Brachydactyly Type B2

Mendelian MONDO:0012658 Pathograph 11 Show in embeddings browser Limb Development Disorders

Brachydactyly type B2 (BDB2) is the NOG-related form of brachydactyly type B: the same terminal deficiency of fingers and toes II-V seen in ROR2-related BDB1, but with proximal symphalangism and carpal/tarsal synostosis added, plus partial cutaneous syndactyly. It was defined molecularly by testing ROR2-negative patients whose joints were fused proximally as well as distally. The causal variants are missense substitutions in NOGGIN, the secreted BMP/GDF antagonist, and they are pointedly not the loss-of-function alleles already known from the NOG symphalangism spectrum: modelling and micromass assays indicate a subtle change in NOG's affinity for BMPs and GDFs rather than a major loss of antagonist activity. BDB2 therefore sits at the junction of two mechanisms — the joint-fusion phenotypes of NOG haploinsufficiency and the terminal digital deficiency of ROR2 — and its existence is the main human evidence that ROR2 and BMP signalling interact in the developing digit.

Ask OpenScientist

Ask a research question about Brachydactyly Type B2. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
3
Pathophys.
7
Phenotypes
11
Pathograph
1
Genes
3
Medical Actions
2
References
🏷

Classifications

ISDS Skeletal Nosology
brachydactyly without extraskeletal manifestations
👪

Inheritance

1
Autosomal Dominant HP:0000006
Heterozygous NOG missense variants, in keeping with the dominant inheritance of the other NOG-related skeletal phenotypes.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:17668388 SUPPORT Human Clinical
"In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG)."
Six heterozygous point mutations across a patient subset establish the dominant NOG-related form.
⚙

