Brachydactyly Type B1

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Classifications

ISDS Skeletal Nosology

👪

Inheritance

1

Autosomal Dominant HP:0000006

Autosomal dominant with variable severity, described in multigenerational pedigrees since MacKinder. A single homozygous individual, the offspring of two affected parents, has been reported with a far more severe reduction deformity, indicating a gene-dosage effect on top of the dominant trait.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:10700182 SUPPORT Human Clinical

"Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies and characterized by terminal deficiency of the fingers and toes."

States the dominant inheritance and the severity rank of BDB among the brachydactylies.

PMID:10986040 SUPPORT Human Clinical

"Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain."

The homozygous case documents dosage sensitivity beyond simple dominance.

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Pathophysiology

3

Truncated ROR2 Receptor with a Specific Mutational Effect

ROR2 is a 943-residue orphan receptor tyrosine kinase that acts as a co-receptor for WNT5A. BDB1 alleles are nonsense, frameshift, or splice variants confined to two narrow windows flanking the intracellular tyrosine kinase domain, removing part or all of the intracellular portion of the protein. Two lines of evidence show this is not haploinsufficiency: individuals heterozygous for 9q22 deletions that remove ROR2 entirely have no BDB, and Ror2 heterozygous null mice are normal. The truncated receptor is therefore doing something a missing receptor does not — the localised clustering of the alleles points to a specific gain of function or dominant-interfering effect. Position within the window grades severity: distal truncations produce a more severe phenotype than proximal ones.

Prechondrogenic Mesenchymal Cell CL:0008019

ROR2 hgnc:10257

Non-canonical Wnt Signaling Pathway GO:0035567 ⚠ ABNORMAL

Downstream

Disrupted WNT5A-ROR2 Planar Cell Polarity Signaling in the Digital Ray The truncated co-receptor perturbs the WNT5A-ROR2 branch of non-canonical Wnt signalling that shapes the limb bud and its digital condensations.

Show evidence (5 references)

PMID:10700182 SUPPORT Human Clinical

"We identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7-amino-acid segment of the 943-amino-acid protein, all of which predict truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain."

Establishes the tight positional clustering of BDB1 alleles.

PMID:10700182 SUPPORT Human Clinical

"We obtained further evidence for this by demonstrating that two patients heterozygous for 9q22 deletions including ROR2 do not exhibit BDB."

Whole-gene deletion carriers without BDB exclude haploinsufficiency as the mechanism.

PMID:10700182 SUPPORT Human Clinical

"The localized nature of these mutations suggests that they confer a specific gain of function."

States the authors' interpretation of the allele clustering.

+ 2 more references

Disrupted WNT5A-ROR2 Planar Cell Polarity Signaling in the Digital Ray

WNT5A/ROR2 can feed several non-canonical branches; mouse genetics implicates the planar cell polarity (PCP) branch in the limb. Mutation of the PCP gene Vangl2 produces digit defects that resemble BDB1, including loss of phalanges, and lowering Wnt5a dosage in Vangl2 mutants worsens them. Mechanistically, PCP loss changes the shape of the early limb bud and of the digit pre-chondrogenic condensates — wider, thicker, shorter — and perturbs the FGF/BMP balance that regulates limb growth. That an aberrant increase in BMP signalling is the proximate cause of the brachydactyly is supported by the rescue: halving Bmp4 dosage partially suppresses the phalangeal loss. This is where the ROR2 and BMP-pathway brachydactylies converge.

Chondrocyte CL:0000138

Establishment of Planar Polarity GO:0001736 ↓ DECREASED BMP Signaling Pathway GO:0030509 ↑ INCREASED Embryonic Digit Morphogenesis GO:0042733 ⚠ ABNORMAL

Downstream

Terminal Deficiency of Digits II-V Shortened, mis-shapen digital condensates fail to form the distal skeletal elements and their overlying nail units.

