Neurofibromatosis-Noonan Syndrome

Genetic MONDO:0011035 Pathograph 6 Show in embeddings browser RASopathy

Neurofibromatosis-Noonan syndrome (NFNS; OMIM:601321) is a rare RASopathy of the RAS-MAPK signaling pathway that combines clinical features of neurofibromatosis type 1 (NF1) - multiple cafe-au-lait macules, skinfold freckling, Lisch nodules, and neurofibromas - with features of Noonan syndrome (NS), including short stature, the characteristic Noonan-like facial dysmorphism (hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly rotated ears), a broad or webbed neck, pectus deformity, and congenital heart defects such as pulmonic valve stenosis. Heterozygous germline NF1 loss-of-function variants are the major molecular cause, so NFNS is best understood as a phenotypic variant of NF1 rather than a distinct gene disorder; loss of the neurofibromin RAS-GTPase activating protein removes restraint on RAS, producing constitutive RAS-MAPK signaling that drives both the NF1 pigmentary/tumor features and the Noonan-like developmental phenotype. Because NF1, NS, and NFNS overlap clinically, molecular genetic testing is often required for a correct diagnosis.

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1
Mappings
1
Inheritance
5
Pathophys.
12
Phenotypes
6
Pathograph
1
Genes
3
Medical Actions
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
🔗

Mappings

MONDO
MONDO:0011035 neurofibromatosis-Noonan syndrome
skos:exactMatch ORPHA:638
Orphanet lists MONDO:0011035 as the cross-reference for neurofibromatosis-Noonan syndrome.
👪

Inheritance

1
Autosomal Dominant HP:0000006
NFNS is inherited in an autosomal dominant pattern, following the inheritance of its underlying NF1 gene defect; it occurs both in familial NF1 pedigrees and as de novo NF1 variants.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:16380919 SUPPORT Human Clinical
"These results support the view that NFNS represents a variant of NF1 and is caused by mutations of the NF1 gene"
NFNS is an allelic variant of autosomal dominant NF1, inheriting the NF1 mode of transmission.
⚙