Pathophysiology

3
Subtle Alteration of NOGGIN Ligand Binding
NOGGIN is a secreted antagonist that sequesters BMPs and GDFs, setting the level of BMP signal a tissue receives. Loss-of-function NOG alleles cause joint-fusion phenotypes — proximal symphalangism, multiple synostoses, stapes ankylosis — but not brachydactyly. The BDB2 variants behave differently: free-binding-energy calculations for the modelled NOG-GDF5 complex and micromass functional assays do not indicate a major loss of function, so the interpretation is a subtle shift in which ligands NOG binds and how tightly, tilting the BMP balance rather than removing the brake. That distinction is what explains why these alleles add terminal digital deficiency to the familiar NOG joint phenotype.
NOG hgnc:7866 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOG (hgnc:7866). hgnc:7866 is a gene from the HUGO Gene Nomenclature Committee.
Negative Regulation of BMP Signaling Pathway GO:0030514 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Negative Regulation of BMP Signaling Pathway (GO:0030514). GO:0030514 is a biological process from the Gene Ontology. ↕ DYSREGULATED BMP Signaling Pathway GO:0030509 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated BMP Signaling Pathway (GO:0030509). GO:0030509 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Deregulated BMP Balance at the Digital Ray and Interphalangeal Joints An altered antagonist changes the BMP/GDF signal reaching the condensing digital ray and the forming joints.
Show evidence (2 references)
PMID:17668388 SUPPORT In Vitro
"In contrast to previously described loss-of-function mutations in NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding..."
Separates the BDB2 allele class from the NOG loss-of-function alleles that cause joint fusion without brachydactyly.
PMID:17668388 SUPPORT In Vitro
"Rather, they presumably alter NOG's ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling."
States the proposed molecular mechanism of the BDB2 alleles.
Deregulated BMP Balance at the Digital Ray and Interphalangeal Joints
BMP signalling both drives chondrocyte differentiation within the digital condensation and specifies where the interzone forms that will become a joint. Shifting the balance therefore hits two things at once: segments fail to form distally (brachydactyly) and joints fail to cavitate proximally (symphalangism, carpal synostosis). The clinical combination in BDB2 — proximal joint fusion together with terminal digital deficiency — is the human read-out of that dual effect, and the authors read it as evidence that the ROR2 and BMP receptor pathways are functionally connected, plausibly via a heteromeric receptor complex at the cell surface.
Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology. Prechondrogenic Mesenchymal Cell CL:0008019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Prechondrogenic Mesenchymal Cell, annotated with mesenchymal cell (CL:0008019). CL:0008019 is a cell type from the Cell Ontology.
BMP Signaling Pathway GO:0030509 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated BMP Signaling Pathway (GO:0030509). GO:0030509 is a biological process from the Gene Ontology. ↕ DYSREGULATED Chondrocyte Differentiation GO:0002062 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Chondrocyte Differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology. ⚠ ABNORMAL Embryonic Digit Morphogenesis GO:0042733 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Embryonic Digit Morphogenesis (GO:0042733). GO:0042733 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Terminal Digital Deficiency with Proximal Joint Fusion Deregulated BMP output produces both the failure of distal segments and the failure of proximal joint cavitation.
Show evidence (2 references)
PMID:17668388 SUPPORT Human Clinical
"The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface."
The combined joint-fusion and terminal-deficiency phenotype is the evidence for BMP-ROR2 cross-talk in the digit.
PMID:19790289 SUPPORT Other
"These studies have shown that the BMP pathway plays a pivotal role in the normal development of digits and joints and that the majority of brachydactyly disease genes are directly or indirectly linked to this pathway."
Supports BMP signalling as the shared effector for both digit and joint formation.
Terminal Digital Deficiency with Proximal Joint Fusion
The realised malformation: hypoplasia or aplasia of distal and middle phalanges of fingers and toes II-V — typically severe in rays IV-V and milder in II-III — together with proximal and occasionally distal symphalangism, fusion of carpal and tarsal bones, and partial cutaneous syndactyly. The joint-fusion component is what separates the phenotype clinically from ROR2-related BDB1.
Limb Morphogenesis GO:0035108 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Limb Morphogenesis (GO:0035108). GO:0035108 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Type B Brachydactyly
Proximal Symphalangism
Distal Finger Symphalangism
Carpal Synostosis
Tarsal Synostosis
Aplasia or Hypoplasia of the Distal Phalanges of the Hand
Cutaneous Syndactyly
Show evidence (1 reference)
PMID:17668388 SUPPORT Human Clinical
"Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes"
Establishes the terminal digital deficiency shared with BDB1.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Brachydactyly Type B2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Limbs 3
Carpal Synostosis FREQUENT HP:0009702 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carpal synostosis (HP:0009702). HP:0009702 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17668388 SUPPORT Human Clinical
"the additional occurrence of proximal symphalangism and carpal synostosis"
Carpal synostosis is named alongside proximal symphalangism in the subtype definition.
Cutaneous Syndactyly OCCASIONAL HP:0012725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous syndactyly (HP:0012725). HP:0012725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36064339 SUPPORT Other
"fusion of carpal or tarsal bones, and partial cutaneous syndactyly"
Partial cutaneous syndactyly is part of the defining BDB2 description, not merely of the type B phenotype in general.
Tarsal Synostosis FREQUENT HP:0008368 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tarsal synostosis (HP:0008368). HP:0008368 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36064339 SUPPORT Other
"fusion of carpal or tarsal bones, and partial cutaneous syndactyly"
Names tarsal alongside carpal fusion in the BDB2 description.
Musculoskeletal 1
Proximal Symphalangism OBLIGATE HP:0100264 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal symphalangism (HP:0100264). HP:0100264 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17668388 SUPPORT Human Clinical
"clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis"
Proximal symphalangism is part of the clinical definition of this subtype.
Other 3
Type B Brachydactyly OBLIGATE HP:0005831 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type B brachydactyly (HP:0005831). HP:0005831 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17668388 SUPPORT Human Clinical
"Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes"
Defines the cardinal digital phenotype of the type B group.
Aplasia or Hypoplasia of the Distal Phalanges of the Hand VERY_FREQUENT Aplasia/Hypoplasia of the distal phalanges of the hand HP:0009835 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/Hypoplasia of the distal phalanges of the hand (HP:0009835). HP:0009835 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17668388 SUPPORT Human Clinical
"Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes"
Terminal deficiency of the fingers is the defining skeletal lesion.
Distal Finger Symphalangism FREQUENT HP:0001204 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal finger symphalangism (HP:0001204). HP:0001204 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36064339 SUPPORT Other
"BDB2611,377Hypoplasia of distal phalanges with distal and proximal symphalangism, fusion of carpal or tarsal bones, and partial cutaneous syndactylyNOG602,991"
A recent review tabulates distal as well as proximal symphalangism in the defining BDB2 description.
🧬