Show evidence (3 references)

PMID:20962035 SUPPORT Model Organism

"We show that a mutation in the mouse PCP gene Vangl2 causes digit defects resembling the clinical phenotypes in BDB1, including loss of phalanges."

A PCP-pathway mouse mutant phenocopies the defining BDB1 phalangeal loss.

PMID:20962035 SUPPORT Model Organism

"The digit pre-chondrogenic condensates also become wider, thicker and shorter."

Identifies the cellular change in the digital condensation caused by PCP disruption.

PMID:20962035 SUPPORT Model Organism

"Halving the dosage of Bmp4 partially suppresses the loss of phalanges in Vangl2 mutants, supporting the hypothesis that an aberrant increase in Bmp signaling is the cause of the brachydactyly defect."

Genetic rescue identifies excess BMP signalling as the proximate cause of phalangeal loss.

Terminal Deficiency of Digits II-V

The realised malformation. Distal phalanges and nails of digits II-V are hypoplastic or absent, with variable middle-phalanx hypoplasia and distal or proximal symphalangism; thumbs and halluces are spared but often broad or partially duplicated. The deficit is symmetric, worse on the ulnar than the radial side, and milder in the feet than the hands. Because nail and distal phalanx develop as one apical unit, anonychia accompanies the bony deficiency rather than being a separate ectodermal disease.

Limb Morphogenesis GO:0035108 ⚠ ABNORMAL

Downstream

Type B Brachydactyly

Aplasia or Hypoplasia of the Distal Phalanges of the Hand

Aplasia or Hypoplasia of the Middle Phalanges of the Hand

Anonychia or Nail Dysplasia

Distal Finger Symphalangism

Broad or Partially Duplicated Thumb

Cutaneous Finger Syndactyly

Aplasia or Hypoplasia of the Distal Phalanges of the Toes

Broad Hallux

Show evidence (2 references)

PMID:10986040 SUPPORT Human Clinical

"readily distinguished from other brachydactylies by the characteristic shortening/hypoplasia of the distal phalanges, the occurrences of nail dysplasia, hypoplasia of middle phalanges, and variable degrees of distal and proximal symphalangism."

Defines the composite BDB skeletal and nail phenotype.

PMID:10700182 SUPPORT Human Clinical

"In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication."

Documents thumb and hallux sparing as part of the pattern.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Integument 1

Anonychia or Nail Dysplasia VERY_FREQUENT HP:0002164

Show evidence (1 reference)

PMID:10986040 SUPPORT Human Clinical

"Affected individuals exhibit typical features of BDB, which include bilateral hypoplasia of distal and middle phalanges of fingers and of toes 2–5, to a varying degree, and hypoplasia of nails on the corresponding rays"

Nail hypoplasia follows the same ray distribution as the bony deficiency.

Limbs 3

Broad or Partially Duplicated Thumb FREQUENT Broad thumb HP:0011304

Show evidence (1 reference)

PMID:10986040 SUPPORT Human Clinical

"Broad thumbs with or without distal duplication/clefts and syndactyly can be additional findings."

Establishes broad or duplicated thumbs as a recognised BDB feature.

Cutaneous Finger Syndactyly OCCASIONAL HP:0010554

Show evidence (2 references)

PMID:36064339 SUPPORT Human Clinical

"Among the 13 affected individuals, 10 had brachydactyly, and the remaining three had brachydactyly with syndactyly"

Quantifies syndactyly within a single large BDB1 pedigree.

PMID:36064339 SUPPORT Human Clinical

"She exhibited bilateral shortening and hypoplasia of the distal and middle phalanges of digits 2 to 5 with cutaneous syndactyly of right fingers 3 to 4."

Documents the cutaneous syndactyly in the molecularly confirmed proband.

Broad Hallux OCCASIONAL HP:0010055

Show evidence (1 reference)

PMID:36064339 SUPPORT Human Clinical

"she also had a broad hallux on both feet with nail dysplasia"

Documents broad halluces with nail dysplasia in an affected mother.

