Legius Syndrome

Genetic MONDO:0012669 Pathograph 4 Show in embeddings browser RASopathy

Legius syndrome (LGSS, also called neurofibromatosis type 1-like syndrome) is an autosomal dominant RASopathy of the RAS-MAPK pathway caused by heterozygous loss-of-function variants in SPRED1. It clinically overlaps the pigmentary features of neurofibromatosis type 1 (NF1) - multiple café-au-lait macules, with or without axillary or inguinal skinfold freckling, and macrocephaly - but is distinguished by the absence of the tumor manifestations and other complications of NF1: no neurofibromas, no Lisch nodules, and no optic pathway gliomas or malignant peripheral nerve sheath tumors. Learning disability, mild cognitive impairment, and attention deficit-hyperactivity disorder occur in a subset. SPRED1 is a Sprouty-related, EVH1 domain-containing negative regulator of RAS-MAPK signaling that binds neurofibromin (the NF1 gene product) and recruits it to the plasma membrane, so SPRED1 loss and NF1 loss converge on the same pathway, explaining the phenotypic overlap. Because Legius syndrome lacks the tumor risk of NF1, distinguishing the two - typically requiring molecular testing - is the central clinical management issue.

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1
Mappings
1
Inheritance
3
Pathophys.
4
Phenotypes
4
Pathograph
1
Genes
2
Medical Actions
1
Differentials
🔗

Mappings

MONDO
MONDO:0012669 Legius syndrome
skos:exactMatch MONDO
Primary disease term for this entry.
👪

Inheritance

1
Autosomal Dominant HP:0000006
Legius syndrome is inherited in an autosomal dominant manner, caused by heterozygous pathogenic SPRED1 variants located on chromosome 15.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:17704776 SUPPORT Human Clinical
"We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder."
Establishes autosomal dominant inheritance.
⚙

Pathophysiology

3
SPRED1 Loss of Function
Legius syndrome is caused by germline heterozygous loss-of-function variants in SPRED1, a member of the SPROUTY/SPRED family that normally acts as a negative regulator of the RAS-RAF interaction and downstream MAPK signaling. Loss of SPRED1 function removes this brake on the pathway. In the affected café-au-lait melanocytes, a second somatic hit inactivating the wild-type SPRED1 allele is found, indicating that complete SPRED1 inactivation drives the pigmentary lesion.
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 MAPK cascade GO:0043409 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of MAPK cascade (GO:0043409). GO:0043409 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neurofibromin Mislocalization and Loss of RAS-GAP Recruitment Loss of SPRED1 removes the adaptor that recruits neurofibromin to the plasma membrane, impairing membrane-localized RAS-GTP hydrolysis.
Show evidence (1 reference)
PMID:17704776 SUPPORT Human Clinical
"We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder."
Establishes germline loss-of-function SPRED1 variants as the cause of the disorder.
Neurofibromin Mislocalization and Loss of RAS-GAP Recruitment
Neurofibromin, the NF1 gene product and a RAS-GTPase-activating protein, is a SPRED1-interacting partner whose inhibitory function toward RAS depends on SPRED1. SPRED1 binding induces plasma-membrane localization of neurofibromin, positioning it to down-regulate RAS-GTP. When SPRED1 is lost, neurofibromin fails to be recruited to the membrane and its RAS-inactivating activity is impaired, providing the molecular bridge that explains why SPRED1 loss (Legius syndrome) and NF1 loss (neurofibromatosis type 1) share overlapping pathophysiology.
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 (neurofibromin) hgnc:7765 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NF1 (neurofibromin), annotated with NF1 (hgnc:7765). hgnc:7765 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
RAS-MAPK Pathway Hyperactivation Impaired neurofibromin-mediated RAS-GTP hydrolysis elevates active RAS and sustains downstream MAPK signaling.
Show evidence (1 reference)
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 the shared SPRED1-neurofibromin mechanism underlying the overlap between Legius syndrome and NF1.
RAS-MAPK Pathway Hyperactivation
Like the other RASopathies, Legius syndrome results from germline dysregulation of the RAS-MAPK (RAS/ERK) signal transduction pathway. SPRED1 normally restrains RAS-RAF coupling and MAPK activation; its loss shifts the pathway toward increased signaling. This shared final common mechanism places Legius syndrome within the group of phenotypically overlapping RAS-MAPK disorders.
positive regulation of MAPK cascade GO:0043410 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. ↑ INCREASED
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 pathway dysregulation.
⬡