Genetic Associations

1
NOG Missense Variants (Causative)
Gene: NOG hgnc:7866 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NOG (hgnc:7866). hgnc:7866 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:17668388 SUPPORT Human Clinical
"we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG)"
Lists the BDB2 allele set.
PMID:17668388 SUPPORT In Vitro
"the newly identified BDB mutations do not indicate a major loss of function"
Distinguishes the BDB2 alleles from NOG null alleles on functional grounds.
💊

Medical Actions

3
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. NCIT:C15240
Counseling for autosomal dominant transmission of a NOG missense allele, including the point that other NOG variants in the family's differential cause joint fusion without brachydactyly.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms."
Supports inheritance- and phenotype-specific counseling.
Function- or Cosmesis-Directed Hand 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
Surgery is reserved for meaningful impairment of hand function or selected cosmetic indications; fused proximal joints limit what reconstruction can restore.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed."
Defines the limited surgical indications in isolated brachydactyly.
Hand Function Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical and occupational therapy where terminal deficiency and joint fusion limit grip and pinch.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"Physical therapy and ergotherapy may ameliorate hand function."
Supports function-directed rehabilitation.
🔬

Diagnosis

1
Clinical-radiographic and molecular diagnosis
Suspect BDB2 in a patient with the type B digital pattern who also has proximal symphalangism and carpal or tarsal synostosis, especially after a negative ROR2 result. Confirmation is by NOG sequencing. Because NOG loss-of-function alleles cause joint fusion without brachydactyly, the variant's predicted effect matters as much as its presence.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Terminal deficiency of digits II-V with proximal symphalangism and carpal synostosis on radiographs, plus a heterozygous NOG missense variant.
Show evidence (2 references)
PMID:17668388 SUPPORT Human Clinical
"In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG)."
Defines both the clinical trigger and the confirmatory test for BDB2.
PMID:18554391 SUPPORT Other
"Diagnosis is clinical, anthropometric and radiological."
Establishes the clinical-radiographic basis of brachydactyly diagnosis.
📊

Prevalence

1
Reported ROR2-negative BDB patients
Cases In Literature Unknown
No population estimate. BDB2 was delineated within a series of ROR2-negative BDB patients, in whom six distinct NOG point mutations were found; it is a minority of an already rare phenotype.
Show evidence (2 references)
PMID:17668388 SUPPORT Human Clinical
"Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) in the majority of patients."
Places the NOG-related form in the minority of BDB, ROR2 accounting for most patients.
PMID:18554391 SUPPORT Other
"The various types of isolated brachydactyly are rare, except for types A3 and D."
Places isolated type B among the rare brachydactylies.
{ }