Other 5

Type B Brachydactyly OBLIGATE HP:0005831

Show evidence (1 reference)

PMID:10986040 SUPPORT Human Clinical

"Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails."

Defines the cardinal BDB phenotype.

Aplasia or Hypoplasia of the Distal Phalanges of the Hand OBLIGATE Aplasia/Hypoplasia of the distal phalanges of the hand HP:0009835

Show evidence (1 reference)

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."

Confirms terminal digital deficiency as the defining ROR2-related BDB lesion.

Distal Finger Symphalangism FREQUENT HP:0001204

Show evidence (1 reference)

PMID:10986040 SUPPORT Human Clinical

"distal hypoplasia of phalanges 2, 4, and 5, nail dysplasia, and distal symphalangism"

Documents distal symphalangism alongside the phalangeal hypoplasia in an affected pedigree.

Aplasia or Hypoplasia of the Distal Phalanges of the Toes VERY_FREQUENT Aplasia/Hypoplasia of the distal phalanges of the toes HP:0010185

Show evidence (1 reference)

PMID:10986040 SUPPORT Human Clinical

"bilateral hypoplasia of distal and middle phalanges of fingers and of toes 2–5, to a varying degree"

Documents symmetric involvement of toes 2-5 alongside the fingers.

Aplasia or Hypoplasia of the Middle Phalanges of the Hand VERY_FREQUENT Aplasia/Hypoplasia of the middle phalanges of the hand HP:0009843

Show evidence (1 reference)

PMID:36064339 SUPPORT Human Clinical

"is characterized by shortening or hypoplasia of the distal and middle phalanges of digits 2 through 5 with or without nail dysplasia, fusion of the middle and distal phalanges, variable degrees of distal and proximal symphalangism, and a broad or bifid thumb"

Middle-phalangeal hypoplasia and middle-distal fusion are part of the defining BDB1 description.

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Genetic Associations

1

ROR2 Truncating Variants Flanking the Tyrosine Kinase Domain (Causative)

Gene: ROR2 hgnc:10257 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:10986040 SUPPORT Human Clinical

"The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein."

Defines the two mutational windows in the BDB1 allele spectrum.

PMID:10932186 SUPPORT Human Clinical

"The nature of these mutations suggests that RRS is caused by loss of ROR2 activity."

Contrasts the recessive loss-of-function allele class with the dominant BDB1 truncations, supporting the allele-class distinction.

PMID:10932186 SUPPORT Human Clinical

"Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families"

Documents the biallelic Robinow alleles distributed across multiple ROR2 domains.

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Medical Actions

3

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling for autosomal dominant transmission with variable severity, including the markedly more severe phenotype expected if two affected partners have a homozygous child.

Show evidence (2 references)

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.

PMID:10986040 SUPPORT Human Clinical

"His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails."

Documents the severe homozygous outcome relevant to counseling two affected partners.

Reconstructive Hand Surgery

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

BDB1 is the most severe isolated brachydactyly and is one of the forms in which surgery is genuinely function-directed rather than cosmetic; the homozygous patient in the original series regained the ability to write after several orthopaedic hand operations.

Show evidence (2 references)

PMID:10986040 SUPPORT Human Clinical

"After several orthopedic operations he has become able to use his hand to write."

A functional gain after reconstructive hand surgery in the severest reported case.

PMID:18554391 SUPPORT Other

"Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed."

The general rule that brachydactyly surgery is reserved for functional impairment. Stated for the brachydactylies collectively rather than for the severe BDB case specifically.

Hand Function Rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Physical and occupational therapy where terminal digital deficiency limits grip and pinch.

Show evidence (1 reference)

PMID:18554391 SUPPORT Other

"Physical therapy and ergotherapy may ameliorate hand function."

Supports function-directed rehabilitation.

