CBL-related Disorder

Mendelian MONDO:0013308 Pathograph 6 Show in embeddings browser RASopathies

CBL-related disorder (also called "CBL syndrome" or Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia) is an autosomal dominant RASopathy caused by heterozygous germline missense variants in CBL, which encodes a multivalent adaptor protein and E3 ubiquitin ligase that normally down-regulates activated receptor tyrosine kinases. Loss of CBL ubiquitin-ligase function impairs receptor down-regulation and dysregulates signal flow through the RAS-MAPK pathway, the shared effector abnormality of the RASopathies. Clinically it produces a variable Noonan-syndrome-like picture - dysmorphic craniofacial features, impaired postnatal growth, developmental delay and learning difficulties, cryptorchidism, microcephaly, and hyperpigmented (café-au-lait) skin lesions - together with a characteristic predisposition to juvenile myelomonocytic leukemia (JMML) and, in some individuals, later vasculitis/vasculopathy. JMML in CBL-related disorder arises via a two-hit mechanism: the germline CBL variant is the first hit and somatic copy-neutral loss of heterozygosity at 11q23 (acquired isodisomy removing the normal CBL allele) is the positively selected second hit, and the JMML is frequently self-remitting (MONDO:0013308; OMIM:613563; CBL). This entry is one of four missing core RASopathy entries requested in issue #6206.

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1
Inheritance
4
Pathophys.
9
Phenotypes
6
Pathograph
1
Genes
2
Medical Actions
1
Differentials
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal Dominant HP:0000006
CBL-related disorder is inherited in an autosomal dominant pattern; heterozygous germline CBL missense variants are sufficient to cause the developmental phenotype, with biallelic (second-hit) inactivation required only for the JMML.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"We describe a dominant developmental disorder resulting from germline missense CBL mutations"
Documents the dominant inheritance of the germline CBL developmental disorder.
⚙

Pathophysiology

4
CBL Loss-of-Function and Impaired E3 Ubiquitin Ligase Activity
Heterozygous germline missense variants cluster in the RING finger domain of CBL (and the linker connecting it to the N-terminal tyrosine-kinase-binding domain), the same mutational hot spot seen in myeloid malignancies. CBL is an E3 ubiquitin ligase, so these variants impair its ubiquitin-ligase function - the molecular starting point of the disorder.
CBL hgnc:1541 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CBL (hgnc:1541). hgnc:1541 is a gene from the HUGO Gene Nomenclature Committee.
protein ubiquitination GO:0016567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein ubiquitination (GO:0016567). GO:0016567 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Receptor Tyrosine Kinase Down-Regulation Because CBL ubiquitinates activated receptor tyrosine kinases to target them for down-regulation, loss of CBL ligase function leaves receptors inappropriately active.
Show evidence (2 references)
PMID:20694012 SUPPORT Other
"CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase."
Establishes CBL as an E3 ubiquitin ligase, the function impaired by pathogenic variants.
PMID:20619386 SUPPORT Human Clinical
"Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies."
Localizes the germline missense variants to the RING finger / linker region that controls CBL's ubiquitin-ligase activity.
Impaired Receptor Tyrosine Kinase Down-Regulation
CBL normally controls proliferative signalling by ubiquitinating and down-regulating growth-factor (receptor tyrosine kinase) signalling cascades. When CBL ligase function is lost, this negative feedback fails and receptor-driven signalling persists, feeding forward into the RAS-MAPK pathway.
Downstream
RAS-MAPK Pathway Hyperactivation Sustained receptor signalling from failed CBL-mediated down-regulation dysregulates signal flow through RAS, raising downstream MAPK/ERK output.
Show evidence (1 reference)
PMID:20543203 SUPPORT Other
"CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types."
Establishes CBL's physiological role in down-regulating growth-factor receptor signalling, the control lost in CBL-related disorder.
RAS-MAPK Pathway Hyperactivation
Failed receptor down-regulation dysregulates RAS and increases downstream ERK/MAPK signalling. This is the shared effector abnormality of the RASopathies; germline CBL variants produce developmental and tumorigenic consequences that resemble other disorders of hyperactive RAS/RAF/MEK/ERK signalling.
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
Somatic Second Hit and JMML Predisposition In hematopoietic cells, biallelic CBL loss produces cytokine-independent growth and constitutive activation of ERK/AKT/S6, driving the myelomonocytic proliferation of JMML.
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling"
Frames CBL-related disorder within the hyperactive RAS/RAF/MEK/ERK (RAS-MAPK) RASopathy spectrum.
Somatic Second Hit and JMML Predisposition
JMML in CBL-related disorder follows a two-hit pattern: the germline CBL variant is the first hit, and somatic copy-neutral loss of heterozygosity of the 11q23 region (acquired isodisomy removing the normal CBL allele) is the positively selected second hit in the leukemic clone. The resulting JMML is frequently self-remitting, though vasculitis may emerge later.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
Downstream
Late Vasculitis/Vasculopathy Some individuals whose JMML regresses spontaneously subsequently develop vasculitis, a recognized late complication of the disorder.
Show evidence (3 references)
PMID:20543203 SUPPORT Human Clinical
"The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells."
Establishes the germline-first-hit / somatic-second-hit mechanism of JMML in CBL-related disorder.
PMID:20543203 SUPPORT Human Clinical
"copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated."
Identifies 11q23 copy-neutral loss of heterozygosity (acquired isodisomy) at the CBL locus as the somatic second hit.
PMID:20694012 SUPPORT Human Clinical
"JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy."
Confirms somatic loss of the normal CBL allele via acquired isodisomy in JMML specimens.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (1):
  • Target 'Late Vasculitis/Vasculopathy' (from 'Somatic Second Hit and JMML Predisposition') not found in named elements
Pathograph: causal mechanism network for CBL-related Disorder 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