Pathophysiology

5
Neurofibromin RAS-GAP Loss
Germline heterozygous NF1 loss-of-function variants reduce neurofibromin dosage. Neurofibromin is a RAS-GTPase activating protein (RAS-GAP) that accelerates hydrolysis of active RAS-GTP to inactive RAS-GDP. Reduced neurofibromin function removes this negative restraint on RAS, the shared initiating lesion of NFNS.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. 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.
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.
regulation of Ras protein signal transduction GO:0046578 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of Ras protein signal transduction (GO:0046578). GO:0046578 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
RAS-MAPK Pathway Hyperactivation Loss of neurofibromin RAS-GAP activity increases RAS effector signaling.
Show evidence (1 reference)
PMID:25877329 SUPPORT Human Clinical
"The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS-MAPK signalling, causing related diseases collectively known as RASopathies."
Establishes neurofibromin as the RAS-GAP whose loss drives RAS-MAPK signaling in the RASopathy spectrum that includes NFNS.
RAS-MAPK Pathway Hyperactivation
Reduced neurofibromin allows prolonged RAS-GTP accumulation and constitutive activation of the RAS-RAF-MEK-ERK cascade. This single biochemical derangement produces the dual clinical output of NFNS: the NF1 pigmentary and tumor features and the Noonan-like developmental phenotype, reflecting the convergence of the RASopathies on RAS-MAPK dysregulation.
Ras protein signal transduction GO:0007265 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Ras protein signal transduction (GO:0007265). GO:0007265 is a biological process from the Gene Ontology. ↑ INCREASED MAPK cascade GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased MAPK cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Melanocyte Pigmentation Program Activation RAS-MAPK hyperactivation drives cafe-au-lait macule and freckling formation.
Schwann Cell Neurofibroma Initiation RAS-MAPK hyperactivation in the Schwann cell lineage initiates neurofibromas.
RASopathy Developmental Program Excess RAS-MAPK signaling perturbs growth, craniofacial, and cardiac development.
Show evidence (1 reference)
PMID:37878067 SUPPORT Human Clinical
"neurofibromatosis/Noonan syndrome which is an accepted variant of NF-1 with clinical features of both NF-1 and Noonan syndrome caused by dysregulation of the RAS-MAPK pathway."
Attributes the combined NFNS phenotype to RAS-MAPK pathway dysregulation.
Melanocyte Pigmentation Program Activation
NF1-deficient melanocytes with hyperactive RAS-MAPK signaling upregulate melanin synthesis programs, producing the multiple cafe-au-lait macules and skinfold freckling that are the most consistent NFNS features.
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.
melanin biosynthetic process GO:0042438 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased melanin biosynthetic process (GO:0042438). GO:0042438 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:39643432 SUPPORT Human Clinical
"The hallmark features of NFNS at diagnosis were 'café au lait' macules, typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad neck and lentigines."
Cafe-au-lait macules are the hallmark pigmentary feature of NFNS.
Schwann Cell Neurofibroma Initiation
RAS-MAPK hyperactivation in the Schwann cell lineage can initiate cutaneous, subcutaneous, and plexiform neurofibromas. Neurofibromas are the hallmark that distinguishes NFNS from the other RASopathies, in which nerve sheath tumors are otherwise rare, and reflect the NF1-driven basis of NFNS.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
Ras protein signal transduction GO:0007265 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Ras protein signal transduction (GO:0007265). GO:0007265 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:39006611 SUPPORT Human Clinical
"Neurofibromas, as a hallmark of NF1, are extremely rare in patients with other RASopathies."
Neurofibromas are essentially NF1-lineage specific among RASopathies, consistent with the NF1-driven basis of NFNS.
RASopathy Developmental Program
Excess RAS-MAPK signaling during development produces the Noonan-overlapping features of NFNS: postnatal short stature, the characteristic Noonan-like facial dysmorphism, a broad/webbed neck, pectus deformity, and congenital heart defects, most characteristically pulmonic valve stenosis.
regulation of ERK1 and ERK2 cascade GO:0070372 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of ERK1 and ERK2 cascade (GO:0070372). GO:0070372 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:40289159 SUPPORT Human Clinical
"CHM were found in 19.2% of NF-NS patients, with pulmonic stenosis present in 7.7%."
Documents congenital heart malformation, including pulmonic stenosis, as a developmental output of the RASopathy program in NFNS.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Neurofibromatosis-Noonan 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

12
Cardiovascular 1
Pulmonic Stenosis OCCASIONAL HP:0001642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonic stenosis (HP:0001642). HP:0001642 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40289159 SUPPORT Human Clinical
"CHM were found in 19.2% of NF-NS patients, with pulmonic stenosis present in 7.7%."
Pulmonic stenosis was present in 7.7% of this NFNS cohort.
Eye 2
Lisch Nodules HP:0009737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lisch nodules (HP:0009737). HP:0009737 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16380919 SUPPORT Human Clinical
"Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with Noonan syndrome (NS) in some patients, which results in the so-called neurofibromatosis-Noonan syndrome (NFNS)."
NFNS carries NF1 diagnostic signs such as Lisch nodules through its phenotypic overlap with NF1.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39643432 SUPPORT Human Clinical
"The hallmark features of NFNS at diagnosis were 'café au lait' macules, typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad neck and lentigines."
Noonan-type facial dysmorphism (which includes hypertelorism) is a hallmark feature of NFNS.
Head and Neck 2
Macrocephaly FREQUENT 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:40289159 SUPPORT Human Clinical
"Macrocephaly 42.3% (11/26) 41.2% (93/226) 31.3% (787/2516) 1 0.443 0.003"
Macrocephaly occurred in 42.3% of this NFNS cohort.
Broad or Webbed Neck HP:0000465 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad/webbed neck, annotated with Webbed neck (HP:0000465). HP:0000465 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39643432 SUPPORT Human Clinical
"The hallmark features of NFNS at diagnosis were 'café au lait' macules, typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad neck and lentigines."
Broad neck is listed among the hallmark features of NFNS.
Integument 2
Multiple Cafe-au-lait Macules VERY_FREQUENT 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:40289159 SUPPORT Human Clinical
"Café au lait spots (> 5) 100% (26/26)"
All 26 patients in this prospective cohort had more than five cafe-au-lait spots, supporting a very frequent occurrence.
Neurofibromas HP:0001067 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurofibroma (HP:0001067). HP:0001067 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39643432 SUPPORT Human Clinical
"Tumours were found in 18.4% of cases."
Tumors, including neurofibromas, occur in a substantial minority of NFNS patients.
Musculoskeletal 2
Pectus Deformity 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:39643432 SUPPORT Human Clinical
"The hallmark features of NFNS at diagnosis were 'café au lait' macules, typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad neck and lentigines."
Pectus abnormalities are listed among the hallmark features of NFNS.
Scoliosis FREQUENT 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:39643432 SUPPORT Human Clinical
"Macrocephaly, scoliosis and cardiopathies occurred in 26%, 42.4% and 36.9% of cases, respectively."
Scoliosis occurred in 42.4% of NFNS cases in this systematic review.
Growth 1
Short Stature OCCASIONAL HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40289159 SUPPORT Human Clinical
"Short stature 23% (6/26) 48.7% (134/275) 17.4% (409/2346) 0.071 0.661 < 0.001"
Short stature occurred in 23% of this NFNS cohort.
Other 2
Skinfold Freckling 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:16380919 SUPPORT Human Clinical
"Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with Noonan syndrome (NS) in some patients, which results in the so-called neurofibromatosis-Noonan syndrome (NFNS)."
NFNS carries NF1 pigmentary signs such as skinfold freckling through its phenotypic overlap with NF1.
Learning Disability 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:16380919 SUPPORT Human Clinical
"Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with Noonan syndrome (NS) in some patients, which results in the so-called neurofibromatosis-Noonan syndrome (NFNS)."
NFNS overlaps NF1 and Noonan syndrome, both of which feature learning difficulties.
🧬