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Diagnosis

1

Clinical-radiographic and molecular diagnosis

Recognised clinically by terminal deficiency of digits II-V with absent or dysplastic nails and spared but broad thumbs; hand and foot radiographs show distal (and variably middle) phalangeal hypoplasia with symphalangism. Confirmation is by ROR2 sequencing. Because BDB1 alleles cluster in two narrow windows, an ROR2 whole-gene deletion found on array is evidence against BDB rather than for it, and an ROR2-negative patient with proximal symphalangism and carpal synostosis should be tested for NOG (type B2).

genetic testing NCIT:C15709

Results: Hypoplastic or absent distal phalanges and nails of digits II-V with spared thumbs, plus a truncating ROR2 variant flanking the tyrosine kinase domain.

Show evidence (2 references)

PMID:18554391 SUPPORT Other

"Diagnosis is clinical, anthropometric and radiological."

Establishes the clinical-radiographic basis of brachydactyly diagnosis.

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 the clinical trigger for testing NOG when ROR2 is negative.

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Prevalence

1

Reported pedigrees worldwide

Cases In Literature Unknown

No population-based estimate. BDB is documented through a small number of multigenerational pedigrees; the mutation series that defined the gene drew on three and five families respectively.

Show evidence (2 references)

PMID:18554391 SUPPORT Other

"The various types of isolated brachydactyly are rare, except for types A3 and D."

Places isolated BDB among the rare brachydactylies.

PMID:10986040 SUPPORT Human Clinical

"We report four novel mutations in ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB."

Illustrates that the BDB evidence base is family-series rather than population based.