Source YAML

click to show 
name: Brachydactyly Type B2
synonyms:
- BDB2
- NOG-related brachydactyly type B
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
description: >
  Brachydactyly type B2 (BDB2) is the NOG-related form of brachydactyly type B:
  the same terminal deficiency of fingers and toes II-V seen in ROR2-related BDB1,
  but with proximal symphalangism and carpal/tarsal synostosis added, plus partial
  cutaneous syndactyly. It was defined molecularly by testing ROR2-negative
  patients whose joints were fused proximally as well as distally. The causal
  variants are missense substitutions in NOGGIN, the secreted BMP/GDF antagonist,
  and they are pointedly not the loss-of-function alleles already known from the
  NOG symphalangism spectrum: modelling and micromass assays indicate a subtle
  change in NOG's affinity for BMPs and GDFs rather than a major loss of
  antagonist activity. BDB2 therefore sits at the junction of two mechanisms —
  the joint-fusion phenotypes of NOG haploinsufficiency and the terminal digital
  deficiency of ROR2 — and its existence is the main human evidence that ROR2
  and BMP signalling interact in the developing digit.
disease_term:
  preferred_term: brachydactyly type B2
  term:
    id: MONDO:0012658
    label: brachydactyly type B2
parents:
- Limb Development Disorders
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous NOG missense variants, in keeping with the dominant inheritance
    of the other NOG-related skeletal phenotypes.
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG)."
    explanation: Six heterozygous point mutations across a patient subset establish the dominant NOG-related form.
classifications:
  isds_skeletal_category:
  - classification_value: brachydactyly_without_extraskeletal_manifestations
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 18 "Brachydactylies (isolated)", which lists
      brachydactyly type B2 (NOG; OMIM 611377) as a row separate from
      ROR2-related type B. The other NOG-related entities — the multiple
      synostoses and proximal symphalangism syndromes — are placed in the
      synostoses group rather than here, so the gene does not determine the
      group. The 2019 revision (PMID:31633310) placed type B2 in group 37
      "Brachydactylies (without extraskeletal manifestations)". Per-row
      re-verification against the 2023 Table 1 is tracked in
      monarch-initiative/dismech#7867.
prevalence:
- population: Reported ROR2-negative BDB patients
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population estimate. BDB2 was delineated within a series of ROR2-negative
    BDB patients, in whom six distinct NOG point mutations were found; it is a
    minority of an already rare phenotype.
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) in the majority of patients."
    explanation: Places the NOG-related form in the minority of BDB, ROR2 accounting for most patients.
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The various types of isolated brachydactyly are rare, except for types A3 and D."
    explanation: Places isolated type B among the rare brachydactylies.
pathophysiology:
- name: Subtle Alteration of NOGGIN Ligand Binding
  conforms_to: "limb_digit_patterning_serial_homology#Limb Patterning Signal Perturbation"
  role: trigger
  biological_scale: MOLECULAR
  description: >
    NOGGIN is a secreted antagonist that sequesters BMPs and GDFs, setting the
    level of BMP signal a tissue receives. Loss-of-function NOG alleles cause
    joint-fusion phenotypes — proximal symphalangism, multiple synostoses,
    stapes ankylosis — but not brachydactyly. The BDB2 variants behave
    differently: free-binding-energy calculations for the modelled NOG-GDF5
    complex and micromass functional assays do not indicate a major loss of
    function, so the interpretation is a subtle shift in which ligands NOG binds
    and how tightly, tilting the BMP balance rather than removing the brake.
    That distinction is what explains why these alleles add terminal digital
    deficiency to the familiar NOG joint phenotype.
  gene:
    preferred_term: NOG
    term:
      id: hgnc:7866
      label: NOG
  biological_processes:
  - preferred_term: Negative Regulation of BMP Signaling Pathway
    term:
      id: GO:0030514
      label: negative regulation of BMP signaling pathway
    modifier: DYSREGULATED
  - preferred_term: BMP Signaling Pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast to previously described loss-of-function mutations in NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 complex and functional analysis of the micromass culture system."
    explanation: >-
      Separates the BDB2 allele class from the NOG loss-of-function alleles that
      cause joint fusion without brachydactyly.
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rather, they presumably alter NOG's ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling."
    explanation: States the proposed molecular mechanism of the BDB2 alleles.
  downstream:
  - target: Deregulated BMP Balance at the Digital Ray and Interphalangeal Joints
    description: >-
      An altered antagonist changes the BMP/GDF signal reaching the condensing
      digital ray and the forming joints.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17668388
      reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "thus disturbing the intricate balance of BMP signaling"
      explanation: Links the altered binding directly to a deregulated BMP signalling balance.
- name: Deregulated BMP Balance at the Digital Ray and Interphalangeal Joints