Genetic Associations

1
NF1 (Germline Loss-of-Function Mutations)
Gene: NF1 hgnc:7765 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NF1 (hgnc:7765). hgnc:7765 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:16380919 SUPPORT Human Clinical
"Heterozygous NF1 defects were identified in 16 of the 17 unrelated subjects included in the study, which provides evidence that mutations in NF1 represent the major molecular event underlying this condition."
Direct human cohort evidence that heterozygous NF1 variants are the major cause of NFNS.
PMID:16380919 SUPPORT Human Clinical
"a high prevalence of inframe defects affecting exons 24 and 25, which encode a portion of the GAP-related domain of the protein, was observed."
Documents the enrichment of GAP-related-domain in-frame NF1 defects in NFNS.
PMID:39643432 SUPPORT Human Clinical
"As for the genetic foundation of NFNS, NF1 gene mutations were depicted in 87.5% of individuals."
Systematic review confirms NF1 mutations underlie the large majority of NFNS cases.
💊

Medical Actions

3
Multidisciplinary Surveillance and Supportive 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 follows NF1 and Noonan syndrome supportive care: periodic cutaneous, ophthalmologic, cardiac, skeletal, and neurodevelopmental surveillance, with symptomatic management of complications.
MEK Inhibitors
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
MEK inhibitors such as selumetinib target the downstream effector of hyperactive RAS-MAPK signaling and are approved for symptomatic, inoperable plexiform neurofibromas in NF1; they are a rational option for the neurofibroma burden of NFNS given its shared NF1/RAS-MAPK basis.
Show evidence (1 reference)
PMID:33395032 SUPPORT Human Clinical
"selumetinib (Koselugo) received FDA approval for children 2 years of age and older with inoperable, symptomatic pNF."
MEK inhibition is an approved targeted therapy for plexiform neurofibromas in the NF1/RASopathy spectrum to which NFNS belongs.
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 addresses the autosomal dominant NF1-based inheritance of NFNS and the recurrence risk in affected families.
{ }