{ }

Source YAML

click to show

name: Brachydactyly Type B1
synonyms:
- BDB1
- Brachydactyly type B
- ROR2-related brachydactyly type B
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
description: >
  Brachydactyly type B1 (BDB1) is the most severe of the isolated
  brachydactylies: an autosomal dominant terminal deficiency in which the distal
  phalanges and nails of fingers and toes II-V are hypoplastic or absent, the
  middle phalanges are variably short, and symphalangism, cutaneous syndactyly,
  and carpal/tarsal fusions are common. The thumbs and halluces are
  characteristically spared, though often broad, split, or partially duplicated,
  and the ulnar rays are affected more severely than the radial. BDB1 is caused
  by heterozygous truncating variants in ROR2, a co-receptor for WNT5A in
  non-canonical Wnt signalling. Crucially the alleles are not simple null
  alleles: they cluster in two narrow segments immediately before and after the
  intracellular tyrosine kinase domain, and carriers of whole-gene 9q22 deletions
  do not have BDB — so the mechanism is a specific mutational effect of the
  truncated receptor, not haploinsufficiency. Biallelic loss of ROR2 function
  instead causes autosomal recessive Robinow syndrome, making ROR2 an instructive
  example of two distinct diseases from one gene by two distinct allele classes.
disease_term:
  preferred_term: brachydactyly type B1
  term:
    id: MONDO:0007220
    label: brachydactyly type B1
parents:
- Limb Development Disorders
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant with variable severity, described in multigenerational
    pedigrees since MacKinder. A single homozygous individual, the offspring of
    two affected parents, has been reported with a far more severe reduction
    deformity, indicating a gene-dosage effect on top of the dominant trait.
  evidence:
  - reference: PMID:10700182
    reference_title: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies and characterized by terminal deficiency of the fingers and toes."
    explanation: States the dominant inheritance and the severity rank of BDB among the brachydactylies.
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain."
    explanation: The homozygous case documents dosage sensitivity beyond simple dominance.
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 B (ROR2; OMIM 113000). The NOG-related type B2 is a
      separate row in the same group and is curated separately as
      Brachydactyly Type B2; recessive Robinow syndrome, the other ROR2 disease,
      is not in this group. The 2019 revision (PMID:31633310) placed type B 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 pedigrees worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population-based estimate. BDB is documented through a small number of
    multigenerational pedigrees; the mutation series that defined the gene drew
    on three and five families respectively.
  evidence:
  - 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 BDB among the rare brachydactylies.
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four novel mutations in ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB."
    explanation: Illustrates that the BDB evidence base is family-series rather than population based.
pathophysiology:
- name: Truncated ROR2 Receptor with a Specific Mutational Effect
  conforms_to: "limb_digit_patterning_serial_homology#Limb Patterning Signal Perturbation"
  role: trigger
  biological_scale: MOLECULAR
  description: >
    ROR2 is a 943-residue orphan receptor tyrosine kinase that acts as a
    co-receptor for WNT5A. BDB1 alleles are nonsense, frameshift, or splice
    variants confined to two narrow windows flanking the intracellular tyrosine
    kinase domain, removing part or all of the intracellular portion of the
    protein. Two lines of evidence show this is not haploinsufficiency:
    individuals heterozygous for 9q22 deletions that remove ROR2 entirely have no
    BDB, and Ror2 heterozygous null mice are normal. The truncated receptor is
    therefore doing something a missing receptor does not — the localised
    clustering of the alleles points to a specific gain of function or
    dominant-interfering effect. Position within the window grades severity:
    distal truncations produce a more severe phenotype than proximal ones.
  gene:
    preferred_term: ROR2
    term:
      id: hgnc:10257
      label: ROR2
  biological_processes:
  - preferred_term: Non-canonical Wnt Signaling Pathway
    term:
      id: GO:0035567
      label: non-canonical Wnt signaling pathway
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Prechondrogenic Mesenchymal Cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  evidence:
  - reference: PMID:10700182
    reference_title: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7-amino-acid segment of the 943-amino-acid protein, all of which predict truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain."
    explanation: Establishes the tight positional clustering of BDB1 alleles.
  - reference: PMID:10700182
    reference_title: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We obtained further evidence for this by demonstrating that two patients heterozygous for 9q22 deletions including ROR2 do not exhibit BDB."
    explanation: Whole-gene deletion carriers without BDB exclude haploinsufficiency as the mechanism.
  - reference: PMID:10700182