9
Cardiovascular 1
Vasculitis HP:0002633 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vasculitis (HP:0002633). HP:0002633 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life."
Supports later-onset vasculitis as part of the natural history of the disorder.
Genitourinary 1
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia"
Lists cryptorchidism among the defining developmental abnormalities of the disorder.
Head and Neck 2
Facial Dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Noonan-like facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20543203 SUPPORT Human Clinical
"The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated."
Supports dysmorphic features as part of the delineated CBL-related disorder phenotype.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20543203 SUPPORT Human Clinical
"The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated."
Supports microcephaly as a feature of CBL-related disorder.
Integument 1
Hyperpigmented Skin Lesions Hyperpigmentation of the skin HP:0000953 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperpigmented (café-au-lait) skin lesions, annotated with Hyperpigmentation of the skin (HP:0000953). HP:0000953 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20543203 SUPPORT Human Clinical
"The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated."
Supports hyperpigmented skin lesions as a feature of CBL-related disorder.
Nervous System 1
Developmental Delay Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia"
Lists developmental delay among the defining developmental abnormalities of the disorder.
Growth 1
Postnatal Growth Retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20543203 SUPPORT Human Clinical
"Learning difficulties and postnatal growth retardation may be part of the phenotype."
Supports postnatal growth retardation as part of the phenotype.
Other 2
Learning Difficulties Specific learning disability HP:0001328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Learning difficulties, annotated with Specific learning disability (HP:0001328). HP:0001328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20543203 SUPPORT Human Clinical
"Learning difficulties and postnatal growth retardation may be part of the phenotype."
Supports learning difficulties as part of the CBL-related disorder phenotype.
Juvenile Myelomonocytic Leukemia Predisposition HP:0012209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Predisposition to juvenile myelomonocytic leukemia, annotated with Juvenile myelomonocytic leukemia (HP:0012209). HP:0012209 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia"
Establishes the predisposition to juvenile myelomonocytic leukemia as a defining feature.
🧬

Genetic Associations

1
CBL (Heterozygous Germline Missense Variants)
Gene: CBL hgnc:1541 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CBL (hgnc:1541). hgnc:1541 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:20694012 SUPPORT Human Clinical
"a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia"
Identifies germline missense CBL variants as the cause of this dominant developmental disorder.
PMID:20619386 SUPPORT Human Clinical
"Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies."
Localizes the causal germline missense variants to the RING finger / linker region of CBL.
💊

Medical Actions

2
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 recurrence risk and the prognostic implications of a confirmed CBL variant, including JMML predisposition.
Hematologic 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
Because JMML in CBL-related disorder is frequently self-remitting, management emphasizes hematologic monitoring and supportive care, reserving intensive therapy (e.g., hematopoietic stem cell transplantation) for aggressive or progressive disease, alongside multidisciplinary developmental support.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from CBL-related Disorder:

Noonan syndrome MONDO:0018997
Overlapping Features Noonan syndrome is the principal differential: CBL-related disorder presents with clinical features fitting or partially overlapping Noonan syndrome, the most common RASopathy. Molecular testing identifying a CBL variant (versus PTPN11, SOS1, RAF1, RIT1, or other Noonan genes) resolves the distinction, and the JMML predisposition with later vasculopathy is characteristic of the CBL phenotype.
Distinguishing Features
  • A pathogenic CBL variant supports CBL-related disorder, whereas PTPN11/SOS1/RAF1/RIT1 variants favor classic Noonan syndrome.
  • Predisposition to (often self-remitting) JMML and later vasculitis/vasculopathy is characteristic of CBL-related disorder.
Show evidence (1 reference)
PMID:20619386 SUPPORT Human Clinical
"can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family."
Establishes Noonan syndrome as the overlapping differential for CBL-related disorder.
{ }

Source YAML

click to show 
name: CBL-related Disorder
creation_date: '2026-07-12T00:00:00Z'
category: Mendelian
description: >-
  CBL-related disorder (also called "CBL syndrome" or Noonan syndrome-like
  disorder with or without juvenile myelomonocytic leukemia) is an autosomal
  dominant RASopathy caused by heterozygous germline missense variants in CBL,
  which encodes a multivalent adaptor protein and E3 ubiquitin ligase that
  normally down-regulates activated receptor tyrosine kinases. Loss of CBL
  ubiquitin-ligase function impairs receptor down-regulation and dysregulates
  signal flow through the RAS-MAPK pathway, the shared effector abnormality of
  the RASopathies. Clinically it produces a variable Noonan-syndrome-like
  picture - dysmorphic craniofacial features, impaired postnatal growth,
  developmental delay and learning difficulties, cryptorchidism, microcephaly,
  and hyperpigmented (café-au-lait) skin lesions - together with a
  characteristic predisposition to juvenile myelomonocytic leukemia (JMML) and,
  in some individuals, later vasculitis/vasculopathy. JMML in CBL-related
  disorder arises via a two-hit mechanism: the germline CBL variant is the first
  hit and somatic copy-neutral loss of heterozygosity at 11q23 (acquired
  isodisomy removing the normal CBL allele) is the positively selected second
  hit, and the JMML is frequently self-remitting (MONDO:0013308; OMIM:613563;
  CBL). This entry is one of four missing core RASopathy entries requested in
  issue #6206.
parents:
- RASopathies
disease_term:
  preferred_term: CBL-related disorder
  description: >-
    An autosomal dominant RASopathy caused by heterozygous germline missense
    variants in the CBL E3 ubiquitin ligase gene, presenting with a
    Noonan-syndrome-like developmental phenotype and a predisposition to
    juvenile myelomonocytic leukemia.
  term:
    id: MONDO:0013308
    label: CBL-related disorder
pathophysiology:
- name: CBL Loss-of-Function and Impaired E3 Ubiquitin Ligase Activity
  description: >-
    Heterozygous germline missense variants cluster in the RING finger domain of
    CBL (and the linker connecting it to the N-terminal tyrosine-kinase-binding
    domain), the same mutational hot spot seen in myeloid malignancies. CBL is
    an E3 ubiquitin ligase, so these variants impair its ubiquitin-ligase
    function - the molecular starting point of the disorder.
  genes:
  - preferred_term: CBL
    term:
      id: hgnc:1541
      label: CBL
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  downstream:
  - target: Impaired Receptor Tyrosine Kinase Down-Regulation
    description: >-
      Because CBL ubiquitinates activated receptor tyrosine kinases to target
      them for down-regulation, loss of CBL ligase function leaves receptors
      inappropriately active.
    evidence:
    - reference: PMID:20619386
      reference_title: "Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Mutations were shown to affect CBL-mediated receptor ubiquitylation and
        dysregulate signal flow through RAS.
      explanation: >-
        Demonstrates that CBL variants impair receptor ubiquitylation, the step
        required to down-regulate activated receptor tyrosine kinases.
  evidence:
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CBL encodes a member of the Cbl family of proteins, which functions as an
      E3 ubiquitin ligase.
    explanation: >-
      Establishes CBL as an E3 ubiquitin ligase, the function impaired by
      pathogenic variants.
  - reference: PMID:20619386
    reference_title: "Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations were missense changes altering evolutionarily conserved residues
      located in the RING finger domain or the linker connecting this domain to
      the N-terminal tyrosine kinase binding domain, a known mutational hot spot
      in myeloid malignancies.
    explanation: >-
      Localizes the germline missense variants to the RING finger / linker
      region that controls CBL's ubiquitin-ligase activity.
- name: Impaired Receptor Tyrosine Kinase Down-Regulation
  description: >-
    CBL normally controls proliferative signalling by ubiquitinating and