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.
●

Phenotypes

4
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 (1 reference)
PMID:17704776 SUPPORT Human Clinical
"consist of multiple café-au-lait spots, axillary freckling and macrocephaly"
Macrocephaly is described among the cardinal features.
Integument 1
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 spots are a cardinal feature in the original description.
Other 2
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
"consist of multiple café-au-lait spots, axillary freckling and macrocephaly"
Axillary freckling is part of the cardinal pigmentary phenotype.
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 (1 reference)
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."
Learning disability is a recognized feature of the SPRED1 NF1-like phenotype.
🧬

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.
Show evidence (1 reference)
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."
Confirms germline loss-of-function SPRED1 variants as the molecular cause in NF1-like patients without an NF1 mutation.
💊

Medical Actions

2
Genetic Counseling and Molecular Diagnosis
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 with SPRED1 molecular testing is central to management, both to confirm the diagnosis and to distinguish Legius syndrome from NF1, which carries a markedly different tumor risk and surveillance burden. Inheritance is autosomal dominant.
Show evidence (1 reference)
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."
Highlights the role of distinguishing Legius syndrome from NF1 for appropriate genetic counseling.
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 supportive and symptom-directed: developmental and educational support for learning disability/ADHD, and clinical reassurance given the absence of the tumor complications of NF1. No disease-specific pharmacotherapy exists.
🔬

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 (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"
States the consensus pigmentary and exclusion criteria used together with identification of a heterozygous pathogenic SPRED1 variant.
📊

Prevalence

1
Worldwide
Birth Prevalence 1.6 per 100,000 1–9 per 100,000
Estimated birth prevalence of 1/46,000-1/75,000 (about 4% of individuals followed at a neurofibromatosis clinic), substantially rarer than NF1 (1/2,000-1/3,000). The normalized rate shown is the midpoint of the 1/46,000-1/75,000 range.
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)"
Source for the Legius syndrome birth-prevalence estimate.
🔀

Differential Diagnoses

1

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

Neurofibromatosis type 1 MONDO:0018975
Overlapping Features NF1 shares the pigmentary presentation of Legius syndrome (multiple café-au-lait macules and skinfold freckling) but, unlike Legius syndrome, develops neurofibromas, Lisch nodules, optic pathway gliomas, and other tumor complications and carries a markedly higher tumor risk. Because roughly half of individuals with Legius syndrome would satisfy the older NIH pigmentary criteria for NF1, molecular testing (identifying a SPRED1 rather than an NF1 variant) is often required to distinguish the two; the revised international consensus criteria formalize this distinction.
Show evidence (1 reference)
PMID:34012067 SUPPORT Human Clinical
"No individuals with LGSS have developed Lisch nodules, neurofibromas, or other complications of NF1."
The absence of NF1 tumor complications is the key clinical distinction between Legius syndrome and NF1.
{ }