  conforms_to: "limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification"
  role: central_effector
  biological_scale: CELLULAR
  description: >
    BMP signalling both drives chondrocyte differentiation within the digital
    condensation and specifies where the interzone forms that will become a
    joint. Shifting the balance therefore hits two things at once: segments fail
    to form distally (brachydactyly) and joints fail to cavitate proximally
    (symphalangism, carpal synostosis). The clinical combination in BDB2 —
    proximal joint fusion together with terminal digital deficiency — is the
    human read-out of that dual effect, and the authors read it as evidence that
    the ROR2 and BMP receptor pathways are functionally connected, plausibly via
    a heteromeric receptor complex at the cell surface.
  biological_processes:
  - preferred_term: BMP Signaling Pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DYSREGULATED
  - preferred_term: Chondrocyte Differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: ABNORMAL
  - preferred_term: Embryonic Digit Morphogenesis
    term:
      id: GO:0042733
      label: embryonic digit morphogenesis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Prechondrogenic Mesenchymal Cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface."
    explanation: >-
      The combined joint-fusion and terminal-deficiency phenotype is the
      evidence for BMP-ROR2 cross-talk in the digit.
  - reference: PMID:19790289
    reference_title: "The brachydactylies: a molecular disease family."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These studies have shown that the BMP pathway plays a pivotal role in the normal development of digits and joints and that the majority of brachydactyly disease genes are directly or indirectly linked to this pathway."
    explanation: Supports BMP signalling as the shared effector for both digit and joint formation.
  downstream:
  - target: Terminal Digital Deficiency with Proximal Joint Fusion
    description: >-
      Deregulated BMP output produces both the failure of distal segments and
      the failure of proximal joint cavitation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17668388
      reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis"
      explanation: Names the composite phenotype that defines this subtype clinically.
- name: Terminal Digital Deficiency with Proximal Joint Fusion
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  role: consequence
  biological_scale: TISSUE
  description: >
    The realised malformation: hypoplasia or aplasia of distal and middle
    phalanges of fingers and toes II-V — typically severe in rays IV-V and milder
    in II-III — together with proximal and occasionally distal symphalangism,
    fusion of carpal and tarsal bones, and partial cutaneous syndactyly. The
    joint-fusion component is what separates the phenotype clinically from
    ROR2-related BDB1.
  biological_processes:
  - preferred_term: Limb Morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes"
    explanation: Establishes the terminal digital deficiency shared with BDB1.
  downstream:
  - target: Type B Brachydactyly
    causal_link_type: DIRECT
  - target: Proximal Symphalangism
    causal_link_type: DIRECT
  - target: Distal Finger Symphalangism
    causal_link_type: DIRECT
  - target: Carpal Synostosis
    causal_link_type: DIRECT
  - target: Tarsal Synostosis
    causal_link_type: DIRECT
  - target: Aplasia or Hypoplasia of the Distal Phalanges of the Hand
    causal_link_type: DIRECT
  - target: Cutaneous Syndactyly
    causal_link_type: DIRECT
phenotypes:
- category: Skeletal
  name: Type B Brachydactyly
  description: >
    Terminal deficiency of fingers and toes II-V, the phenotype shared with the
    ROR2-related form.
  phenotype_term:
    preferred_term: Type B brachydactyly
    term:
      id: HP:0005831
      label: Type B brachydactyly
  frequency: OBLIGATE
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes"
    explanation: Defines the cardinal digital phenotype of the type B group.
- category: Skeletal
  name: Proximal Symphalangism
  description: >
    Fusion of the proximal interphalangeal joints is the feature that clinically
    defines the NOG-related subtype and prompts NOG testing in an ROR2-negative
    patient.
  phenotype_term:
    preferred_term: Proximal symphalangism
    term:
      id: HP:0100264
      label: Proximal symphalangism
  frequency: OBLIGATE
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis"
    explanation: Proximal symphalangism is part of the clinical definition of this subtype.
- category: Skeletal
  name: Carpal Synostosis
  description: >
    Fusion of carpal (and tarsal) bones accompanies the interphalangeal fusion,
    reflecting a general failure of joint formation.
  phenotype_term:
    preferred_term: Carpal synostosis
    term:
      id: HP:0009702
      label: Carpal synostosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the additional occurrence of proximal symphalangism and carpal synostosis"
    explanation: Carpal synostosis is named alongside proximal symphalangism in the subtype definition.
- category: Skeletal
  name: Aplasia or Hypoplasia of the Distal Phalanges of the Hand
  description: >
    Distal and middle phalangeal deficiency of fingers II-V, characteristically
    more severe in rays IV-V than in II-III.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the distal phalanges of the hand
    term:
      id: HP:0009835
      label: Aplasia/Hypoplasia of the distal phalanges of the hand
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes"
