CBL-related Disorder

Mendelian MONDO:0013308 Pathograph 23 Show in embeddings browser RASopathy

CBL-related disorder (CBL syndrome; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, NSLL) is an autosomal dominant RASopathy caused by heterozygous germline missense, splice-site, or in-frame variants in CBL, which encodes a multivalent adaptor protein with E3 ubiquitin ligase activity that normally terminates activated receptor tyrosine kinase signaling. Pathogenic variants cluster in the RING finger domain and the adjacent linker region — the same hot spot mutated somatically in myeloid malignancy — and abolish CBL-mediated receptor ubiquitylation while also inhibiting residual wild-type CBL and CBL-B, so activated kinases escape degradation and signal flow through RAS-MAPK is prolonged. The clinical phenotype overlaps Noonan syndrome (facial dysmorphism, impaired growth, cryptorchidism, developmental delay and a relatively high frequency of neurological features, with a comparatively low prevalence of cardiac defects) and is distinguished by two characteristic non-Noonan complications: a strong predisposition to juvenile myelomonocytic leukemia (JMML), which arises when the wild-type CBL allele is lost through acquired 11q uniparental isodisomy and which frequently regresses spontaneously; and a cerebral and systemic vasculopathy that includes early-onset moyamoya arteriopathy and later-onset vasculitis. Prenatal and lymphatic manifestations (hydrops fetalis, fetal pleural effusions, chylothorax, primary lymphedema) further connect the disorder to the RASopathy family.

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1
Mappings
1
Inheritance
10
Pathophys.
18
Phenotypes
2
Gaps
23
Pathograph
1
Genes
4
Medical Actions
2
Differentials
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0013308 CBL-related disorder
skos:exactMatch MONDO
Primary disease term for this entry.
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Inheritance

1
Autosomal Dominant HP:0000006
Autosomal dominant. Both de novo occurrence (including in probands presenting with isolated moyamoya) and vertical familial transmission have been documented; the germline variant is heterozygous, with tissue-restricted loss of the wild-type allele driving the neoplastic complications.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:20694012 SUPPORT Human Clinical
"We describe a dominant developmental disorder resulting from germline missense CBL mutations"
States the dominant inheritance pattern of the disorder.
PMID:28343148 SUPPORT Human Clinical
"We identified two germline de novo mutations in CBL in two out of the four trio probands"
Documents de novo occurrence confirmed by trio sequencing.
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Discussions and Knowledge Gaps

2
Beyond juvenile myelomonocytic leukemia, what is the lifetime tumor risk in germline CBL-related disorder, and does the acquired 11q23 copy-neutral loss-of-heterozygosity mechanism predispose to germ cell tumors as a reproducible second tumor class?
KNOWLEDGE GAP OPEN gap_cbl_tumor_risk_beyond_jmml
Attached to
pathophysiology#Acquired 11q Isodisomy and Biallelic CBL Inactivation pathophysiology#Juvenile Myelomonocytic Leukemia
The same copy-neutral 11q23 LOH second hit that produces JMML has been documented in three teratomas from a single patient, which would imply a tumor-predisposition mechanism that is not tissue-restricted to the myeloid compartment. That observation rests on one case report, so the entry records the mechanism without asserting a quantified extra-hematologic tumor risk or recommending a surveillance protocol.
Proposed experiments
Prospective tumor surveillance with 11q23 LOH genotyping in a germline-CBL cohort
exp_cbl_extrahematologic_tumor_surveillance
Assemble an international registry of individuals with a confirmed germline CBL variant and follow them prospectively for any incident neoplasm. Genotype every available tumor specimen for copy-neutral loss of heterozygosity at 11q23 and for the germline allele, and compare observed tumor incidence against age- and sex-matched population rates.
Decision criterion
Recurrent non-myeloid tumors carrying the 11q23 second hit at above-background incidence would establish a broader tumor-predisposition syndrome and justify a surveillance protocol; absence of such tumors across an adequately powered cohort would confine the predisposition to the myeloid compartment.
Show evidence (1 reference)
PMID:24458550 SUPPORT INDIRECT Human Clinical
"Copy neutral loss of heterozygosity for the CBL mutation due to acquired segmental uniparental disomy of 11q23 was observed in three teratomas, suggesting a specific association of CBL mutations in germ cell tumor predisposition."
Supports the existence of the gap indirectly: the three teratomas come from a single patient, so the observation proposes rather than establishes germ cell tumor predisposition, which is why the question remains open.
What determines which germline CBL carriers develop juvenile myelomonocytic leukemia, which develop isolated early-onset moyamoya angiopathy with only subtle RASopathy signs, and which regress spontaneously versus progressing to require transplantation?
KNOWLEDGE GAP OPEN gap_cbl_phenotype_determinants
Attached to
pathophysiology#Myeloid Progenitor Cytokine Hypersensitivity pathophysiology#Cerebral and Systemic Vasculopathy pathophysiology#Juvenile Myelomonocytic Leukemia
Two probands carrying CBL variants that had previously been reported in JMML-predisposing Noonan-like disease instead presented with severe infancy-onset moyamoya and never developed leukemia, so allele identity alone does not predict which arm of the phenotype manifests. Because the management decision that matters most clinically — observe versus transplant — turns on this, the absence of a predictor is a substantive gap rather than a descriptive one.
Proposed experiments
Genotype-stratified natural history with clonal-architecture sequencing
exp_cbl_genotype_stratified_natural_history
Follow germline CBL carriers prospectively with serial blood counts and cerebrovascular imaging, stratified by germline allele. In parallel, use serial deep sequencing of hematopoietic samples to measure the timing and clone size of the acquired 11q23 second hit, and test whether second-hit kinetics rather than germline allele identity separate the leukemic, spontaneously regressing, and cerebrovascular-predominant courses.
Decision criterion
A reproducible association between second-hit timing or clone size and subsequent course would support clonal-kinetics-based risk stratification; segregation by germline allele instead would support allele-based counselling; neither would indicate an unidentified modifier.
Show evidence (2 references)
PMID:28343148 SUPPORT Human Clinical
"Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up."
Demonstrates that previously JMML-associated germline alleles can present with an essentially isolated cerebrovascular phenotype.
PMID:25952305 SUPPORT INDIRECT Human Clinical
"Genotype-phenotype correlation analysis performed on available records indicated that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac..."
Supports the gap indirectly: the best available genotype-phenotype analysis characterizes the phenotype only in aggregate, from which it follows that per-individual outcome prediction is unresolved.
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Pathophysiology