    reference_title: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The localized nature of these mutations suggests that they confer a specific gain of function."
    explanation: States the authors' interpretation of the allele clustering.
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation."
    explanation: Documents the position-severity gradient within the mutational window.
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome."
    explanation: Separates the BDB allele class from the recessive Robinow loss-of-function class.
  downstream:
  - target: Disrupted WNT5A-ROR2 Planar Cell Polarity Signaling in the Digital Ray
    description: >-
      The truncated co-receptor perturbs the WNT5A-ROR2 branch of non-canonical
      Wnt signalling that shapes the limb bud and its digital condensations.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20962035
      reference_title: Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Brachydactyly type B (BDB1) and Robinow syndrome (RRS) are two skeletal disorders caused by mutations in ROR2, a co-receptor of Wnt5a."
      explanation: Places ROR2 in the WNT5A non-canonical signalling axis relevant to both disorders.
- name: Disrupted WNT5A-ROR2 Planar Cell Polarity Signaling in the Digital Ray
  conforms_to: "limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification"
  role: central_effector
  biological_scale: CELLULAR
  description: >
    WNT5A/ROR2 can feed several non-canonical branches; mouse genetics implicates
    the planar cell polarity (PCP) branch in the limb. Mutation of the PCP gene
    Vangl2 produces digit defects that resemble BDB1, including loss of
    phalanges, and lowering Wnt5a dosage in Vangl2 mutants worsens them.
    Mechanistically, PCP loss changes the shape of the early limb bud and of the
    digit pre-chondrogenic condensates — wider, thicker, shorter — and perturbs
    the FGF/BMP balance that regulates limb growth. That an aberrant increase in
    BMP signalling is the proximate cause of the brachydactyly is supported by
    the rescue: halving Bmp4 dosage partially suppresses the phalangeal loss.
    This is where the ROR2 and BMP-pathway brachydactylies converge.
  biological_processes:
  - preferred_term: Establishment of Planar Polarity
    term:
      id: GO:0001736
      label: establishment of planar polarity
    modifier: DECREASED
  - preferred_term: BMP Signaling Pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: INCREASED
  - 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
  evidence:
  - reference: PMID:20962035
    reference_title: Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that a mutation in the mouse PCP gene Vangl2 causes digit defects resembling the clinical phenotypes in BDB1, including loss of phalanges."
    explanation: A PCP-pathway mouse mutant phenocopies the defining BDB1 phalangeal loss.
  - reference: PMID:20962035
    reference_title: Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The digit pre-chondrogenic condensates also become wider, thicker and shorter."
    explanation: Identifies the cellular change in the digital condensation caused by PCP disruption.
  - reference: PMID:20962035
    reference_title: Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Halving the dosage of Bmp4 partially suppresses the loss of phalanges in Vangl2 mutants, supporting the hypothesis that an aberrant increase in Bmp signaling is the cause of the brachydactyly defect."
    explanation: Genetic rescue identifies excess BMP signalling as the proximate cause of phalangeal loss.
  downstream:
  - target: Terminal Deficiency of Digits II-V
    description: >-
      Shortened, mis-shapen digital condensates fail to form the distal skeletal
      elements and their overlying nail units.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered limb-bud and condensate geometry
    - aberrant increase in BMP signalling
    evidence:
    - reference: PMID:10700182
      reference_title: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "BDB arises as a primary defect of skeletal patterning"
      explanation: Limb-bud Ror2 expression places the lesion in skeletal patterning rather than later growth.
- name: Terminal Deficiency of Digits II-V
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  role: consequence
  biological_scale: TISSUE
  description: >
    The realised malformation. Distal phalanges and nails of digits II-V are
    hypoplastic or absent, with variable middle-phalanx hypoplasia and distal or
    proximal symphalangism; thumbs and halluces are spared but often broad or
    partially duplicated. The deficit is symmetric, worse on the ulnar than the
    radial side, and milder in the feet than the hands. Because nail and distal
    phalanx develop as one apical unit, anonychia accompanies the bony deficiency
    rather than being a separate ectodermal disease.
  biological_processes:
  - preferred_term: Limb Morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "readily distinguished from other brachydactylies by the characteristic shortening/hypoplasia of the distal phalanges, the occurrences of nail dysplasia, hypoplasia of middle phalanges, and variable degrees of distal and proximal symphalangism."
    explanation: Defines the composite BDB skeletal and nail phenotype.
  - reference: PMID:10700182
    reference_title: Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication."
    explanation: Documents thumb and hallux sparing as part of the pattern.
  downstream:
  - target: Type B Brachydactyly
