Brachydactyly Type C

Mendelian MONDO:0007221 Pathograph 11 Show in embeddings browser Limb Development Disorders

Brachydactyly type C (BDC) is an isolated hand malformation with an unusual signature: shortening of the middle phalanges of the index, middle, and little fingers combined with hyperphalangy — an extra, often triangular phalangeal segment — of the index and middle fingers, plus a short first metacarpal. The ring finger is spared and therefore ends up the longest digit, which is the single most useful bedside sign. BDC is caused by heterozygous loss-of-function variants in GDF5 (CDMP1), and the disease is locus homogeneous: the earlier suggestion of a second locus on chromosome 12 resolved to a GDF5 frameshift. Penetrance is incomplete and intra- and interfamilial variability is considerable, so an apparently skipped generation does not exclude the diagnosis. GDF5 dosage grades a whole allelic series — heterozygous loss-of-function gives BDC, while biallelic loss gives the far more severe Grebe type chondrodysplasia and Du Pan syndrome — and distinct GDF5 alleles that impair ligand processing or receptor affinity instead produce brachydactyly type A2 or A1.

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1
Inheritance
3
Pathophys.
7
Phenotypes
11
Pathograph
1
Genes
4
Medical Actions
3
References
🏷

Classifications

ISDS Skeletal Nosology
brachydactyly without extraskeletal manifestations
👪

Inheritance

1
Autosomal Dominant with Incomplete Penetrance HP:0000006
Autosomal dominant with demonstrated non-penetrance in mutation carriers and marked intra- and interfamilial variability. Rare families with an affected sibling pair born to unaffected consanguineous parents raised the possibility of a recessive form, and a semidominant pattern has been described in a consanguineous kindred in which homozygotes were more severely affected than heterozygotes.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:12357473 SUPPORT Human Clinical
"We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier."
Documents both dominant transmission and non-penetrance within the same series.
PMID:33872773 SUPPORT Human Clinical
"with severe GTC associated with homozygosity, and with a wide phenotypic variability among heterozygous carriers, ranging from unaffected non-penetrant carriers, to classical BDC and to novel unclassified types of brachydactylies"
A six-generation family shows the dosage effect and the full range of heterozygous expressivity.
⚙