10
Germline CBL RING-Linker Variant
A heterozygous germline variant in CBL, most often a missense change altering an evolutionarily conserved residue in the RING finger domain or in the linker connecting that domain to the N-terminal tyrosine kinase binding domain. This is the same region mutated somatically in myeloid malignancies; p.Tyr371His is the recurrent hot-spot allele. Splice-site changes, an in-frame deletion, and a nonsense change generating a v-Cbl-like truncated protein have also been reported.
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.
Downstream
Loss of CBL E3 Ubiquitin Ligase Activity RING/linker variants disrupt the domain that recruits the E2 ubiquitin-conjugating enzyme, abolishing ligase function.
Show evidence (2 references)
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."
Establishes the germline variant class and its localization to the RING/linker mutational hot spot.
PMID:25952305 SUPPORT Human Clinical
"Among them, two splice-site changes, one in-frame deletion, and one missense mutation affected the RING domain and/or the adjacent linker region, overlapping cancer-associated defects."
Extends the germline allelic spectrum beyond missense while confirming the same RING/linker localization.
Loss of CBL E3 Ubiquitin Ligase Activity
Mutant CBL protein loses E3 ubiquitin ligase activity. Critically, the effect is not a simple haploinsufficiency: mutant CBL also inhibits the ligase activity of residual wild-type CBL and of the paralogue CBL-B, so a single heterozygous allele already prolongs tyrosine kinase activation after cytokine stimulation.
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.
ubiquitin protein ligase activity GO:0061630 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ubiquitin protein ligase activity (GO:0061630). GO:0061630 is a molecular function from the Gene Ontology.
Downstream
Impaired Receptor Tyrosine Kinase Downregulation Without functional Cbl-family ligase activity, activated receptor tyrosine kinases are not ubiquitylated and therefore are not sorted for degradation.
Show evidence (1 reference)
PMID:19620960 SUPPORT In Vitro
"C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation."
Demonstrates both the loss of ligase activity and its dominant-inhibitory action on the remaining wild-type ligases.
Impaired Receptor Tyrosine Kinase Downregulation
Cbl-family ligases are the dominant activation-selective ubiquitin ligases for protein tyrosine kinases, targeting activated receptors either for endocytic sorting into lysosomes or for proteasomal degradation. When this step fails, activated receptors and their signaling intermediates persist at the membrane and continue to transmit signal.
protein ubiquitination GO:0016567 ↓ DECREASED 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. receptor internalization GO:0031623 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased receptor internalization (GO:0031623). GO:0031623 is a biological process from the Gene Ontology. cell surface receptor protein tyrosine kinase signaling pathway GO:0007169 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169). GO:0007169 is a biological process from the Gene Ontology.
Downstream
RAS-MAPK Pathway Hyperactivation Persistent receptor tyrosine kinase signaling feeds prolonged flow through the RAS/RAF/MEK/ERK cascade.
Show evidence (1 reference)
PMID:23085373 SUPPORT In Vitro
"Structural, biochemical and cell biological studies have established that Cbl protein-dependent ubiquitination targets activated PTKs for degradation either by facilitating their endocytic sorting into lysosomes or by promoting their proteasomal degradation."
Establishes the normal Cbl-dependent receptor-downregulation step whose failure underlies the disorder.
RAS-MAPK Pathway Hyperactivation
The shared final common pathway of the RASopathies: enhanced and prolonged signal flow through RAS and the RAF/MEK/ERK cascade (with parallel PI3K-AKT-S6 activation), which perturbs proliferation, differentiation, and morphogenesis across many tissues.
Ras protein signal transduction GO:0007265 ↑ INCREASED 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. ERK1 and ERK2 cascade GO:0070371 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ERK1 and ERK2 cascade (GO:0070371). GO:0070371 is a biological process from the Gene Ontology.
Downstream
Developmental RASopathy Phenotype Excess RAS-MAPK signaling during development produces the Noonan-like craniofacial, growth, genital, and neurodevelopmental phenotype.
Myeloid Progenitor Cytokine Hypersensitivity In the hematopoietic compartment, failure to terminate cytokine receptor signaling lowers the threshold for progenitor proliferation.
Cerebral and Systemic Vasculopathy Prolonged RAS pathway signaling is proposed to disrupt cerebrovascular development, producing progressive stenosis of the terminal internal carotid arteries with collateral vessel formation.
Lymphatic Developmental Dysregulation The RAS/MAPK pathway is a major regulator of lymphangiogenesis; its dysregulation produces the prenatal effusion and lymphedema phenotypes shared across RASopathies.
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome."
Places CBL-related disorder in the RASopathy family by shared Ras/Raf/MEK/ERK hyperactivation.
Myeloid Progenitor Cytokine Hypersensitivity
Hematopoietic stem and progenitor cells carrying a mutant CBL allele respond to a broader spectrum of cytokines at lower concentrations, and cells in which the normal allele is additionally lost acquire outright cytokine-independent growth — the proliferative substrate for juvenile myelomonocytic leukemia.
hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology. granulocyte monocyte progenitor cell CL:0000557 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulocyte monocyte progenitor cell (CL:0000557). CL:0000557 is a cell type from the Cell Ontology.
cytokine-mediated signaling pathway GO:0019221 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cytokine-mediated signaling pathway (GO:0019221). GO:0019221 is a biological process from the Gene Ontology.
Downstream
Acquired 11q Isodisomy and Biallelic CBL Inactivation Selective pressure in the hematopoietic compartment favors clones that lose the residual wild-type CBL allele by copy-neutral loss of heterozygosity.
Show evidence (1 reference)
PMID:20694012 SUPPORT In Vitro
"the common p.371Y>H altered Cbl protein 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"
Cytokine-independent growth appears specifically in hematopoietic cells and requires reduction of the normal allele.
Acquired 11q Isodisomy and Biallelic CBL Inactivation
A somatic second hit: acquired segmental uniparental (iso)disomy of chromosome 11q23, the CBL locus, converts the germline heterozygous variant to homozygosity in the affected clone. This is the canonical two-hit step separating the germline developmental disorder from overt leukemia, and the same mechanism has been documented in CBL-associated teratomas.
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.
Downstream
Juvenile Myelomonocytic Leukemia Biallelic CBL inactivation in a hematopoietic clone drives the myeloproliferative expansion diagnosed as JMML.
Show evidence (2 references)
PMID:19571318 SUPPORT Human Clinical
"we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples"
Identifies 11q isodisomy at the CBL locus and quantifies CBL involvement in a JMML cohort.
PMID:24458550 SUPPORT Human Clinical
"Copy neutral loss of heterozygosity for the CBL mutation due to acquired segmental uniparental disomy of 11q23 was observed in three teratomas, suggesting a specific association of CBL mutations in germ cell tumor predisposition."
Shows the same copy-neutral LOH second-hit mechanism outside the myeloid compartment.
Juvenile Myelomonocytic Leukemia
An aggressive myeloproliferative neoplasm of early childhood arising in the hematopoietic stem cell compartment. In CBL-related disorder its natural history is distinctive: a substantial proportion of cases regress spontaneously without hematopoietic stem cell transplantation, and long-term survival without transplant has been documented, although affected individuals may later develop vasculitis.
granulocyte monocyte progenitor cell CL:0000557 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulocyte monocyte progenitor cell (CL:0000557). CL:0000557 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:20694012 SUPPORT Human Clinical
"Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life."
Documents the characteristic spontaneous regression and the later vasculitic complication.
PMID:26911351 SUPPORT Human Clinical
"Here we report that two JMML patients survived >20 years without HSCT and both patients had uniparental disomy of 11q23 where CBL is located"
Long-term transplant-free survival supports the indolent natural history of CBL-mutant JMML.
Cerebral and Systemic Vasculopathy
A vascular arm of the disorder that is not part of classic Noonan syndrome: progressive stenosis of the terminal internal carotid arteries with abnormal deep collateral vessels (moyamoya angiopathy), which may present in infancy, plus systemic vasculitis emerging later in life. Notably, moyamoya can be the presenting and near-isolated manifestation in individuals who never develop JMML and show only subtle RASopathy signs.
vascular associated smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology. endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Downstream
Moyamoya Angiopathy Progressive stenosis of the terminal internal carotid arteries with the abnormal deep collateral network is the cerebral expression of this vasculopathy, and can be its presenting and near-isolated manifestation.
Vasculitis The systemic arm of the same vasculopathy, emerging later in life and reported in individuals whose JMML had already regressed.
Show evidence (2 references)
PMID:28343148 SUPPORT Human Clinical
"We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA."
Establishes germline CBL variants as a cause of infancy-onset moyamoya angiopathy.
PMID:20694012 SUPPORT Human Clinical
"Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life."
Documents the later-onset systemic vasculitis arm of the vasculopathy.
Lymphatic Developmental Dysregulation
Disturbed lymphangiogenesis producing prenatal and postnatal lymphatic manifestations — hydrops fetalis, fetal pleural effusions, congenital hydrothorax/chylothorax, and primary lymphedema of the lower limbs.
Downstream
Hydrops Fetalis Disturbed lymphangiogenesis presenting prenatally as fetal hydrops.
Fetal Pleural Effusion The same lymphangiogenic disturbance presenting as fetal pleural fluid accumulation.
Chylothorax Congenital hydrothorax/chylothorax as the postnatal continuation of the same lymphatic drainage failure.
Lymphedema Primary lymphedema of the lower limbs, the postnatal peripheral expression of the same disturbed lymphangiogenesis.
Show evidence (1 reference)
PMID:25358541 SUPPORT Human Clinical
"Here we report on three unrelated patients with CBL mutations manifesting with hydrops fetalis, fetal pleural effusions and/or congenital hydro-/chylothorax."
Documents the prenatal lymphatic phenotype in molecularly confirmed CBL patients.
Developmental RASopathy Phenotype
The germline developmental consequence of RAS-MAPK hyperactivation: impaired growth, developmental delay and other neurological features, cryptorchidism, Noonan-like facial dysmorphism, and ectodermal findings, which the cited series reports as hyperpigmented skin lesions without specifying a lesion morphology. Compared with Noonan syndrome caused by other RASopathy genes, neurological involvement is relatively frequent while cardiac defects, reduced growth, and cryptorchidism are comparatively less prevalent.
Downstream
Impaired Growth Growth impairment as part of the core germline developmental phenotype of RAS-MAPK hyperactivation.
Developmental Delay Developmental delay as part of the same core germline developmental phenotype.
Cryptorchidism Cryptorchidism as part of the same core germline developmental phenotype, at lower prevalence than in other RASopathies.
Noonan-like Facial Dysmorphism The Noonan-like craniofacial gestalt shared with the other RASopathies, which is what places this disorder in that group clinically.
Bilateral Ptosis Bilateral ptosis as a component of the Noonan-like craniofacial presentation.
Intellectual Disability Intellectual disability as one of the neurological features that are comparatively frequent in this RASopathy.
Show evidence (2 references)
PMID:20694012 SUPPORT Human Clinical
"We describe 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 (JMML)."
Defines the core developmental phenotype of the disorder.
PMID:25952305 SUPPORT Human Clinical
"Genotype-phenotype correlation analysis performed on available records indicated that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac..."
Quantifies how the CBL phenotype is weighted relative to other RASopathies.
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Pathograph