Source YAML

click to show 
name: Neurofibromatosis-Noonan Syndrome
creation_date: "2026-07-14T00:00:00Z"
category: Genetic
description: >-
  Neurofibromatosis-Noonan syndrome (NFNS; OMIM:601321) is a rare RASopathy of
  the RAS-MAPK signaling pathway that combines clinical features of
  neurofibromatosis type 1 (NF1) - multiple cafe-au-lait macules, skinfold
  freckling, Lisch nodules, and neurofibromas - with features of Noonan syndrome
  (NS), including short stature, the characteristic Noonan-like facial
  dysmorphism (hypertelorism, ptosis, downslanting palpebral fissures, low-set
  posteriorly rotated ears), a broad or webbed neck, pectus deformity, and
  congenital heart defects such as pulmonic valve stenosis. Heterozygous germline
  NF1 loss-of-function variants are the major molecular cause, so NFNS is best
  understood as a phenotypic variant of NF1 rather than a distinct gene disorder;
  loss of the neurofibromin RAS-GTPase activating protein removes restraint on
  RAS, producing constitutive RAS-MAPK signaling that drives both the NF1
  pigmentary/tumor features and the Noonan-like developmental phenotype. Because
  NF1, NS, and NFNS overlap clinically, molecular genetic testing is often
  required for a correct diagnosis.
disease_term:
  preferred_term: neurofibromatosis-Noonan syndrome
  term:
    id: MONDO:0011035
    label: neurofibromatosis-Noonan syndrome
parents:
- RASopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011035
      label: neurofibromatosis-Noonan syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:638
    mapping_justification: Orphanet lists MONDO:0011035 as the cross-reference for neurofibromatosis-Noonan syndrome.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:37878067
      reference_title: "A bicarotid trunk with associated right retroesophageal subclavian artery in a child with neurofibromatosis type 1 complicated by a left hemispheric stroke."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        there is a recognized condition known as neurofibromatosis/Noonan
        syndrome which is an accepted variant of NF-1 with clinical features of
        both NF-1 and Noonan syndrome caused by dysregulation of the RAS-MAPK
        pathway.
      explanation: >-
        Establishes NFNS as an inherited RAS-MAPK pathway disorder, supporting a
        genetics/hereditary disease classification.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    NFNS is inherited in an autosomal dominant pattern, following the inheritance
    of its underlying NF1 gene defect; it occurs both in familial NF1 pedigrees
    and as de novo NF1 variants.
  evidence:
  - reference: PMID:16380919
    reference_title: "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results support the view that NFNS represents a variant of NF1 and
      is caused by mutations of the NF1 gene
    explanation: >-
      NFNS is an allelic variant of autosomal dominant NF1, inheriting the NF1
      mode of transmission.
genetic:
- name: NF1
  gene_term:
    preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  relationship_type: CAUSATIVE
  association: Germline Loss-of-Function Mutations
  notes: >-
    Heterozygous loss-of-function variants in NF1, which encodes the RAS-GTPase
    activating protein neurofibromin, are the major molecular cause of NFNS. A
    notable enrichment of in-frame defects affecting the GAP-related domain
    (exons 24-25 in older nomenclature) has been reported in NFNS cohorts. PTPN11
    mutations, the most common cause of classic Noonan syndrome, are typically
    absent, indicating that NFNS and NS are genetically distinct.
  evidence:
  - reference: PMID:16380919
    reference_title: "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous NF1 defects were identified in 16 of the 17 unrelated
      subjects included in the study, which provides evidence that mutations in
      NF1 represent the major molecular event underlying this condition.
    explanation: >-
      Direct human cohort evidence that heterozygous NF1 variants are the major
      cause of NFNS.
  - reference: PMID:16380919
    reference_title: "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a high prevalence of inframe defects affecting exons 24 and 25, which
      encode a portion of the GAP-related domain of the protein, was observed.
    explanation: >-
      Documents the enrichment of GAP-related-domain in-frame NF1 defects in NFNS.
  - reference: PMID:39643432
    reference_title: "Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As for the genetic foundation of NFNS, NF1 gene mutations were depicted in
      87.5% of individuals.
    explanation: >-
      Systematic review confirms NF1 mutations underlie the large majority of NFNS cases.
pathophysiology:
- name: Neurofibromin RAS-GAP Loss