Source YAML

click to show 
name: Legius Syndrome
creation_date: "2026-07-13T00:00:00Z"
description: >-
  Legius syndrome (LGSS, also called neurofibromatosis type 1-like syndrome) is an
  autosomal dominant RASopathy of the RAS-MAPK pathway caused by heterozygous
  loss-of-function variants in SPRED1. It clinically overlaps the pigmentary features
  of neurofibromatosis type 1 (NF1) - multiple café-au-lait macules, with or without
  axillary or inguinal skinfold freckling, and macrocephaly - but is distinguished by
  the absence of the tumor manifestations and other complications of NF1: no
  neurofibromas, no Lisch nodules, and no optic pathway gliomas or malignant peripheral
  nerve sheath tumors. Learning disability, mild cognitive impairment, and attention
  deficit-hyperactivity disorder occur in a subset. SPRED1 is a Sprouty-related, EVH1
  domain-containing negative regulator of RAS-MAPK signaling that binds neurofibromin
  (the NF1 gene product) and recruits it to the plasma membrane, so SPRED1 loss and NF1
  loss converge on the same pathway, explaining the phenotypic overlap. Because Legius
  syndrome lacks the tumor risk of NF1, distinguishing the two - typically requiring
  molecular testing - is the central clinical management issue.
category: Genetic
parents:
- RASopathy
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.
disease_term:
  preferred_term: Legius syndrome
  description: >-
    An autosomal dominant RASopathy caused by loss-of-function SPRED1 variants,
    presenting with an NF1-like pigmentary phenotype but without the tumors and other
    complications of neurofibromatosis type 1.
  term:
    id: MONDO:0012669
    label: Legius syndrome
pathophysiology:
- name: SPRED1 Loss of Function
  description: >-
    Legius syndrome is caused by germline heterozygous loss-of-function variants in
    SPRED1, a member of the SPROUTY/SPRED family that normally acts as a negative
    regulator of the RAS-RAF interaction and downstream MAPK signaling. Loss of SPRED1
    function removes this brake on the pathway. In the affected café-au-lait
    melanocytes, a second somatic hit inactivating the wild-type SPRED1 allele is
    found, indicating that complete SPRED1 inactivation drives the pigmentary lesion.
  genes:
  - preferred_term: SPRED1
    term:
      id: hgnc:20249
      label: SPRED1
  biological_processes:
  - preferred_term: negative regulation of MAPK cascade
    term:
      id: GO:0043409
      label: negative regulation of MAPK cascade
    modifier: DECREASED
  downstream:
  - target: Neurofibromin Mislocalization and Loss of RAS-GAP Recruitment
    description: >-
      Loss of SPRED1 removes the adaptor that recruits neurofibromin to the plasma
      membrane, impairing membrane-localized RAS-GTP hydrolysis.
    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: >-
        SPRED1 loss removes the signal that localizes neurofibromin to the membrane,
        the mechanistic link to increased RAS-GTP.
  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.
    explanation: >-
      Establishes germline loss-of-function SPRED1 variants as the cause of the
      disorder.
- name: Neurofibromin Mislocalization and Loss of RAS-GAP Recruitment
  description: >-
    Neurofibromin, the NF1 gene product and a RAS-GTPase-activating protein, is a
    SPRED1-interacting partner whose inhibitory function toward RAS depends on SPRED1.
    SPRED1 binding induces plasma-membrane localization of neurofibromin, positioning
    it to down-regulate RAS-GTP. When SPRED1 is lost, neurofibromin fails to be
    recruited to the membrane and its RAS-inactivating activity is impaired, providing
    the molecular bridge that explains why SPRED1 loss (Legius syndrome) and NF1 loss
    (neurofibromatosis type 1) share overlapping pathophysiology.
  genes:
  - preferred_term: SPRED1
    term:
      id: hgnc:20249
      label: SPRED1
  - preferred_term: NF1 (neurofibromin)
    term:
      id: hgnc:7765
      label: NF1
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: >-
      Impaired neurofibromin-mediated RAS-GTP hydrolysis elevates active RAS and
      sustains downstream MAPK signaling.
    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: >-
        Here we show that neurofibromin, the NF1 gene product, is a
        Spred1-interacting protein that is necessary for Spred1's inhibitory function.
      explanation: >-
        Loss of SPRED1 impairs neurofibromin's RAS-inhibitory function, elevating RAS
        signaling.
  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: >-
      This novel mechanism for the regulation of neurofibromin provides a molecular
      bridge for understanding the overlapping pathophysiology of NF1 and Legius
      syndrome.
    explanation: >-
      Establishes the shared SPRED1-neurofibromin mechanism underlying the overlap
      between Legius syndrome and NF1.
- name: RAS-MAPK Pathway Hyperactivation
  description: >-
    Like the other RASopathies, Legius syndrome results from germline dysregulation of
    the RAS-MAPK (RAS/ERK) signal transduction pathway. SPRED1 normally restrains
    RAS-RAF coupling and MAPK activation; its loss shifts the pathway toward increased
    signaling. This shared final common mechanism places Legius syndrome within the
    group of phenotypically overlapping RAS-MAPK disorders.
  biological_processes:
  - preferred_term: positive regulation of MAPK cascade
    term:
      id: GO:0043410