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

18
Blood 1
Juvenile Myelomonocytic Leukemia HP:0012209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Juvenile myelomonocytic leukemia (HP:0012209). HP:0012209 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"We describe 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 (JMML)."
Establishes JMML predisposition as a defining feature.
Cardiovascular 3
Moyamoya Angiopathy Moyamoya phenomenon HP:0011834 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Moyamoya phenomenon (HP:0011834). HP:0011834 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28343148 SUPPORT Human Clinical
"We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA."
Documents infancy-onset moyamoya angiopathy caused by germline CBL variants.
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28414188 SUPPORT Human Clinical
"We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome"
Documents splenomegaly as a presenting feature of CBL syndrome.
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."
Documents later-life vasculitis in affected individuals.
Eye 1
Bilateral Ptosis HP:0001488 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral ptosis (HP:0001488). HP:0001488 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24458550 SUPPORT Human Clinical
"We describe a girl with a Noonan-like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL."
Documents bilateral ptosis in a confirmed germline CBL patient.
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
"We describe 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 (JMML)."
Cryptorchidism is listed among the core features.
Head and Neck 2
Noonan-like Facial Dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20619386 SUPPORT Human Clinical
"heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS)"
Supports the Noonan-overlapping dysmorphic phenotype; individual facial features are not separately quantified in the abstract.
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.
Metabolism 4
Hydrops Fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25358541 SUPPORT Human Clinical
"Here we report on three unrelated patients with CBL mutations manifesting with hydrops fetalis, fetal pleural effusions and/or congenital hydro-/chylothorax."
Documents hydrops fetalis in molecularly confirmed CBL patients.
Fetal Pleural Effusion HP:0002202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pleural effusion (HP:0002202). HP:0002202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25358541 SUPPORT Human Clinical
"Here we report on three unrelated patients with CBL mutations manifesting with hydrops fetalis, fetal pleural effusions and/or congenital hydro-/chylothorax."
Documents fetal pleural effusion in molecularly confirmed CBL patients.
Chylothorax HP:0010310 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chylothorax (HP:0010310). HP:0010310 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25358541 SUPPORT Human Clinical
"Here we report on three unrelated patients with CBL mutations manifesting with hydrops fetalis, fetal pleural effusions and/or congenital hydro-/chylothorax."
Documents congenital chylothorax in molecularly confirmed CBL patients.
Lymphedema HP:0001004 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphedema (HP:0001004). HP:0001004 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24458550 SUPPORT Human Clinical
"We describe a girl with a Noonan-like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL."
Documents primary lymphedema of the lower limbs.
Nervous System 3
Developmental Delay Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20694012 SUPPORT Human Clinical
"We describe 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 (JMML)."
Developmental delay is listed among the core features.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24458550 SUPPORT Human Clinical
"We describe a girl with a Noonan-like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL."
Documents intellectual disability in a confirmed CBL patient.
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.
Growth 2
Impaired Growth Short stature 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:20694012 SUPPORT Human Clinical
"We describe 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 (JMML)."
Impaired growth is listed among the core features.
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.
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Genetic Associations

1
CBL (Heterozygous germline pathogenic variants (autosomal dominant))
Gene: CBL hgnc:1541 gene page 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 (1 reference)
PMID:20619386 SUPPORT Human Clinical
"Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes."
Original gene-disease discovery cohort establishing CBL as the disease gene.
💊

Medical Actions

4
Observation for Spontaneously Regressing JMML
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 CBL-mutant JMML frequently follows an indolent course with spontaneous regression, a watch-and-wait strategy without immediate hematopoietic stem cell transplantation is appropriate for many patients; long-term transplant-free survival beyond 20 years has been documented. Ongoing hematologic surveillance is required, and later vasculitis may still develop.
Show evidence (2 references)
PMID:26911351 SUPPORT Human Clinical
"Here we report that two JMML patients survived >20 years without HSCT and both patients had uniparental disomy of 11q23 where CBL is located"
Supports a non-transplant observation strategy for CBL-mutant JMML.
PMID:39196581 SUPPORT Other
"Similarly, CBL syndrome patients can present with a less clinically aggressive form of JMML, and clinical management now recommends watchful waiting"
A 2024 AACR Cancer Predisposition Working Group consensus update states watchful waiting as the recommended management for CBL-syndrome JMML, raising this treatment from a case-series inference to a current guideline position. Graded OTHER because the quoted sentence is a consensus recommendation rather than a result the paper reports.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
Reserved for progressive or non-regressing JMML. Transplantation is the curative modality for aggressive JMML generally, but carries substantial relapse and regimen-related toxicity, which is why the indolent CBL-mutant subgroup is often observed instead.
Show evidence (1 reference)
PMID:26911351 SUPPORT INDIRECT Human Clinical
"Juvenile myelomonocytic leukemia (JMML) appears to be a life-threatening disease and showed poor prognosis even after hematopoietic stem cell transplantation (HSCT) because of high relapse rate."
Establishes HSCT as the standard JMML modality and documents its relapse burden. Support is indirect: the abstract reports the burden, and the inference step is that this is what motivates reserving transplantation for progressive CBL-mutant disease rather than applying it up front.
Cerebral Revascularization Surgery
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical revascularization is the established management for symptomatic moyamoya angiopathy, and CBL-related moyamoya can be severe and infancy-onset.
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 for the proband and family, covering autosomal dominant inheritance, both de novo and inherited occurrence, and the tumor- and vasculopathy-surveillance implications of a germline CBL variant.
📊

Prevalence

2
Worldwide
Cases In Literature Ultra Rare
Very rare. As of the 2015 review of the prenatal phenotype, 25 patients with germline CBL mutations had been reported, 20 of whom had JMML — a case-ascertainment count, not a population rate, and one biased toward hematologic presentation.
Show evidence (1 reference)
PMID:25358541 SUPPORT Human Clinical
"Recently, germline mutations in the Casitas B-cell lymphoma (CBL) gene were reported in 25 patients and of these, 20 had juvenile myelomonocytic leukemia (JMML)."
Reports the cumulative number of published cases at that time.
Children with juvenile myelomonocytic leukemia
Unknown Unknown
CBL lesions (germline and somatic combined) accounted for 27 of 159 JMML samples (~17%) in the defining cohort. This is the frequency of CBL involvement within JMML, not the frequency of JMML within CBL-related disorder. It is a per-gene case fraction of a mutational-screening case series — a cross-sectional proportion with no observation window and no population denominator — so no PrevalenceMeasureEnum value describes it and measure_type is UNKNOWN rather than PERIOD_PREVALENCE. prevalence_class is likewise left UNKNOWN: a magnitude band here would read as a disease prevalence, which this is not. The structurally correct home for this figure is Genetic.case_fractions on the JMML side; it is kept here, labelled, rather than restructured in a review round.
Show evidence (1 reference)
PMID:19571318 SUPPORT Human Clinical
"we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples"
Quantifies CBL involvement within a JMML cohort.
🔀