  description: >-
    Germline heterozygous NF1 loss-of-function variants reduce neurofibromin
    dosage. Neurofibromin is a RAS-GTPase activating protein (RAS-GAP) that
    accelerates hydrolysis of active RAS-GTP to inactive RAS-GDP. Reduced
    neurofibromin function removes this negative restraint on RAS, the shared
    initiating lesion of NFNS.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  biological_processes:
  - preferred_term: regulation of Ras protein signal transduction
    modifier: DECREASED
    term:
      id: GO:0046578
      label: regulation of Ras protein signal transduction
  genes:
  - preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  evidence:
  - reference: PMID:25877329
    reference_title: "A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin
      and is one of several genes that (when mutant) affect RAS-MAPK signalling,
      causing related diseases collectively known as RASopathies.
    explanation: >-
      Establishes neurofibromin as the RAS-GAP whose loss drives RAS-MAPK
      signaling in the RASopathy spectrum that includes NFNS.
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: Loss of neurofibromin RAS-GAP activity increases RAS effector signaling.
    causal_link_type: DIRECT
- name: RAS-MAPK Pathway Hyperactivation
  description: >-
    Reduced neurofibromin allows prolonged RAS-GTP accumulation and constitutive
    activation of the RAS-RAF-MEK-ERK cascade. This single biochemical
    derangement produces the dual clinical output of NFNS: the NF1 pigmentary
    and tumor features and the Noonan-like developmental phenotype, reflecting
    the convergence of the RASopathies on RAS-MAPK dysregulation.
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  evidence:
  - reference: PMID:37878067
    reference_title: "A bicarotid trunk with associated right retroesophageal subclavian artery in a child with neurofibromatosis type 1 complicated by a left hemispheric stroke."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neurofibromatosis/Noonan syndrome which is an accepted variant of NF-1
      with clinical features of both NF-1 and Noonan syndrome caused by
      dysregulation of the RAS-MAPK pathway.
    explanation: >-
      Attributes the combined NFNS phenotype to RAS-MAPK pathway dysregulation.
  downstream:
  - target: Melanocyte Pigmentation Program Activation
    description: RAS-MAPK hyperactivation drives cafe-au-lait macule and freckling formation.
    causal_link_type: DIRECT
  - target: Schwann Cell Neurofibroma Initiation
    description: RAS-MAPK hyperactivation in the Schwann cell lineage initiates neurofibromas.
    causal_link_type: DIRECT
  - target: RASopathy Developmental Program
    description: Excess RAS-MAPK signaling perturbs growth, craniofacial, and cardiac development.
    causal_link_type: DIRECT
- name: Melanocyte Pigmentation Program Activation
  description: >-
    NF1-deficient melanocytes with hyperactive RAS-MAPK signaling upregulate
    melanin synthesis programs, producing the multiple cafe-au-lait macules and
    skinfold freckling that are the most consistent NFNS features.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  biological_processes:
  - preferred_term: melanin biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0042438
      label: melanin biosynthetic process
  evidence:
  - reference: PMID:39643432
    reference_title: "Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hallmark features of NFNS at diagnosis were 'café au lait' macules,
      typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad
      neck and lentigines.
    explanation: >-
      Cafe-au-lait macules are the hallmark pigmentary feature of NFNS.
- name: Schwann Cell Neurofibroma Initiation
  description: >-
    RAS-MAPK hyperactivation in the Schwann cell lineage can initiate cutaneous,
    subcutaneous, and plexiform neurofibromas. Neurofibromas are the hallmark
    that distinguishes NFNS from the other RASopathies, in which nerve sheath
    tumors are otherwise rare, and reflect the NF1-driven basis of NFNS.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  evidence:
  - reference: PMID:39006611
    reference_title: "Orbital and Lumbosacral Plexiform Neurofibroma with PTPN11 Mutation: A Form of the RASopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurofibromas, as a hallmark of NF1, are extremely rare in patients with
      other RASopathies.
    explanation: >-
      Neurofibromas are essentially NF1-lineage specific among RASopathies,
      consistent with the NF1-driven basis of NFNS.
- name: RASopathy Developmental Program
  description: >-
    Excess RAS-MAPK signaling during development produces the Noonan-overlapping
    features of NFNS: postnatal short stature, the characteristic Noonan-like