    causal_link_type: DIRECT
  - target: Aplasia or Hypoplasia of the Distal Phalanges of the Hand
    causal_link_type: DIRECT
  - target: Aplasia or Hypoplasia of the Middle Phalanges of the Hand
    causal_link_type: DIRECT
  - target: Anonychia or Nail Dysplasia
    causal_link_type: DIRECT
  - target: Distal Finger Symphalangism
    causal_link_type: DIRECT
  - target: Broad or Partially Duplicated Thumb
    causal_link_type: DIRECT
  - target: Cutaneous Finger Syndactyly
    causal_link_type: DIRECT
  - target: Aplasia or Hypoplasia of the Distal Phalanges of the Toes
    causal_link_type: DIRECT
  - target: Broad Hallux
    causal_link_type: DIRECT
phenotypes:
- category: Skeletal
  name: Type B Brachydactyly
  description: >
    The defining pattern: terminal deficiency of digits II-V with absent or
    hypoplastic distal phalanges and nails, sparing the thumbs and halluces.
  phenotype_term:
    preferred_term: Type B brachydactyly
    term:
      id: HP:0005831
      label: Type B brachydactyly
  frequency: OBLIGATE
  evidence:
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails."
    explanation: Defines the cardinal BDB phenotype.
- category: Skeletal
  name: Aplasia or Hypoplasia of the Distal Phalanges of the Hand
  description: >
    Distal phalangeal deficiency of fingers II-V is the core skeletal lesion and
    is more severe on the ulnar side of the hand.
  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: 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, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) in the majority of patients."
    explanation: Confirms terminal digital deficiency as the defining ROR2-related BDB lesion.
- category: Skeletal
  name: Anonychia or Nail Dysplasia
  description: >
    Nails on the affected rays are dysplastic or absent, tracking the distal
    phalangeal deficiency because nail and terminal phalanx develop together.
  phenotype_term:
    preferred_term: Nail dysplasia
    term:
      id: HP:0002164
      label: Nail dysplasia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals exhibit typical features of BDB, which include bilateral hypoplasia of distal and middle phalanges of fingers and of toes 2–5, to a varying degree, and hypoplasia of nails on the corresponding rays"
    explanation: Nail hypoplasia follows the same ray distribution as the bony deficiency.
- category: Skeletal
  name: Distal Finger Symphalangism
  description: >
    Fusion of the interphalangeal joints, particularly distally, is a
    characteristic accompaniment of the terminal deficiency.
  phenotype_term:
    preferred_term: Distal finger symphalangism
    term:
      id: HP:0001204
      label: Distal finger symphalangism
  frequency: FREQUENT
  evidence:
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distal hypoplasia of phalanges 2, 4, and 5, nail dysplasia, and distal symphalangism"
    explanation: Documents distal symphalangism alongside the phalangeal hypoplasia in an affected pedigree.
- category: Skeletal
  name: Broad or Partially Duplicated Thumb
  description: >
    The thumb escapes the terminal deficiency but is frequently broad, flattened,
    split, or partially duplicated at the distal phalanx.
  phenotype_term:
    preferred_term: Broad thumb
    term:
      id: HP:0011304
      label: Broad thumb
  frequency: FREQUENT
  evidence:
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Broad thumbs with or without distal duplication/clefts and syndactyly can be additional findings."
    explanation: Establishes broad or duplicated thumbs as a recognised BDB feature.
- category: Skeletal
  name: Aplasia or Hypoplasia of the Distal Phalanges of the Toes
  description: >
    Feet are affected in the same distribution as the hands but less severely.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the distal phalanges of the toes
    term:
      id: HP:0010185
      label: Aplasia/Hypoplasia of the distal phalanges of the toes
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral hypoplasia of distal and middle phalanges of fingers and of toes 2–5, to a varying degree"
    explanation: Documents symmetric involvement of toes 2-5 alongside the fingers.
- category: Skeletal
  name: Aplasia or Hypoplasia of the Middle Phalanges of the Hand
  description: >
    Middle-phalangeal hypoplasia accompanies the distal deficiency, and in the
    severe end of the spectrum the middle and distal phalanges fuse rather than
    forming separately.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the middle phalanges of the hand
    term:
      id: HP:0009843
      label: Aplasia/Hypoplasia of the middle phalanges of the hand
  frequency: VERY_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: HUMAN_CLINICAL
    snippet: "is characterized by shortening or hypoplasia of the distal and middle phalanges of digits 2 through 5 with or without nail dysplasia, fusion of the middle and distal phalanges, variable degrees of distal and proximal symphalangism, and a broad or bifid thumb"
    explanation: Middle-phalangeal hypoplasia and middle-distal fusion are part of the defining BDB1 description.
- category: Skeletal
  name: Cutaneous Finger Syndactyly
  description: >
    Soft-tissue syndactyly of the affected rays occurs in a substantial minority
    and is the finding that most often brings a child to surgery; in a
    five-generation Chinese pedigree 3 of 13 affected members had syndactyly in
    addition to brachydactyly.