Differential Diagnoses

2

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

Noonan syndrome MONDO:0018997
Overlapping Features The principal differential. CBL-related disorder presents with clinical features fitting or partially overlapping Noonan syndrome, the most common RASopathy, and is resolved by molecular testing. The JMML predisposition and the later vasculopathy are characteristic of the CBL phenotype, while cardiac defects — a Noonan hallmark — are comparatively uncommon.
Distinguishing Features
  • A pathogenic CBL variant supports CBL-related disorder, whereas PTPN11, SOS1, RAF1, or RIT1 variants favour classic Noonan syndrome.
  • Predisposition to often self-remitting JMML, and later vasculitis or moyamoya arteriopathy, is characteristic of CBL-related disorder.
  • Cardiac defects, reduced growth, and cryptorchidism are of comparatively low prevalence in the CBL phenotype.
Show evidence (2 references)
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.
PMID:25952305 SUPPORT Human Clinical
"Genotype-phenotype correlation analysis performed on available records indicated that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac..."
Provides the feature weighting that distinguishes the CBL phenotype from classic Noonan syndrome.
Moyamoya disease MONDO:0016820
Overlapping Features In children presenting with early-onset moyamoya angiopathy, CBL-related disorder is an important differential for apparently non-syndromic moyamoya disease, because CBL-mutated probands may show only subtle RASopathy signs and may never develop JMML. This is a diagnostically consequential differential rather than a phenotypic look-alike: it changes whether the child is entered into hematologic and RASopathy surveillance.
Distinguishing Features
  • Germline CBL testing is recommended in early-onset moyamoya even when RASopathy features are absent or subtle.
  • A germline CBL variant carries JMML and RASopathy surveillance implications that isolated moyamoya disease does not.
Show evidence (1 reference)
PMID:28343148 SUPPORT Human Clinical
"These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy."
Supports treating CBL-related disorder as a differential in apparently isolated early-onset moyamoya.
{ }