    facial dysmorphism, a broad/webbed neck, pectus deformity, and congenital
    heart defects, most characteristically pulmonic valve stenosis.
  biological_processes:
  - preferred_term: regulation of ERK1 and ERK2 cascade
    modifier: INCREASED
    term:
      id: GO:0070372
      label: regulation of ERK1 and ERK2 cascade
  evidence:
  - reference: PMID:40289159
    reference_title: "Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHM were found in 19.2% of NF-NS patients, with pulmonic stenosis present
      in 7.7%.
    explanation: >-
      Documents congenital heart malformation, including pulmonic stenosis, as a
      developmental output of the RASopathy program in NFNS.
phenotypes:
- category: Integumentary
  name: Multiple Cafe-au-lait Macules
  description: >-
    Multiple cafe-au-lait macules are the most consistent feature of NFNS,
    present in essentially all patients and shared with NF1.
  phenotype_term:
    preferred_term: Multiple cafe-au-lait spots
    term:
      id: HP:0007565
      label: Multiple cafe-au-lait spots
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40289159
    reference_title: "Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Café au lait spots (> 5) 100% (26/26)"
    explanation: >-
      All 26 patients in this prospective cohort had more than five cafe-au-lait
      spots, supporting a very frequent occurrence.
- category: Integumentary
  name: Skinfold Freckling
  description: >-
    Axillary and inguinal (skinfold) freckling, an NF1 pigmentary sign, is part
    of the NFNS phenotype through its overlap with NF1.
  phenotype_term:
    preferred_term: Axillary freckling
    term:
      id: HP:0000997
      label: Axillary freckling
  evidence:
  - reference: PMID:16380919
    reference_title: "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with
      Noonan syndrome (NS) in some patients, which results in the so-called
      neurofibromatosis-Noonan syndrome (NFNS).
    explanation: >-
      NFNS carries NF1 pigmentary signs such as skinfold freckling through its
      phenotypic overlap with NF1.
- category: Neoplastic
  name: Neurofibromas
  description: >-
    Cutaneous, subcutaneous, and plexiform neurofibromas occur in NFNS and are
    the tumor feature that ties NFNS to NF1 rather than to classic Noonan syndrome.
  phenotype_term:
    preferred_term: Neurofibroma
    term:
      id: HP:0001067
      label: Neurofibroma
  evidence:
  - reference: PMID:39643432
    reference_title: "Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tumours were found in 18.4% of cases.
    explanation: >-
      Tumors, including neurofibromas, occur in a substantial minority of NFNS patients.
- category: Ophthalmologic
  name: Lisch Nodules
  description: >-
    Iris Lisch nodules, an NF1 diagnostic sign, are reported in NFNS through its
    overlap with NF1.
  phenotype_term:
    preferred_term: Lisch nodules
    term:
      id: HP:0009737
      label: Lisch nodules
  evidence:
  - reference: PMID:16380919
    reference_title: "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with
      Noonan syndrome (NS) in some patients, which results in the so-called
      neurofibromatosis-Noonan syndrome (NFNS).
    explanation: >-
      NFNS carries NF1 diagnostic signs such as Lisch nodules through its
      phenotypic overlap with NF1.
- category: Growth
  name: Short Stature
  description: >-
    Postnatal short stature is a Noonan-overlapping feature of NFNS.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40289159
    reference_title: "Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature 23% (6/26) 48.7% (134/275) 17.4% (409/2346) 0.071
      0.661 < 0.001
    explanation: >-
      Short stature occurred in 23% of this NFNS cohort.
- category: Craniofacial
  name: Macrocephaly
  description: >-
    Relative macrocephaly, seen in both NF1 and Noonan syndrome, is frequent in NFNS.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:40289159
    reference_title: "Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Macrocephaly 42.3% (11/26) 41.2% (93/226) 31.3% (787/2516) 1 0.443
      0.003
    explanation: >-
      Macrocephaly occurred in 42.3% of this NFNS cohort.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Hypertelorism is part of the Noonan-like facial dysmorphism of NFNS.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:39643432
    reference_title: "Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hallmark features of NFNS at diagnosis were 'café au lait' macules,
      typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad
      neck and lentigines.
    explanation: >-
      Noonan-type facial dysmorphism (which includes hypertelorism) is a
      hallmark feature of NFNS.
- category: Musculoskeletal
  name: Broad or Webbed Neck