  phenotype_term:
    preferred_term: Cutaneous finger syndactyly
    term:
      id: HP:0010554
      label: Cutaneous finger 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: HUMAN_CLINICAL
    snippet: "Among the 13 affected individuals, 10 had brachydactyly, and the remaining three had brachydactyly with syndactyly"
    explanation: Quantifies syndactyly within a single large BDB1 pedigree.
  - reference: PMID:36064339
    reference_title: "A novel variant in the ROR2 gene underlying brachydactyly type B: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She exhibited bilateral shortening and hypoplasia of the distal and middle phalanges of digits 2 to 5 with cutaneous syndactyly of right fingers 3 to 4."
    explanation: Documents the cutaneous syndactyly in the molecularly confirmed proband.
- category: Skeletal
  name: Broad Hallux
  description: >
    The great toe is spared the terminal deficiency in the same way the thumb
    is, and like the thumb it is often broad, sometimes with nail dysplasia.
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
  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: HUMAN_CLINICAL
    snippet: "she also had a broad hallux on both feet with nail dysplasia"
    explanation: Documents broad halluces with nail dysplasia in an affected mother.
genetic:
- name: ROR2 Truncating Variants Flanking the Tyrosine Kinase Domain
  gene_term:
    preferred_term: ROR2
    term:
      id: hgnc:10257
      label: ROR2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Heterozygous nonsense, frameshift, and splice variants on 9q22 confined to
    two windows immediately before and after the intracellular tyrosine kinase
    domain. Distal truncations give a more severe phenotype than proximal ones.
    Whole-gene deletions do not cause BDB, and biallelic loss-of-function
    variants across the Frizzled-like, kringle, and kinase domains instead cause
    autosomal recessive Robinow syndrome — so the same gene yields two diseases
    through two different allele classes.
  evidence:
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein."
    explanation: Defines the two mutational windows in the BDB1 allele spectrum.
  - reference: PMID:10932186
    reference_title: Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The nature of these mutations suggests that RRS is caused by loss of ROR2 activity."
    explanation: >-
      Contrasts the recessive loss-of-function allele class with the dominant
      BDB1 truncations, supporting the allele-class distinction.
  - reference: PMID:10932186
    reference_title: Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families"
    explanation: Documents the biallelic Robinow alleles distributed across multiple ROR2 domains.
diagnosis:
- name: Clinical-radiographic and molecular diagnosis
  description: >-
    Recognised clinically by terminal deficiency of digits II-V with absent or
    dysplastic nails and spared but broad thumbs; hand and foot radiographs show
    distal (and variably middle) phalangeal hypoplasia with symphalangism.
    Confirmation is by ROR2 sequencing. Because BDB1 alleles cluster in two
    narrow windows, an ROR2 whole-gene deletion found on array is evidence
    against BDB rather than for it, and an ROR2-negative patient with proximal
    symphalangism and carpal synostosis should be tested for NOG (type B2).
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Hypoplastic or absent distal phalanges and nails of digits II-V with spared
    thumbs, plus a truncating ROR2 variant flanking the tyrosine kinase domain.
  evidence:
  - 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.
  - 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 the clinical trigger for testing NOG when ROR2 is negative.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for autosomal dominant transmission with variable severity,
    including the markedly more severe phenotype expected if two affected
    partners have a homozygous child.
  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.
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails."
    explanation: Documents the severe homozygous outcome relevant to counseling two affected partners.
- name: Reconstructive Hand Surgery
  description: >-
    BDB1 is the most severe isolated brachydactyly and is one of the forms in
    which surgery is genuinely function-directed rather than cosmetic; the
    homozygous patient in the original series regained the ability to write after
    several orthopaedic hand operations.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:10986040
    reference_title: Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After several orthopedic operations he has become able to use his hand to write."
    explanation: A functional gain after reconstructive hand surgery in the severest reported case.
  - 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: >-
      The general rule that brachydactyly surgery is reserved for functional
      impairment. Stated for the brachydactylies collectively rather than for
      the severe BDB case specifically.
- name: Hand Function Rehabilitation
  description: >-
    Physical and occupational therapy where terminal digital deficiency limits
    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.

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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.

Brachydactyly Type B1

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