      label: positive regulation of MAPK cascade
    modifier: INCREASED
  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 pathway
      dysregulation.
phenotypes:
- name: Multiple Cafe-au-lait Macules
  description: >-
    Multiple café-au-lait macules, typically six or more and bilaterally distributed,
    are the cardinal and most frequent feature, closely resembling the pigmentary
    presentation of NF1.
  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 spots are a cardinal feature in the original description.
- name: Axillary Freckling
  description: Skinfold (axillary or inguinal) freckling, a component of the NF1-like pigmentary phenotype.
  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: >-
      consist of multiple café-au-lait spots, axillary freckling and macrocephaly
    explanation: Axillary freckling is part of the cardinal pigmentary phenotype.
- name: Macrocephaly
  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 features.
- name: Specific Learning Disability
  description: >-
    Learning disability occurs in a subset of individuals, part of the mild
    neurocognitive profile that overlaps NF1.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - 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: >-
      Learning disability is a recognized feature of the SPRED1 NF1-like phenotype.
inheritance:
- name: Autosomal Dominant
  description: >-
    Legius syndrome is inherited in an autosomal dominant manner, caused by
    heterozygous pathogenic SPRED1 variants located on chromosome 15.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  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.
    explanation: Establishes autosomal dominant inheritance.
genetic:
- name: SPRED1
  gene_term:
    preferred_term: SPRED1
    term:
      id: hgnc:20249
      label: SPRED1
  association: Pathogenic Variants
  notes: >-
    Legius syndrome is caused by heterozygous loss-of-function SPRED1 variants
    (nonsense, frameshift, splice, and missense). SPRED1 encodes a Sprouty-related,
    EVH1 domain-containing negative regulator of RAS-MAPK signaling that recruits
    neurofibromin to the plasma membrane. SPRED1 variants account for roughly 1% of
    sporadic and 19% of familial cases presenting with pigmentary NF1 features
    (café-au-lait macules and freckling) only.
  evidence:
  - 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: >-
      Confirms germline loss-of-function SPRED1 variants as the molecular cause in
      NF1-like patients without an NF1 mutation.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.6
  notes: >-
    Estimated birth prevalence of 1/46,000-1/75,000 (about 4% of individuals followed
    at a neurofibromatosis clinic), substantially rarer than NF1 (1/2,000-1/3,000).
    The normalized rate shown is the midpoint of the 1/46,000-1/75,000 range.
  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: Source for the Legius syndrome birth-prevalence estimate.
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.
differential_diagnoses:
- name: Neurofibromatosis type 1
  description: >-
    NF1 shares the pigmentary presentation of Legius syndrome (multiple café-au-lait
    macules and skinfold freckling) but, unlike Legius syndrome, develops
    neurofibromas, Lisch nodules, optic pathway gliomas, and other tumor complications
    and carries a markedly higher tumor risk. Because roughly half of individuals with
    Legius syndrome would satisfy the older NIH pigmentary criteria for NF1, molecular
    testing (identifying a SPRED1 rather than an NF1 variant) is often required to
    distinguish the two; the revised international consensus criteria formalize this
    distinction.
  disease_term:
    preferred_term: neurofibromatosis type 1
    term:
      id: MONDO:0018975
      label: neurofibromatosis type 1
  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 absence of NF1 tumor complications is the key clinical distinction between
      Legius syndrome and NF1.
treatments:
- name: Genetic Counseling and Molecular Diagnosis
  description: >-
    Genetic counseling with SPRED1 molecular testing is central to management, both to
    confirm the diagnosis and to distinguish Legius syndrome from NF1, which carries a
    markedly different tumor risk and surveillance burden. Inheritance is autosomal
    dominant.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - 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: >-
      Highlights the role of distinguishing Legius syndrome from NF1 for appropriate
      genetic counseling.
- name: Supportive and Multidisciplinary Care
  description: >-
    Management is supportive and symptom-directed: developmental and educational
    support for learning disability/ADHD, and clinical reassurance given the absence of
    the tumor complications of NF1. No disease-specific pharmacotherapy exists.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
notes: >-
  Legius syndrome is one of the germline RASopathies identified in issue #6206 as
  missing from the knowledge base. Related NF1-spectrum entries already present include
  Neurofibromatosis_Type_1 and Neurofibroma. The remaining requested RASopathy entries
  (Neurofibromatosis-Noonan syndrome, CBL-related disorder) are left as follow-ups. A
  key differential is the absence of neurofibromas, Lisch nodules, optic pathway
  gliomas, and malignant peripheral nerve sheath tumors, which distinguishes Legius
  syndrome from NF1.