  description: >-
    A broad or webbed neck is a Noonan-overlapping feature of NFNS.
  phenotype_term:
    preferred_term: Broad/webbed neck
    term:
      id: HP:0000465
      label: Webbed neck
  evidence:
  - reference: PMID:39643432
    reference_title: "Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hallmark features of NFNS at diagnosis were 'café au lait' macules,
      typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad
      neck and lentigines.
    explanation: >-
      Broad neck is listed among the hallmark features of NFNS.
- category: Musculoskeletal
  name: Pectus Deformity
  description: >-
    Pectus abnormalities (excavatum or carinatum), typical of Noonan syndrome,
    are part of the NFNS phenotype.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:39643432
    reference_title: "Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hallmark features of NFNS at diagnosis were 'café au lait' macules,
      typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad
      neck and lentigines.
    explanation: >-
      Pectus abnormalities are listed among the hallmark features of NFNS.
- category: Cardiovascular
  name: Pulmonic Stenosis
  description: >-
    Congenital heart defects, most characteristically pulmonic valve stenosis,
    reflect the Noonan/RASopathy contribution to NFNS.
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40289159
    reference_title: "Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHM were found in 19.2% of NF-NS patients, with pulmonic stenosis present
      in 7.7%.
    explanation: >-
      Pulmonic stenosis was present in 7.7% of this NFNS cohort.
- category: Musculoskeletal
  name: Scoliosis
  description: >-
    Scoliosis, seen in NF1, occurs frequently in NFNS.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:39643432
    reference_title: "Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Macrocephaly, scoliosis and cardiopathies occurred in 26%, 42.4% and 36.9%
      of cases, respectively.
    explanation: >-
      Scoliosis occurred in 42.4% of NFNS cases in this systematic review.
- category: Neurologic
  name: Learning Disability
  description: >-
    Specific learning disabilities and cognitive difficulties, common to both
    NF1 and Noonan syndrome, are part of the NFNS neurodevelopmental profile.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: PMID:16380919
    reference_title: "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with
      Noonan syndrome (NS) in some patients, which results in the so-called
      neurofibromatosis-Noonan syndrome (NFNS).
    explanation: >-
      NFNS overlaps NF1 and Noonan syndrome, both of which feature learning
      difficulties.
treatments:
- name: Multidisciplinary Surveillance and Supportive Care
  description: >-
    Management follows NF1 and Noonan syndrome supportive care: periodic
    cutaneous, ophthalmologic, cardiac, skeletal, and neurodevelopmental
    surveillance, with symptomatic management of complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: MEK Inhibitors
  description: >-
    MEK inhibitors such as selumetinib target the downstream effector of
    hyperactive RAS-MAPK signaling and are approved for symptomatic, inoperable
    plexiform neurofibromas in NF1; they are a rational option for the
    neurofibroma burden of NFNS given its shared NF1/RAS-MAPK basis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  evidence:
  - reference: PMID:33395032
    reference_title: "MEK inhibitors in RASopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      selumetinib (Koselugo) received FDA approval for children 2 years of age
      and older with inoperable, symptomatic pNF.
    explanation: >-
      MEK inhibition is an approved targeted therapy for plexiform neurofibromas
      in the NF1/RASopathy spectrum to which NFNS belongs.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the autosomal dominant NF1-based inheritance of
    NFNS and the recurrence risk in affected families.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
notes: >-
  NFNS (OMIM:601321, Orphanet:638) should be distinguished from classic NF1,
  classic Noonan syndrome, and Legius syndrome (SPRED1). It is caused
  predominantly by NF1 variants (so is an allelic variant of NF1), whereas
  classic Noonan syndrome is most often caused by PTPN11 and Legius syndrome by
  SPRED1. Neurofibromas and Lisch nodules favor the NF1/NFNS end of the
  spectrum, while their absence with isolated pigmentary features should prompt
  consideration of Legius syndrome. This is an initial entry created to complete
  the RASopathy set alongside Noonan syndrome, Costello syndrome,
  cardiofaciocutaneous syndrome, NF1, and NSLH; it can be enriched with
  additional cohort/frequency evidence in follow-up.