Source YAML

click to show 
name: CBL-related Disorder
creation_date: "2026-08-04T00:00:00Z"
description: >-
  CBL-related disorder (CBL syndrome; Noonan syndrome-like disorder with or
  without juvenile myelomonocytic leukemia, NSLL) is an autosomal dominant
  RASopathy caused by heterozygous germline missense, splice-site, or in-frame
  variants in CBL, which encodes a multivalent adaptor protein with E3 ubiquitin
  ligase activity that normally terminates activated receptor tyrosine kinase
  signaling. Pathogenic variants cluster in the RING finger domain and the
  adjacent linker region — the same hot spot mutated somatically in myeloid
  malignancy — and abolish CBL-mediated receptor ubiquitylation while also
  inhibiting residual wild-type CBL and CBL-B, so activated kinases escape
  degradation and signal flow through RAS-MAPK is prolonged. The clinical
  phenotype overlaps Noonan syndrome (facial dysmorphism, impaired growth,
  cryptorchidism, developmental delay and a relatively high frequency of
  neurological features, with a comparatively low prevalence of cardiac defects)
  and is distinguished by two characteristic non-Noonan complications: a strong
  predisposition to juvenile myelomonocytic leukemia (JMML), which arises when
  the wild-type CBL allele is lost through acquired 11q uniparental isodisomy and
  which frequently regresses spontaneously; and a cerebral and systemic
  vasculopathy that includes early-onset moyamoya arteriopathy and later-onset
  vasculitis. Prenatal and lymphatic manifestations (hydrops fetalis, fetal
  pleural effusions, chylothorax, primary lymphedema) further connect the
  disorder to the RASopathy family.
category: Mendelian
parents:
- RASopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013308
      label: CBL-related disorder
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary disease term for this entry.
disease_term:
  preferred_term: CBL-related disorder
  description: >-
    An autosomal dominant RASopathy caused by germline CBL variants that impair
    E3-ubiquitin-ligase-mediated termination of receptor tyrosine kinase
    signaling, producing a Noonan-like developmental phenotype with
    predisposition to juvenile myelomonocytic leukemia and vasculopathy.
  term:
    id: MONDO:0013308
    label: CBL-related disorder
pathophysiology:
- name: Germline CBL RING-Linker Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous germline variant in CBL, most often a missense change altering
    an evolutionarily conserved residue in the RING finger domain or in the
    linker connecting that domain to the N-terminal tyrosine kinase binding
    domain. This is the same region mutated somatically in myeloid malignancies;
    p.Tyr371His is the recurrent hot-spot allele. Splice-site changes, an
    in-frame deletion, and a nonsense change generating a v-Cbl-like truncated
    protein have also been reported.
  genes:
  - preferred_term: CBL
    term:
      id: hgnc:1541
      label: CBL
  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: >-
      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: >-
      Establishes the germline variant class and its localization to the
      RING/linker mutational hot spot.
  - reference: PMID:25952305
    reference_title: "Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among them, two splice-site changes, one in-frame deletion, and one
      missense mutation affected the RING domain and/or the adjacent linker
      region, overlapping cancer-associated defects.
    explanation: >-
      Extends the germline allelic spectrum beyond missense while confirming the
      same RING/linker localization.
  downstream:
  - target: Loss of CBL E3 Ubiquitin Ligase Activity
    description: >-
      RING/linker variants disrupt the domain that recruits the E2
      ubiquitin-conjugating enzyme, abolishing ligase function.
    evidence:
    - reference: PMID:28343148
      reference_title: "De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both mutations were predicted to alter the ubiquitin ligase activity of
        the CBL protein that acts as a negative regulator of the RAS pathway.
      explanation: >-
        Links the germline variant directly to predicted loss of ubiquitin ligase
        function.
- name: Loss of CBL E3 Ubiquitin Ligase Activity
  biological_scale: MOLECULAR
  description: >-
    Mutant CBL protein loses E3 ubiquitin ligase activity. Critically, the effect
    is not a simple haploinsufficiency: mutant CBL also inhibits the ligase
    activity of residual wild-type CBL and of the paralogue CBL-B, so a single
    heterozygous allele already prolongs tyrosine kinase activation after
    cytokine stimulation.
  genes:
  - preferred_term: CBL
    term:
      id: hgnc:1541
      label: CBL
  molecular_functions:
  - preferred_term: ubiquitin protein ligase activity
    term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:19620960
    reference_title: "Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that
      of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged
      activation of tyrosine kinases after cytokine stimulation.
    explanation: >-
      Demonstrates both the loss of ligase activity and its dominant-inhibitory
      action on the remaining wild-type ligases.
  downstream:
  - target: Impaired Receptor Tyrosine Kinase Downregulation
    description: >-
      Without functional Cbl-family ligase activity, activated receptor tyrosine
      kinases are not ubiquitylated and therefore are not sorted for degradation.
    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: >-
        Directly connects loss of ligase function to impaired receptor
        ubiquitylation and downstream RAS dysregulation.
- name: Impaired Receptor Tyrosine Kinase Downregulation
  biological_scale: MOLECULAR
  description: >-
    Cbl-family ligases are the dominant activation-selective ubiquitin ligases
    for protein tyrosine kinases, targeting activated receptors either for
    endocytic sorting into lysosomes or for proteasomal degradation. When this
    step fails, activated receptors and their signaling intermediates persist at
    the membrane and continue to transmit signal.
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  - preferred_term: receptor internalization
    term:
      id: GO:0031623
      label: receptor internalization
    modifier: DECREASED
  - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:23085373
    reference_title: "Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Structural, biochemical and cell biological studies have established that
      Cbl protein-dependent ubiquitination targets activated PTKs for degradation
      either by facilitating their endocytic sorting into lysosomes or by
      promoting their proteasomal degradation.
    explanation: >-
      Establishes the normal Cbl-dependent receptor-downregulation step whose
      failure underlies the disorder.
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: >-
      Persistent receptor tyrosine kinase signaling feeds prolonged flow through
      the RAS/RAF/MEK/ERK cascade.
    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: >-
        the common p.371Y>H altered Cbl protein 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 constitutive ERK/AKT/S6 phosphorylation downstream of the recurrent
        mutant allele, and that loss of the normal allele is required.
- name: RAS-MAPK Pathway Hyperactivation
  biological_scale: CELLULAR
  description: >-
    The shared final common pathway of the RASopathies: enhanced and prolonged
    signal flow through RAS and the RAF/MEK/ERK cascade (with parallel
    PI3K-AKT-S6 activation), which perturbs proliferation, differentiation, and
    morphogenesis across many tissues.
  biological_processes:
  - preferred_term: Ras protein signal transduction
    term:
      id: GO:0007265
      label: Ras protein signal transduction
    modifier: INCREASED
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  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 conclude that germline CBL mutations have developmental, tumorigenic and
      functional consequences that resemble disorders that are caused by
      hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1,
      Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and
      Legius syndrome.
    explanation: >-
      Places CBL-related disorder in the RASopathy family by shared
      Ras/Raf/MEK/ERK hyperactivation.
  downstream:
  - target: Developmental RASopathy Phenotype
    description: >-
      Excess RAS-MAPK signaling during development produces the Noonan-like
      craniofacial, growth, genital, and neurodevelopmental phenotype.
    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: >-
        These findings document that germline mutations in CBL alter development
        to cause a clinically variable condition that resembles NS and that
        possibly predisposes to malignancies.
      explanation: >-
        Connects germline CBL-driven RAS dysregulation to the developmental
        phenotype.
  - target: Myeloid Progenitor Cytokine Hypersensitivity
    description: >-
      In the hematopoietic compartment, failure to terminate cytokine receptor
      signaling lowers the threshold for progenitor proliferation.
    evidence:
    - reference: PMID:19620960
      reference_title: "Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        c-Cbl(-/-) haematopoietic stem/progenitor cells (HSPCs) showed enhanced
        sensitivity to a variety of cytokines compared to c-Cbl(+/+) HSPCs
      explanation: >-
        Mouse hematopoietic stem/progenitor cells lacking c-Cbl are hypersensitive
        to cytokines, supporting the hematopoietic arm of the mechanism.
  - target: Cerebral and Systemic Vasculopathy
    description: >-
      Prolonged RAS pathway signaling is proposed to disrupt cerebrovascular
      development, producing progressive stenosis of the terminal internal
      carotid arteries with collateral vessel formation.
    evidence:
    - reference: PMID:25283271
      reference_title: "Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Prolonged RAS pathway signaling may cause disruption of cerebrovascular development."
      explanation: >-
        Proposes the causal link from sustained RAS signaling to the
        cerebrovascular phenotype.
  - target: Lymphatic Developmental Dysregulation
    description: >-
      The RAS/MAPK pathway is a major regulator of lymphangiogenesis; its
      dysregulation produces the prenatal effusion and lymphedema phenotypes
      shared across RASopathies.
    evidence:
    - reference: PMID:25358541
      reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These syndromes, collectively called RASopathies, are caused by mutations
        in the RAS/MAPK pathway, which is known to play a major role in
        lymphangiogenesis.
      explanation: >-
        Provides the mechanistic rationale linking RAS/MAPK dysregulation to the
        lymphatic phenotype.