    down-regulating growth-factor (receptor tyrosine kinase) signalling
    cascades. When CBL ligase function is lost, this negative feedback fails and
    receptor-driven signalling persists, feeding forward into the RAS-MAPK
    pathway.
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: >-
      Sustained receptor signalling from failed CBL-mediated down-regulation
      dysregulates signal flow through RAS, raising downstream MAPK/ERK output.
    evidence:
    - reference: PMID:20619386
      reference_title: "Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Mutations were shown to affect CBL-mediated receptor ubiquitylation and
        dysregulate signal flow through RAS.
      explanation: >-
        Links impaired CBL-mediated receptor ubiquitylation to dysregulated RAS
        signalling.
  evidence:
  - reference: PMID:20543203
    reference_title: "Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls
      proliferative signalling networks by downregulating the growth factor
      receptor signalling cascades in various cell types.
    explanation: >-
      Establishes CBL's physiological role in down-regulating growth-factor
      receptor signalling, the control lost in CBL-related disorder.
- name: RAS-MAPK Pathway Hyperactivation
  description: >-
    Failed receptor down-regulation dysregulates RAS and increases downstream
    ERK/MAPK signalling. This is the shared effector abnormality of the
    RASopathies; germline CBL variants produce developmental and tumorigenic
    consequences that resemble other disorders of hyperactive RAS/RAF/MEK/ERK
    signalling.
  biological_processes:
  - preferred_term: Ras protein signal transduction
    term:
      id: GO:0007265
      label: Ras protein signal transduction
    modifier: INCREASED
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: INCREASED
  downstream:
  - target: Somatic Second Hit and JMML Predisposition
    description: >-
      In hematopoietic cells, biallelic CBL loss produces cytokine-independent
      growth and constitutive activation of ERK/AKT/S6, driving the
      myelomonocytic proliferation of JMML.
    evidence:
    - reference: PMID:20694012
      reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        induces cytokine-independent growth and constitutive phosphorylation of
        ERK, AKT and S6 only in hematopoietic cells in which normal Cbl
        expression is reduced by RNA interference.
      explanation: >-
        Shows that biallelic CBL loss drives cytokine-independent hematopoietic
        growth with constitutive ERK/AKT/S6 activation.
  evidence:
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      germline CBL mutations have developmental, tumorigenic and functional
      consequences that resemble disorders that are caused by hyperactive
      Ras/Raf/MEK/ERK signaling
    explanation: >-
      Frames CBL-related disorder within the hyperactive RAS/RAF/MEK/ERK
      (RAS-MAPK) RASopathy spectrum.
- name: Somatic Second Hit and JMML Predisposition
  description: >-
    JMML in CBL-related disorder follows a two-hit pattern: the germline CBL
    variant is the first hit, and somatic copy-neutral loss of heterozygosity of
    the 11q23 region (acquired isodisomy removing the normal CBL allele) is the
    positively selected second hit in the leukemic clone. The resulting JMML is
    frequently self-remitting, though vasculitis may emerge later.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  downstream:
  - target: Late Vasculitis/Vasculopathy
    description: >-
      Some individuals whose JMML regresses spontaneously subsequently develop
      vasculitis, a recognized late complication of the disorder.
    evidence:
    - reference: PMID:20694012
      reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Some individuals experienced spontaneous regression of their JMML but
        developed vasculitis later in life.
      explanation: >-
        Documents spontaneous JMML regression followed by later-onset
        vasculitis.
  evidence:
  - reference: PMID:20543203
    reference_title: "Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The germline mutation represents the first hit, with somatic loss of
      heterozygosity being the second hit positively selected in JMML cells.
    explanation: >-
      Establishes the germline-first-hit / somatic-second-hit mechanism of JMML
      in CBL-related disorder.
  - reference: PMID:20543203
    reference_title: "Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      copy neutral loss of heterozygosity of the 11q23 chromosomal region,
      encompassing the CBL locus, was demonstrated.
    explanation: >-
      Identifies 11q23 copy-neutral loss of heterozygosity (acquired isodisomy)
      at the CBL locus as the somatic second hit.
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      JMML specimens from affected children show loss of the normal CBL allele
      through acquired isodisomy.
    explanation: >-
      Confirms somatic loss of the normal CBL allele via acquired isodisomy in
      JMML specimens.
phenotypes:
- category: Craniofacial
  name: Facial Dysmorphism
  phenotype_term:
    preferred_term: Noonan-like facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  description: >-
    Dysmorphic craniofacial features fitting or partially overlapping Noonan
    syndrome are a core feature of the disorder.
  evidence:
  - reference: PMID:20543203
    reference_title: "Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The three patients display a variable combination of dysmorphic features,
      hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome'
      to be tentatively delineated.
    explanation: >-
      Supports dysmorphic features as part of the delineated CBL-related
      disorder phenotype.
- category: Cutaneous
  name: Hyperpigmented Skin Lesions
  phenotype_term:
    preferred_term: Hyperpigmented (café-au-lait) skin lesions
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  description: >-
    Hyperpigmented (café-au-lait) skin lesions are an ectodermal feature of the
    disorder, consistent with its RASopathy classification.
  evidence:
  - reference: PMID:20543203
    reference_title: "Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The three patients display a variable combination of dysmorphic features,
      hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome'
      to be tentatively delineated.
    explanation: >-
      Supports hyperpigmented skin lesions as a feature of CBL-related disorder.
- category: Neurologic
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  description: >-
    Microcephaly is reported as part of the delineated CBL syndrome phenotype.
  evidence:
  - reference: PMID:20543203
    reference_title: "Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The three patients display a variable combination of dysmorphic features,
      hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome'
      to be tentatively delineated.
    explanation: >-
      Supports microcephaly as a feature of CBL-related disorder.
- category: Neurodevelopmental
  name: Developmental Delay
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Developmental delay is one of the core developmental abnormalities caused by
    germline CBL variants.
  evidence:
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a dominant developmental disorder resulting from germline missense CBL
      mutations, which is characterized by impaired growth, developmental delay,
      cryptorchidism and a predisposition to juvenile myelomonocytic leukemia
    explanation: >-
      Lists developmental delay among the defining developmental abnormalities
      of the disorder.
- category: Neurodevelopmental
  name: Learning Difficulties
  phenotype_term:
    preferred_term: Learning difficulties
    term:
      id: HP:0001328
      label: Specific learning disability
  description: >-
    Learning difficulties may be part of the phenotype. Frequency band is
    intentionally omitted pending a quantitative source.
  evidence:
  - reference: PMID:20543203
    reference_title: "Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Learning difficulties and postnatal growth retardation may be part of the
      phenotype.
    explanation: >-
      Supports learning difficulties as part of the CBL-related disorder
      phenotype.
- category: Growth
  name: Postnatal Growth Retardation
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  description: >-
    Impaired postnatal growth is a recognized feature of the disorder.
  evidence:
  - reference: PMID:20543203
    reference_title: "Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Learning difficulties and postnatal growth retardation may be part of the
      phenotype.
    explanation: >-
      Supports postnatal growth retardation as part of the phenotype.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: >-
    Cryptorchidism is among the developmental abnormalities associated with
    germline CBL variants.
  evidence:
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a dominant developmental disorder resulting from germline missense CBL
      mutations, which is characterized by impaired growth, developmental delay,
      cryptorchidism and a predisposition to juvenile myelomonocytic leukemia
    explanation: >-
      Lists cryptorchidism among the defining developmental abnormalities of the
      disorder.
- category: Neoplastic
  name: Juvenile Myelomonocytic Leukemia Predisposition
  phenotype_term:
    preferred_term: Predisposition to juvenile myelomonocytic leukemia
    term:
      id: HP:0012209
      label: Juvenile myelomonocytic leukemia
  description: >-
    A characteristic predisposition to juvenile myelomonocytic leukemia (JMML)
    distinguishes CBL-related disorder; the JMML is frequently self-remitting.
  evidence:
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a dominant developmental disorder resulting from germline missense CBL
      mutations, which is characterized by impaired growth, developmental delay,
      cryptorchidism and a predisposition to juvenile myelomonocytic leukemia
    explanation: >-
