolving this determines whether any oncologic
    surveillance is warranted.
  evidence:
  - reference: PMID:19920235
    reference_title: "Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete
      cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or
      symptomatic optic pathway gliomas.
    explanation: >-
      Supports the absence of NF1 tumor manifestations, but the reported
      confidence interval bounds the residual risk only loosely at 7%, which is
      what leaves this question open.
  proposed_experiments:
  - experiment_id: exp_legius_population_scale_cancer_risk_ascertainment
    name: Genomic-ascertainment cohort of adult SPRED1 variant carriers
    description: >-
      Identify carriers of pathogenic and likely pathogenic germline SPRED1
      variants in large unselected biobank/health-system genomic datasets rather
      than in neurofibromatosis clinics, and compare age-stratified adult cancer
      incidence against non-carrier controls. Genomic rather than clinical
      ascertainment removes the referral bias that inflates the apparent
      specificity of the pigmentary phenotype, and biobank scale provides the
      person-years needed to tighten the upper confidence bound well below 7%.
- discussion_id: gap_legius_human_model_cognitive_mechanism
  prompt: >-
    Does the hippocampal LTP/LTD disequilibrium seen in Spred1-null mice account
    for the learning disability and ADHD observed in humans with heterozygous
    SPRED1 loss of function?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Hippocampal Synaptic Plasticity Impairment
  rationale: >-
    The mechanistic account of the neurocognitive phenotype rests entirely on a
    mouse model, and two gaps separate it from the human disease. First is a
    dosage mismatch: the electrophysiology and behavioral deficits are reported
    in homozygous Spred1(-/-) animals, whereas humans with Legius syndrome are
    heterozygous. Second, no human study has demonstrated a corresponding
    hippocampal plasticity or ERK-signaling abnormality, so the inference from
    rodent CA1 physiology to human learning disability remains an extrapolation
    rather than a demonstrated mechanism. This matters therapeutically, because
    MEK-inhibitor-based cognitive rescue strategies proposed for RASopathies
    presuppose that the human deficit is ERK-driven in the same way.
  evidence:
  - reference: PMID:19118178
    reference_title: "Spred1 is required for synaptic plasticity and hippocampus-dependent learning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We investigated hippocampus-dependent learning and memory as well as
      synaptic plasticity in Spred1(-/-) mice, an animal model of this newly
      discovered human syndrome.
    explanation: >-
      The mechanism is established in homozygous null mice, whereas human Legius
      syndrome results from heterozygous loss of function.
  proposed_experiments:
  - experiment_id: exp_legius_heterozygous_model_and_human_cognitive_phenotyping
    name: Heterozygous Spred1 model plus matched human cognitive-electrophysiological phenotyping
    description: >-
      Repeat the CA1 LTP/LTD and Morris water maze characterization in
      Spred1(+/-) animals to test whether the phenotype survives at the dosage
      that models human disease, and pair this with a prospective human cohort
      combining standardized neuropsychological testing, ADHD assessment, and
      non-invasive plasticity readouts in SPRED1 carriers versus NF1-matched and
      unaffected controls.
notes: >-
  Naming: the disorder was described in 2007 as an "NF1-like syndrome" (NFLS).
  The eponym "Legius syndrome" was subsequently proposed and widely adopted
  because reference to NF1 in the name was thought to confuse families about
  prognosis. The 2021 international consensus group considered classifying it as
  an NF1 subtype and explicitly rejected this, reasoning that in the absence of
  neurofibromas it is inappropriate to consider it a type of neurofibromatosis;
  the group did, however, note that a more appropriate nomenclature for the
  neurofibromatosis family as a whole remains a future task.

  Relationship to NF1 at the mechanistic level: Legius syndrome and NF1 are not
  merely phenotypic look-alikes but converge on the same molecular step. SPRED1
  recruits neurofibromin to activated RAS at the plasma membrane; NF1 encodes
  neurofibromin itself. Losing either protein impairs GAP-mediated RAS
  inactivation. The clinical divergence — pigmentary-only versus tumor-prone —
  therefore reflects a quantitative and cell-type-dependent difference in the
  severity of RAS dysregulation rather than involvement of a different pathway.

  Grouping: this entry uses the free-text `RASopathy` parent tag established by
  the Noonan, Costello, and cardiofaciocutaneous entries. A dedicated
  `kb/groupings/RASopathies.yaml` grouping is a reasonable follow-up now that
  enough RASopathy entries exist, but is intentionally out of scope here.
references:
- reference: PMID:20945555
  title: "Legius Syndrome."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20945555
Legius Syndrome.
No top-level findings curated for this source.