- name: Myeloid Progenitor Cytokine Hypersensitivity
  biological_scale: CELLULAR
  description: >-
    Hematopoietic stem and progenitor cells carrying a mutant CBL allele respond
    to a broader spectrum of cytokines at lower concentrations, and cells in which
    the normal allele is additionally lost acquire outright cytokine-independent
    growth — the proliferative substrate for juvenile myelomonocytic leukemia.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: granulocyte monocyte progenitor cell
    term:
      id: CL:0000557
      label: granulocyte monocyte progenitor cell
  biological_processes:
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    modifier: INCREASED
  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: >-
      the common p.371Y>H altered Cbl protein 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: >-
      Cytokine-independent growth appears specifically in hematopoietic cells and
      requires reduction of the normal allele.
  downstream:
  - target: Acquired 11q Isodisomy and Biallelic CBL Inactivation
    description: >-
      Selective pressure in the hematopoietic compartment favors clones that lose
      the residual wild-type CBL allele by copy-neutral loss of heterozygosity.
    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: >-
        Importantly, JMML specimens from affected children show loss of the normal
        CBL allele through acquired isodisomy.
      explanation: >-
        Documents the acquired second hit in patient leukemia specimens.
- name: Acquired 11q Isodisomy and Biallelic CBL Inactivation
  biological_scale: CELLULAR
  description: >-
    A somatic second hit: acquired segmental uniparental (iso)disomy of chromosome
    11q23, the CBL locus, converts the germline heterozygous variant to
    homozygosity in the affected clone. This is the canonical two-hit step
    separating the germline developmental disorder from overt leukemia, and the
    same mechanism has been documented in CBL-associated teratomas.
  genes:
  - preferred_term: CBL
    term:
      id: hgnc:1541
      label: CBL
  evidence:
  - reference: PMID:19571318
    reference_title: "Mutations in CBL occur frequently in juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a region of 11q isodisomy that contains the CBL gene in
      several JMML samples, and subsequently identified CBL mutations in 27 of 159
      JMML samples
    explanation: >-
      Identifies 11q isodisomy at the CBL locus and quantifies CBL involvement in
      a JMML cohort.
  - reference: PMID:24458550
    reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Copy neutral loss of heterozygosity for the CBL mutation due to acquired
      segmental uniparental disomy of 11q23 was observed in three teratomas,
      suggesting a specific association of CBL mutations in germ cell tumor
      predisposition.
    explanation: >-
      Shows the same copy-neutral LOH second-hit mechanism outside the myeloid
      compartment.
  downstream:
  - target: Juvenile Myelomonocytic Leukemia
    description: >-
      Biallelic CBL inactivation in a hematopoietic clone drives the
      myeloproliferative expansion diagnosed as JMML.
    evidence:
    - reference: PMID:19571318
      reference_title: "Mutations in CBL occur frequently in juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we also demonstrate that CBL and RAS/PTPN11 mutations were mutually
        exclusive in these patients
      explanation: >-
        Mutual exclusivity with the other RAS-pathway JMML lesions establishes CBL
        loss as an independent, sufficient JMML driver.
- name: Juvenile Myelomonocytic Leukemia
  biological_scale: ORGANISM
  description: >-
    An aggressive myeloproliferative neoplasm of early childhood arising in the
    hematopoietic stem cell compartment. In CBL-related disorder its natural
    history is distinctive: a substantial proportion of cases regress
    spontaneously without hematopoietic stem cell transplantation, and long-term
    survival without transplant has been documented, although affected
    individuals may later develop vasculitis.
  cell_types:
  - preferred_term: granulocyte monocyte progenitor cell
    term:
      id: CL:0000557
      label: granulocyte monocyte progenitor cell
  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 the characteristic spontaneous regression and the later
      vasculitic complication.
  - reference: PMID:26911351
    reference_title: "Adults with germline CBL mutation complicated with juvenile myelomonocytic leukemia at infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report that two JMML patients survived >20 years without HSCT and
      both patients had uniparental disomy of 11q23 where CBL is located
    explanation: >-
      Long-term transplant-free survival supports the indolent natural history of
      CBL-mutant JMML.
- name: Cerebral and Systemic Vasculopathy
  biological_scale: TISSUE
  description: >-
    A vascular arm of the disorder that is not part of classic Noonan syndrome:
    progressive stenosis of the terminal internal carotid arteries with abnormal
    deep collateral vessels (moyamoya angiopathy), which may present in infancy,
    plus systemic vasculitis emerging later in life. Notably, moyamoya can be the
    presenting and near-isolated manifestation in individuals who never develop
    JMML and show only subtle RASopathy signs.
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:28343148
    reference_title: "De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two germline de novo mutations in CBL in two out of the four
      trio probands, two girls presenting with an infancy-onset severe MMA.
    explanation: >-
      Establishes germline CBL variants as a cause of infancy-onset moyamoya
      angiopathy.
  - 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 the later-onset systemic vasculitis arm of the vasculopathy.
  downstream:
  - target: Moyamoya Angiopathy
    description: >-
      Progressive stenosis of the terminal internal carotid arteries with the
      abnormal deep collateral network is the cerebral expression of this
      vasculopathy, and can be its presenting and near-isolated manifestation.
    evidence:
    - reference: PMID:28343148
      reference_title: "De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified two germline de novo mutations in CBL in two out of the four
        trio probands, two girls presenting with an infancy-onset severe MMA.
      explanation: >-
        Germline CBL variants are reported directly as the cause of the
        infancy-onset moyamoya angiopathy this edge asserts.
  - target: Vasculitis
    description: >-
      The systemic arm of the same vasculopathy, emerging later in life and
      reported in individuals whose JMML had already regressed.
    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: >-
        Reports systemic vasculitis as a later-onset manifestation in germline
        CBL carriers, which is the phenotype this edge produces.
- name: Lymphatic Developmental Dysregulation
  biological_scale: TISSUE
  description: >-
    Disturbed lymphangiogenesis producing prenatal and postnatal lymphatic
    manifestations — hydrops fetalis, fetal pleural effusions, congenital
    hydrothorax/chylothorax, and primary lymphedema of the lower limbs.
  evidence:
  - reference: PMID:25358541
    reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on three unrelated patients with CBL mutations manifesting
      with hydrops fetalis, fetal pleural effusions and/or congenital
      hydro-/chylothorax.
    explanation: >-
      Documents the prenatal lymphatic phenotype in molecularly confirmed CBL
      patients.
  downstream:
  - target: Hydrops Fetalis
    description: >-
      Disturbed lymphangiogenesis presenting prenatally as fetal hydrops.
    evidence:
    - reference: PMID:25358541
      reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report on three unrelated patients with CBL mutations manifesting
        with hydrops fetalis, fetal pleural effusions and/or congenital
        hydro-/chylothorax.
      explanation: >-
        Names hydrops fetalis among the prenatal lymphatic manifestations of
        molecularly confirmed CBL mutation.
  - target: Fetal Pleural Effusion
    description: >-
      The same lymphangiogenic disturbance presenting as fetal pleural fluid
      accumulation.
    evidence:
    - reference: PMID:25358541
      reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report on three unrelated patients with CBL mutations manifesting
        with hydrops fetalis, fetal pleural effusions and/or congenital
        hydro-/chylothorax.
      explanation: >-
        Names fetal pleural effusions among the prenatal lymphatic manifestations
        of molecularly confirmed CBL mutation.
  - target: Chylothorax
    description: >-
      Congenital hydrothorax/chylothorax as the postnatal continuation of the
      same lymphatic drainage failure.
    evidence:
    - reference: PMID:25358541
      reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report on three unrelated patients with CBL mutations manifesting
        with hydrops fetalis, fetal pleural effusions and/or congenital
        hydro-/chylothorax.
      explanation: >-
        Names congenital hydro-/chylothorax among the lymphatic manifestations of
        molecularly confirmed CBL mutation.
  - target: Lymphedema
    description: >-
      Primary lymphedema of the lower limbs, the postnatal peripheral expression
      of the same disturbed lymphangiogenesis.
    evidence:
    - reference: PMID:24458550
      reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a girl with a Noonan-like phenotype of bilateral ptosis,
        lymphedema of the lower limbs and moderate intellectual disability, due to
        a de novo heterozygous mutation in CBL.
      explanation: >-
        Reports lower-limb lymphedema in a molecularly confirmed germline CBL
        carrier, which is the phenotype this edge produces.
- name: Developmental RASopathy Phenotype
  biological_scale: ORGANISM
  description: >-
    The germline developmental consequence of RAS-MAPK hyperactivation: impaired
    growth, developmental delay and other neurological features, cryptorchidism,
    Noonan-like facial dysmorphism, and ectodermal findings, which the cited
    series reports as hyperpigmented skin lesions without specifying a lesion
    morphology. Compared with Noonan syndrome caused by other RASopathy genes,
    neurological involvement is relatively frequent while cardiac defects,
    reduced growth, and cryptorchidism are comparatively less prevalent.
  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, which is characterized by impaired growth,
      developmental delay, cryptorchidism and a predisposition to juvenile
      myelomonocytic leukemia (JMML).
    explanation: >-
      Defines the core developmental phenotype of the disorder.
  - reference: PMID:25952305
    reference_title: "Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotype-phenotype correlation analysis performed on available records