      Establishes the predisposition to juvenile myelomonocytic leukemia as a
      defining feature.
- category: Vascular
  name: Vasculitis
  phenotype_term:
    preferred_term: Vasculitis
    term:
      id: HP:0002633
      label: Vasculitis
  description: >-
    Vasculitis is a recognized later-life complication, sometimes emerging after
    spontaneous regression of JMML.
  evidence:
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals experienced spontaneous regression of their JMML but
      developed vasculitis later in life.
    explanation: >-
      Supports later-onset vasculitis as part of the natural history of the
      disorder.
genetic:
- name: CBL
  gene_term:
    preferred_term: CBL
    term:
      id: hgnc:1541
      label: CBL
  association: Heterozygous Germline Missense Variants
  notes: >-
    CBL (chromosome 11q23.3) encodes a multivalent adaptor protein with E3
    ubiquitin ligase activity. Heterozygous germline missense variants in the
    RING finger domain or the adjacent linker region (a mutational hot spot also
    seen in myeloid malignancies) cause CBL-related disorder. The recurrent
    p.Y371H substitution is a common allele. In JMML, the germline variant is the
    first hit and somatic copy-neutral loss of heterozygosity at 11q23 (acquired
    isodisomy) is the second hit.
  evidence:
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a dominant developmental disorder resulting from germline missense CBL
      mutations, which is characterized by impaired growth, developmental delay,
      cryptorchidism and a predisposition to juvenile myelomonocytic leukemia
    explanation: >-
      Identifies germline missense CBL variants as the cause of this dominant
      developmental disorder.
  - reference: PMID:20619386
    reference_title: "Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations were missense changes altering evolutionarily conserved residues
      located in the RING finger domain or the linker connecting this domain to
      the N-terminal tyrosine kinase binding domain, a known mutational hot spot
      in myeloid malignancies.
    explanation: >-
      Localizes the causal germline missense variants to the RING finger /
      linker region of CBL.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    CBL-related disorder is inherited in an autosomal dominant pattern;
    heterozygous germline CBL missense variants are sufficient to cause the
    developmental phenotype, with biallelic (second-hit) inactivation required
    only for the JMML.
  evidence:
  - reference: PMID:20694012
    reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a dominant developmental disorder resulting from germline
      missense CBL mutations
    explanation: >-
      Documents the dominant inheritance of the germline CBL developmental
      disorder.
differential_diagnoses:
- name: Noonan syndrome
  disease_term:
    preferred_term: Noonan syndrome
    term:
      id: MONDO:0018997
      label: Noonan syndrome
  description: >-
    Noonan syndrome is the principal differential: CBL-related disorder presents
    with clinical features fitting or partially overlapping Noonan syndrome, the
    most common RASopathy. Molecular testing identifying a CBL variant (versus
    PTPN11, SOS1, RAF1, RIT1, or other Noonan genes) resolves the distinction,
    and the JMML predisposition with later vasculopathy is characteristic of the
    CBL phenotype.
  distinguishing_features:
  - A pathogenic CBL variant supports CBL-related disorder, whereas PTPN11/SOS1/RAF1/RIT1 variants favor classic Noonan syndrome.
  - Predisposition to (often self-remitting) JMML and later vasculitis/vasculopathy is characteristic of CBL-related disorder.
  evidence:
  - reference: PMID:20619386
    reference_title: "Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      can underlie a phenotype with clinical features fitting or partially
      overlapping Noonan syndrome (NS), the most common condition of this
      disease family.
    explanation: >-
      Establishes Noonan syndrome as the overlapping differential for
      CBL-related disorder.
treatments:
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the autosomal dominant recurrence risk and the
    prognostic implications of a confirmed CBL variant, including JMML
    predisposition.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Hematologic Surveillance and Supportive Care
  description: >-
    Because JMML in CBL-related disorder is frequently self-remitting,
    management emphasizes hematologic monitoring and supportive care, reserving
    intensive therapy (e.g., hematopoietic stem cell transplantation) for
    aggressive or progressive disease, alongside multidisciplinary developmental
    support.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:20694012
      reference_title: "Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a dominant developmental disorder resulting from germline
        missense CBL mutations
      explanation: >-
        Supports classification as an inherited (germline, autosomal dominant)
        RAS-MAPK pathway genetic disorder.