    explanation: Terminal deficiency of the fingers is the defining skeletal lesion.
- category: Skeletal
  name: Cutaneous Syndactyly
  description: >
    Partial soft-tissue syndactyly of the affected rays is a recurrent minor
    feature.
  phenotype_term:
    preferred_term: Cutaneous syndactyly
    term:
      id: HP:0012725
      label: Cutaneous syndactyly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36064339
    reference_title: "A novel variant in the ROR2 gene underlying brachydactyly type B: a case report."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "fusion of carpal or tarsal bones, and partial cutaneous syndactyly"
    explanation: >-
      Partial cutaneous syndactyly is part of the defining BDB2 description,
      not merely of the type B phenotype in general.
- category: Skeletal
  name: Distal Finger Symphalangism
  description: >
    Distal interphalangeal fusion occurs alongside the proximal fusion that
    defines the subtype, so the joint failure is not confined to one level.
  phenotype_term:
    preferred_term: Distal finger symphalangism
    term:
      id: HP:0001204
      label: Distal finger symphalangism
  frequency: FREQUENT
  evidence:
  - reference: PMID:36064339
    reference_title: "A novel variant in the ROR2 gene underlying brachydactyly type B: a case report."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BDB2611,377Hypoplasia of distal phalanges with distal and proximal symphalangism, fusion of carpal or tarsal bones, and partial cutaneous syndactylyNOG602,991"
    explanation: >-
      A recent review tabulates distal as well as proximal symphalangism in the
      defining BDB2 description.
- category: Skeletal
  name: Tarsal Synostosis
  description: >
    Fusion extends to the tarsal bones as well as the carpals, the hindlimb
    counterpart of the same joint-formation failure.
  phenotype_term:
    preferred_term: Tarsal synostosis
    term:
      id: HP:0008368
      label: Tarsal synostosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:36064339
    reference_title: "A novel variant in the ROR2 gene underlying brachydactyly type B: a case report."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "fusion of carpal or tarsal bones, and partial cutaneous syndactyly"
    explanation: Names tarsal alongside carpal fusion in the BDB2 description.
genetic:
- name: NOG Missense Variants
  gene_term:
    preferred_term: NOG
    term:
      id: hgnc:7866
      label: NOG
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Six heterozygous missense substitutions (P35A, P35S, A36P, E48K, R167G,
    P187S) were reported in ROR2-negative BDB patients. Unlike the NOG
    loss-of-function alleles behind the symphalangism and multiple-synostoses
    spectrum, these are interpreted as altering ligand binding subtly rather
    than abolishing antagonist activity.
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG)"
    explanation: Lists the BDB2 allele set.
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the newly identified BDB mutations do not indicate a major loss of function"
    explanation: Distinguishes the BDB2 alleles from NOG null alleles on functional grounds.
diagnosis:
- name: Clinical-radiographic and molecular diagnosis
  description: >-
    Suspect BDB2 in a patient with the type B digital pattern who also has
    proximal symphalangism and carpal or tarsal synostosis, especially after a
    negative ROR2 result. Confirmation is by NOG sequencing. Because NOG
    loss-of-function alleles cause joint fusion without brachydactyly, the
    variant's predicted effect matters as much as its presence.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Terminal deficiency of digits II-V with proximal symphalangism and carpal
    synostosis on radiographs, plus a heterozygous NOG missense variant.
  evidence:
  - reference: PMID:17668388
    reference_title: A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG)."
    explanation: Defines both the clinical trigger and the confirmatory test for BDB2.
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis is clinical, anthropometric and radiological."
    explanation: Establishes the clinical-radiographic basis of brachydactyly diagnosis.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for autosomal dominant transmission of a NOG missense allele,
    including the point that other NOG variants in the family's differential
    cause joint fusion without brachydactyly.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms."
    explanation: Supports inheritance- and phenotype-specific counseling.
- name: Function- or Cosmesis-Directed Hand Surgery
  description: >-
    Surgery is reserved for meaningful impairment of hand function or selected
    cosmetic indications; fused proximal joints limit what reconstruction can
    restore.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed."
    explanation: Defines the limited surgical indications in isolated brachydactyly.
- name: Hand Function Rehabilitation
  description: >-
    Physical and occupational therapy where terminal deficiency and joint fusion
    limit grip and pinch.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Physical therapy and ergotherapy may ameliorate hand function."
    explanation: Supports function-directed rehabilitation.
references:
- reference: PMID:19790289
  title: "The brachydactylies: a molecular disease family."
- reference: PMID:18554391
  title: Brachydactyly.
📚

References & Deep Research

References

2
PMID:19790289
The brachydactylies: a molecular disease family.
No top-level findings curated for this source.
PMID:18554391
Brachydactyly.
No top-level findings curated for this source.