      indicated that germline CBL mutations cause a variable phenotype
      characterized by a relatively high frequency of neurological features,
      predisposition to juvenile myelomonocytic leukemia, and low prevalence of
      cardiac defects, reduced growth, and cryptorchidism.
    explanation: >-
      Quantifies how the CBL phenotype is weighted relative to other RASopathies.
  downstream:
  - target: Impaired Growth
    description: >-
      Growth impairment as part of the core germline developmental phenotype of
      RAS-MAPK hyperactivation.
    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, which is characterized by impaired growth,
        developmental delay, cryptorchidism and a predisposition to juvenile
        myelomonocytic leukemia (JMML).
      explanation: >-
        Names impaired growth as a defining feature of the germline CBL
        developmental disorder this node represents.
  - target: Developmental Delay
    description: >-
      Developmental delay as part of the same core germline developmental
      phenotype.
    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, which is characterized by impaired growth,
        developmental delay, cryptorchidism and a predisposition to juvenile
        myelomonocytic leukemia (JMML).
      explanation: >-
        Names developmental delay as a defining feature of the germline CBL
        developmental disorder this node represents.
  - target: Cryptorchidism
    description: >-
      Cryptorchidism as part of the same core germline developmental phenotype,
      at lower prevalence than in other RASopathies.
    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, which is characterized by impaired growth,
        developmental delay, cryptorchidism and a predisposition to juvenile
        myelomonocytic leukemia (JMML).
      explanation: >-
        Names cryptorchidism as a defining feature of the germline CBL
        developmental disorder this node represents.
  - target: Noonan-like Facial Dysmorphism
    description: >-
      The Noonan-like craniofacial gestalt shared with the other RASopathies,
      which is what places this disorder in that group clinically.
    evidence:
    - reference: PMID:24458550
      reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a girl with a Noonan-like phenotype of bilateral ptosis,
        lymphedema of the lower limbs and moderate intellectual disability, due to
        a de novo heterozygous mutation in CBL.
      explanation: >-
        Reports the Noonan-like phenotype in a molecularly confirmed germline CBL
        carrier.
  - target: Bilateral Ptosis
    description: >-
      Bilateral ptosis as a component of the Noonan-like craniofacial
      presentation.
    evidence:
    - reference: PMID:24458550
      reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a girl with a Noonan-like phenotype of bilateral ptosis,
        lymphedema of the lower limbs and moderate intellectual disability, due to
        a de novo heterozygous mutation in CBL.
      explanation: >-
        Reports bilateral ptosis in a molecularly confirmed germline CBL carrier.
  - target: Intellectual Disability
    description: >-
      Intellectual disability as one of the neurological features that are
      comparatively frequent in this RASopathy.
    evidence:
    - reference: PMID:24458550
      reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a girl with a Noonan-like phenotype of bilateral ptosis,
        lymphedema of the lower limbs and moderate intellectual disability, due to
        a de novo heterozygous mutation in CBL.
      explanation: >-
        Reports moderate intellectual disability in a molecularly confirmed
        germline CBL carrier.
phenotypes:
- category: Neoplasm
  name: Juvenile Myelomonocytic Leukemia
  description: >-
    Myeloproliferative neoplasm of infancy/early childhood, the hallmark tumor
    predisposition of this disorder, arising after acquired loss of the wild-type
    CBL allele.
  phenotype_term:
    preferred_term: Juvenile myelomonocytic leukemia
    term:
      id: HP:0012209
      label: Juvenile myelomonocytic leukemia
  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, which is characterized by impaired growth,
      developmental delay, cryptorchidism and a predisposition to juvenile
      myelomonocytic leukemia (JMML).
    explanation: Establishes JMML predisposition as a defining feature.
- category: Vascular
  name: Moyamoya Angiopathy
  description: >-
    Progressive stenosis of the terminal internal carotid arteries with abnormal
    deep collateral vessels; may be severe and infancy-onset, and can occur
    without JMML or overt RASopathy features.
  phenotype_term:
    preferred_term: Moyamoya phenomenon
    term:
      id: HP:0011834
      label: Moyamoya phenomenon
  evidence:
  - reference: PMID:28343148
    reference_title: "De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two germline de novo mutations in CBL in two out of the four
      trio probands, two girls presenting with an infancy-onset severe MMA.
    explanation: Documents infancy-onset moyamoya angiopathy caused by germline CBL variants.
- category: Growth
  name: Impaired Growth
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  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, which is characterized by impaired growth,
      developmental delay, cryptorchidism and a predisposition to juvenile
      myelomonocytic leukemia (JMML).
    explanation: Impaired growth is listed among the core features.
- category: Neurologic
  name: Developmental Delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  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, which is characterized by impaired growth,
      developmental delay, cryptorchidism and a predisposition to juvenile
      myelomonocytic leukemia (JMML).
    explanation: Developmental delay is listed among the core features.
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Reported at moderate severity in a molecularly confirmed patient; neurological
    involvement is relatively frequent in this RASopathy.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:24458550
    reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a girl with a Noonan-like phenotype of bilateral ptosis,
      lymphedema of the lower limbs and moderate intellectual disability, due to a
      de novo heterozygous mutation in CBL.
    explanation: Documents intellectual disability in a confirmed CBL patient.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  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, which is characterized by impaired growth,
      developmental delay, cryptorchidism and a predisposition to juvenile
      myelomonocytic leukemia (JMML).
    explanation: Cryptorchidism is listed among the core features.
- category: Lymphatic
  name: Hydrops Fetalis
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:25358541
    reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on three unrelated patients with CBL mutations manifesting
      with hydrops fetalis, fetal pleural effusions and/or congenital
      hydro-/chylothorax.
    explanation: Documents hydrops fetalis in molecularly confirmed CBL patients.
- category: Respiratory
  name: Fetal Pleural Effusion
  phenotype_term:
    preferred_term: Pleural effusion
    term:
      id: HP:0002202
      label: Pleural effusion
  evidence:
  - reference: PMID:25358541
    reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on three unrelated patients with CBL mutations manifesting
      with hydrops fetalis, fetal pleural effusions and/or congenital
      hydro-/chylothorax.
    explanation: Documents fetal pleural effusion in molecularly confirmed CBL patients.
- category: Respiratory
  name: Chylothorax
  phenotype_term:
    preferred_term: Chylothorax
    term:
      id: HP:0010310
      label: Chylothorax
  evidence:
  - reference: PMID:25358541
    reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on three unrelated patients with CBL mutations manifesting
      with hydrops fetalis, fetal pleural effusions and/or congenital
      hydro-/chylothorax.
    explanation: Documents congenital chylothorax in molecularly confirmed CBL patients.
- category: Lymphatic
  name: Lymphedema
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  evidence:
  - reference: PMID:24458550
    reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a girl with a Noonan-like phenotype of bilateral ptosis,
      lymphedema of the lower limbs and moderate intellectual disability, due to a
      de novo heterozygous mutation in CBL.
    explanation: Documents primary lymphedema of the lower limbs.
- category: Hematologic
  name: Splenomegaly
  description: >-
    May be the presenting sign leading to molecular diagnosis, in the absence of
    overt leukemia.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:28414188
    reference_title: "A case of splenomegaly in CBL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a child with unexplained splenomegaly to highlight this feature
      as a presenting sign of the RASopathy CBL syndrome
    explanation: Documents splenomegaly as a presenting feature of CBL syndrome.
- category: Vascular
  name: Vasculitis
  description: Systemic vasculitis reported later in life, including after spontaneous JMML regression.
  phenotype_term:
    preferred_term: Vasculitis
    term:
      id: HP:0002633
      label: Vasculitis
  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 later-life vasculitis in affected individuals.
- category: Craniofacial
  name: Noonan-like Facial Dysmorphism
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  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: >-
      heterozygous germline mutations in CBL, a tumor-suppressor gene that is
      mutated in myeloid malignancies and encodes a multivalent adaptor protein
      with E3 ubiquitin ligase activity, can underlie a phenotype with clinical
      features fitting or partially overlapping Noonan syndrome (NS)
    explanation: >-
      Supports the Noonan-overlapping dysmorphic phenotype; individual facial
      features are not separately quantified in the abstract.
- category: Craniofacial
  name: Bilateral Ptosis
  description: >-
    Bilateral drooping of the upper eyelids, reported as part of the Noonan-like
    facial phenotype in a molecularly confirmed patient.
  phenotype_term:
    preferred_term: Bilateral ptosis
    term:
      id: HP:0001488
      label: Bilateral ptosis
  evidence:
  - reference: PMID:24458550
    reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a girl with a Noonan-like phenotype of bilateral ptosis,
      lymphedema of the lower limbs and moderate intellectual disability, due to a
      de novo heterozygous mutation in CBL.
    explanation: Documents bilateral ptosis in a confirmed germline CBL patient.
- 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: 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.

genetic:
- name: CBL
  gene_term:
    preferred_term: CBL
    term:
      id: hgnc:1541
      label: CBL
  association: Heterozygous germline pathogenic variants (autosomal dominant)
  notes: >-
    CBL encodes a multivalent adaptor protein with E3 ubiquitin ligase activity
    that acts as a tumor suppressor in myeloid malignancy. Germline pathogenic
    variants are typically missense changes in the RING finger domain or adjacent
    linker (recurrent p.Tyr371His), with splice-site, in-frame deletion, and
    v-Cbl-like nonsense alleles also reported. Leukemic and teratomatous tissue
    additionally shows acquired copy-neutral loss of heterozygosity at 11q23,
    converting the germline heterozygous allele to homozygosity.
  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: >-
      Independent CBL mutations were identified in two sporadic cases and two
      families from among 365 unrelated subjects who had NS or suggestive features
      and were negative for mutations in previously identified disease genes.
    explanation: >-
      Original gene-disease discovery cohort establishing CBL as the disease gene.
inheritance:
- name: Autosomal Dominant
  description: >-
    Autosomal dominant. Both de novo occurrence (including in probands presenting
    with isolated moyamoya) and vertical familial transmission have been
    documented; the germline variant is heterozygous, with tissue-restricted loss
    of the wild-type allele driving the neoplastic complications.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  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: States the dominant inheritance pattern of the disorder.
  - reference: PMID:28343148
    reference_title: "De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two germline de novo mutations in CBL in two out of the four
      trio probands
    explanation: Documents de novo occurrence confirmed by trio sequencing.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Very rare. As of the 2015 review of the prenatal phenotype, 25 patients with
    germline CBL mutations had been reported, 20 of whom had JMML — a
    case-ascertainment count, not a population rate, and one biased toward
    hematologic presentation.
  evidence:
  - reference: PMID:25358541
    reference_title: "Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, germline mutations in the Casitas B-cell lymphoma (CBL) gene were
      reported in 25 patients and of these, 20 had juvenile myelomonocytic
      leukemia (JMML).
    explanation: Reports the cumulative number of published cases at that time.
- population: Children with juvenile myelomonocytic leukemia
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    CBL lesions (germline and somatic combined) accounted for 27 of 159 JMML
    samples (~17%) in the defining cohort. This is the frequency of CBL
    involvement within JMML, not the frequency of JMML within CBL-related
    disorder. It is a per-gene case fraction of a mutational-screening case
    series — a cross-sectional proportion with no observation window and no
    population denominator — so no PrevalenceMeasureEnum value describes it and
    measure_type is UNKNOWN rather than PERIOD_PREVALENCE. prevalence_class is
    likewise left UNKNOWN: a magnitude band here would read as a disease
    prevalence, which this is not. The structurally correct home for this figure
    is Genetic.case_fractions on the JMML side; it is kept here, labelled, rather
    than restructured in a review round.
  evidence:
  - reference: PMID:19571318
    reference_title: "Mutations in CBL occur frequently in juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a region of 11q isodisomy that contains the CBL gene in
      several JMML samples, and subsequently identified CBL mutations in 27 of 159
      JMML samples
    explanation: Quantifies CBL involvement within a JMML cohort.
differential_diagnoses:
- name: Noonan syndrome
  disease_term:
    preferred_term: Noonan syndrome
    term:
      id: MONDO:0018997
      label: Noonan syndrome
  description: >-
    The principal differential. CBL-related disorder presents with clinical
    features fitting or partially overlapping Noonan syndrome, the most common
    RASopathy, and is resolved by molecular testing. The JMML predisposition and
    the later vasculopathy are characteristic of the CBL phenotype, while cardiac
    defects — a Noonan hallmark — are comparatively uncommon.
  distinguishing_features:
  - A pathogenic CBL variant supports CBL-related disorder, whereas PTPN11, SOS1, RAF1, or RIT1 variants favour classic Noonan syndrome.
  - Predisposition to often self-remitting JMML, and later vasculitis or moyamoya arteriopathy, is characteristic of CBL-related disorder.
  - Cardiac defects, reduced growth, and cryptorchidism are of comparatively low prevalence in the CBL phenotype.
  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.
  - reference: PMID:25952305
    reference_title: "Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotype-phenotype correlation analysis performed on available records
      indicated that germline CBL mutations cause a variable phenotype
      characterized by a relatively high frequency of neurological features,
      predisposition to juvenile myelomonocytic leukemia, and low prevalence of
      cardiac defects, reduced growth, and cryptorchidism.
    explanation: >-
      Provides the feature weighting that distinguishes the CBL phenotype from
      classic Noonan syndrome.
- name: Moyamoya disease
  disease_term:
    preferred_term: Moyamoya disease
    term:
      id: MONDO:0016820
      label: Moyamoya disease
  description: >-
    In children presenting with early-onset moyamoya angiopathy, CBL-related
    disorder is an important differential for apparently non-syndromic moyamoya
    disease, because CBL-mutated probands may show only subtle RASopathy signs
    and may never develop JMML. This is a diagnostically consequential
    differential rather than a phenotypic look-alike: it changes whether the
    child is entered into hematologic and RASopathy surveillance.
  distinguishing_features:
  - Germline CBL testing is recommended in early-onset moyamoya even when RASopathy features are absent or subtle.
  - A germline CBL variant carries JMML and RASopathy surveillance implications that isolated moyamoya disease does not.
  evidence:
  - reference: PMID:28343148
    reference_title: "De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data suggest that CBL gene screening should be considered in
      early-onset moyamoya, even in the absence of obvious signs of RASopathy.
    explanation: >-
      Supports treating CBL-related disorder as a differential in apparently
      isolated early-onset moyamoya.
treatments:
- name: Observation for Spontaneously Regressing JMML
  description: >-
    Because CBL-mutant JMML frequently follows an indolent course with spontaneous
    regression, a watch-and-wait strategy without immediate hematopoietic stem cell
    transplantation is appropriate for many patients; long-term transplant-free
    survival beyond 20 years has been documented. Ongoing hematologic surveillance
    is required, and later vasculitis may still develop.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:26911351
    reference_title: "Adults with germline CBL mutation complicated with juvenile myelomonocytic leukemia at infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report that two JMML patients survived >20 years without HSCT and
      both patients had uniparental disomy of 11q23 where CBL is located
    explanation: >-
      Supports a non-transplant observation strategy for CBL-mutant JMML.
  - reference: PMID:39196581
    reference_title: "Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Similarly, CBL syndrome patients can present with a less clinically
      aggressive form of JMML, and clinical management now recommends watchful
      waiting
    explanation: >-
      A 2024 AACR Cancer Predisposition Working Group consensus update states
      watchful waiting as the recommended management for CBL-syndrome JMML,
      raising this treatment from a case-series inference to a current guideline
      position. Graded OTHER because the quoted sentence is a consensus
      recommendation rather than a result the paper reports.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Reserved for progressive or non-regressing JMML. Transplantation is the
    curative modality for aggressive JMML generally, but carries substantial
    relapse and regimen-related toxicity, which is why the indolent CBL-mutant
    subgroup is often observed instead.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:26911351
    reference_title: "Adults with germline CBL mutation complicated with juvenile myelomonocytic leukemia at infancy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Juvenile myelomonocytic leukemia (JMML) appears to be a life-threatening
      disease and showed poor prognosis even after hematopoietic stem cell
      transplantation (HSCT) because of high relapse rate.
    explanation: >-
      Establishes HSCT as the standard JMML modality and documents its relapse
      burden. Support is indirect: the abstract reports the burden, and the
      inference step is that this is what motivates reserving transplantation for
      progressive CBL-mutant disease rather than applying it up front.
- name: Cerebral Revascularization Surgery
  description: >-
    Surgical revascularization is the established management for symptomatic
    moyamoya angiopathy, and CBL-related moyamoya can be severe and
    infancy-onset.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  notes: >-
    No surgical-outcome evidence is cited here because none of the CBL-specific
    references reports revascularization results; the general moyamoya
    revascularization literature has not been screened for this entry. The
    early-onset-moyamoya CBL screening recommendation that previously sat on this
    treatment as evidence is a diagnostic claim, not evidence for surgery, and is
    curated under differential_diagnoses#Moyamoya disease instead.
- name: Genetic Counseling
  description: >-
    Genetic counseling for the proband and family, covering autosomal dominant
    inheritance, both de novo and inherited occurrence, and the tumor- and
    vasculopathy-surveillance implications of a germline CBL variant.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: gap_cbl_tumor_risk_beyond_jmml
  prompt: >-
    Beyond juvenile myelomonocytic leukemia, what is the lifetime tumor risk in
    germline CBL-related disorder, and does the acquired 11q23 copy-neutral
    loss-of-heterozygosity mechanism predispose to germ cell tumors as a
    reproducible second tumor class?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Acquired 11q Isodisomy and Biallelic CBL Inactivation
  - pathophysiology#Juvenile Myelomonocytic Leukemia
  rationale: >-
    The same copy-neutral 11q23 LOH second hit that produces JMML has been
    documented in three teratomas from a single patient, which would imply a
    tumor-predisposition mechanism that is not tissue-restricted to the myeloid
    compartment. That observation rests on one case report, so the entry records
    the mechanism without asserting a quantified extra-hematologic tumor risk or
    recommending a surveillance protocol.
  proposed_experiments:
  - experiment_id: exp_cbl_extrahematologic_tumor_surveillance
    name: Prospective tumor surveillance with 11q23 LOH genotyping in a germline-CBL cohort
    description: >-
      Assemble an international registry of individuals with a confirmed germline
      CBL variant and follow them prospectively for any incident neoplasm.
      Genotype every available tumor specimen for copy-neutral loss of
      heterozygosity at 11q23 and for the germline allele, and compare observed
      tumor incidence against age- and sex-matched population rates.
    decision_criterion: >-
      Recurrent non-myeloid tumors carrying the 11q23 second hit at above-background
      incidence would establish a broader tumor-predisposition syndrome and justify
      a surveillance protocol; absence of such tumors across an adequately powered
      cohort would confine the predisposition to the myeloid compartment.
  evidence:
  - reference: PMID:24458550
    reference_title: "Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Copy neutral loss of heterozygosity for the CBL mutation due to acquired
      segmental uniparental disomy of 11q23 was observed in three teratomas,
      suggesting a specific association of CBL mutations in germ cell tumor
      predisposition.
    explanation: >-
      Supports the existence of the gap indirectly: the three teratomas come from
      a single patient, so the observation proposes rather than establishes germ
      cell tumor predisposition, which is why the question remains open.
- discussion_id: gap_cbl_phenotype_determinants
  prompt: >-
    What determines which germline CBL carriers develop juvenile myelomonocytic
    leukemia, which develop isolated early-onset moyamoya angiopathy with only
    subtle RASopathy signs, and which regress spontaneously versus progressing to
    require transplantation?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Myeloid Progenitor Cytokine Hypersensitivity
  - pathophysiology#Cerebral and Systemic Vasculopathy
  - pathophysiology#Juvenile Myelomonocytic Leukemia
  rationale: >-
    Two probands carrying CBL variants that had previously been reported in
    JMML-predisposing Noonan-like disease instead presented with severe
    infancy-onset moyamoya and never developed leukemia, so allele identity alone
    does not predict which arm of the phenotype manifests. Because the management
    decision that matters most clinically — observe versus transplant — turns on
    this, the absence of a predictor is a substantive gap rather than a
    descriptive one.
  proposed_experiments:
  - experiment_id: exp_cbl_genotype_stratified_natural_history
    name: Genotype-stratified natural history with clonal-architecture sequencing
    description: >-
      Follow germline CBL carriers prospectively with serial blood counts and
      cerebrovascular imaging, stratified by germline allele. In parallel, use
      serial deep sequencing of hematopoietic samples to measure the timing and
      clone size of the acquired 11q23 second hit, and test whether second-hit
      kinetics rather than germline allele identity separate the leukemic,
      spontaneously regressing, and cerebrovascular-predominant courses.
    decision_criterion: >-
      A reproducible association between second-hit timing or clone size and
      subsequent course would support clonal-kinetics-based risk stratification;
      segregation by germline allele instead would support allele-based
      counselling; neither would indicate an unidentified modifier.
  evidence:
  - reference: PMID:28343148
    reference_title: "De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, the two mutated girls never developed JMML and presented only
      subtle signs of RASopathy that did not lead to evoke this diagnosis during
      follow-up.
    explanation: >-
      Demonstrates that previously JMML-associated germline alleles can present
      with an essentially isolated cerebrovascular phenotype.
  - reference: PMID:25952305
    reference_title: "Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotype-phenotype correlation analysis performed on available records
      indicated that germline CBL mutations cause a variable phenotype
      characterized by a relatively high frequency of neurological features,
      predisposition to juvenile myelomonocytic leukemia, and low prevalence of
      cardiac defects, reduced growth, and cryptorchidism.
    explanation: >-
      Supports the gap indirectly: the best available genotype-phenotype analysis
      characterizes the phenotype only in aggregate, from which it follows that
      per-individual outcome prediction is unresolved.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
  Relationship to neighbouring dismech entries. This entry models the germline
  RASopathy; `Juvenile_Myelomonocytic_Leukemia` already carries a `CBL-associated`
  subtype covering the leukemia that arises in these patients, so the JMML
  pathophysiology node and phenotype here are deliberately scoped to the
  predisposition and its distinctive natural history rather than duplicating JMML
  disease biology. `Noonan_Syndrome` cites CBL among its associated genes; the
  two are kept as separate entries because the CBL phenotype is distinguished by
  JMML predisposition, vasculopathy/moyamoya, and a comparatively low prevalence
  of cardiac defects.