Pathophysiology

3
GDF5 Functional Haploinsufficiency
GDF5 (CDMP1) is a secreted BMP-family ligand that acts through BMPR1B to drive chondrocyte differentiation and joint formation. BDC alleles are heterozygous frameshift, nonsense, and active-domain missense variants. Truncating alleles simply remove a functional copy; the missense alleles reach the same endpoint by a different route, failing to form the disulfide-linked dimers that the mature growth factor requires. Both converge on functional haploinsufficiency — roughly half the normal GDF5 activity — which distinguishes BDC from the dominant-negative BMPR1B alleles of type A2 and from the processing-site GDF5 allele that also causes A2.
GDF5 hgnc:4220 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GDF5 (hgnc:4220). hgnc:4220 is a gene from the HUGO Gene Nomenclature Committee.
BMP Signaling Pathway GO:0030509 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased BMP Signaling Pathway (GO:0030509). GO:0030509 is a biological process from the Gene Ontology. ↓ DECREASED SMAD Protein Signal Transduction GO:0060395 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased SMAD Protein Signal Transduction (GO:0060395). GO:0060395 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced GDF5-BMPR1B Signaling in the Digital Ray and Interzone Halved GDF5 activity lowers signalling through BMPR1B in the condensing digital ray and at the forming interphalangeal joints.
Show evidence (3 references)
PMID:12357473 SUPPORT Human Clinical
"Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC)."
Establishes heterozygous GDF5 variants as the cause of BDC.
PMID:12357473 SUPPORT In Vitro
"Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro."
Explains how active-domain missense alleles lose function.
PMID:12357473 SUPPORT In Vitro
"These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5."
States the inferred mechanism for BDC.
Reduced GDF5-BMPR1B Signaling in the Digital Ray and Interzone
GDF5 is expressed in the joint interzone and controls both chondrocyte differentiation in the digital ray and the segmentation that separates phalanges. Lowering it disturbs the segmentation program in two directions at once, which is why BDC uniquely pairs missing middle-phalangeal length with supernumerary phalangeal segments: some interzones fail to make a normal segment, while others produce an extra, malformed one. GDF5 is also the BDA2 and (in semidominant families) the BDA1 gene, so the type of brachydactyly tracks the allele's specific effect on ligand maturation and receptor affinity rather than the identity of the gene.
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.
Chondrocyte Differentiation GO:0002062 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Chondrocyte Differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology. ↓ DECREASED 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
Brachymesophalangy with Hyperphalangy of the Radial Digits The disturbed segmentation program yields short middle phalanges in rays II, III, and V and an extra phalangeal segment in rays II and III.
Show evidence (3 references)
PMID:14523231 SUPPORT Other
"GDF5, the most prominent member of the GDFs, was shown to play a vital role in the differentiation of chondrocytes and the formation of joints"
Establishes GDF5's dual role in chondrocyte differentiation and joint formation.
PMID:14523231 SUPPORT Other
"BDC is characterized by brachymesophalangia of the second, third, and fifth fingers, sometimes together with hyperphalangia, usually of the second and third fingers."
Describes the paired shortening-plus-extra-segment pattern that the segmentation defect produces.
PMID:19790289 SUPPORT Other
"As a consequence of the close interactions within the network, overlapping phenotypes are generated that are, nevertheless, characterized by specific recognizable patterns."
Supports the reading that the distinct brachydactyly patterns arise from graded perturbations of one shared regulatory network.
Brachymesophalangy with Hyperphalangy of the Radial Digits
The realised malformation: short middle phalanges of the index, middle, and little fingers; an extra phalangeal segment in the index and middle fingers, often with an anomalous proximal-phalanx configuration that deviates the index finger ulnarly; and a short first metacarpal. Because the ring finger is spared it becomes the longest digit. Feet are normal or show only ordinary brachydactyly, so unlike most brachydactylies the hand carries nearly all of the phenotype. The "angel-shaped phalanx" is a distinctive radiographic variant within the same CDMP1 spectrum.
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 C Brachydactyly
Finger Hyperphalangy
Short Middle Phalanx of Finger
Short First Metacarpal
Ulnar Deviation of the Index Finger
Clinodactyly of the Index or Middle Finger
Angel-Shaped Phalanx
Show evidence (2 references)
PMID:22828468 SUPPORT Human Clinical
"An "angel-shaped phalanx" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias"
Records the angel-shaped phalanx as a recognised BDC radiographic sign.
PMID:18554391 SUPPORT Other
"The ring finger is always the longest, longer than the index"
States the ring-finger sign that distinguishes BDC clinically.
⬡

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 C 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
Short Middle Phalanx of Finger OBLIGATE HP:0005819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short middle phalanx of finger (HP:0005819). HP:0005819 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22828468 SUPPORT Human Clinical
"displays brachymesophalangy of the second, third, and fifth fingers"
Names the affected rays.
Short First Metacarpal FREQUENT Short 1st metacarpal HP:0010034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short 1st metacarpal (HP:0010034). HP:0010034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22828468 SUPPORT Human Clinical
"a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger"
Lists the short first metacarpal among the defining features.
Clinodactyly of the Index or Middle Finger FREQUENT HP:0030084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly (HP:0030084). HP:0030084 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35502951 SUPPORT Human Clinical
"The clinodactyly defect was mostly observed in the index or middle fingers."
Localises the clinodactyly to the radial digits in 42 affected children.
PMID:35502951 SUPPORT Human Clinical
"Some of the affected children have severe clinodactyly requiring surgery."
Establishes clinodactyly as the clinically consequential component of BDC.
Other 4
Type C Brachydactyly OBLIGATE HP:0009373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type C brachydactyly (HP:0009373). HP:0009373 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22828468 SUPPORT Human Clinical
"Brachydactyly type C (BDC), a well-recognized autosomal dominant hand malformation, displays brachymesophalangy of the second, third, and fifth fingers, a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger."
Defines the cardinal BDC digital pattern.
Finger Hyperphalangy VERY_FREQUENT HP:0030367 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Finger hyperphalangy (HP:0030367). HP:0030367 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14523231 SUPPORT Other
"BDC is characterized by brachymesophalangia of the second, third, and fifth fingers, sometimes together with hyperphalangia, usually of the second and third fingers."
Places hyperphalangy in rays II and III as part of the defining description.
Ulnar Deviation of the Index Finger FREQUENT Ulnar deviation of the 2nd finger HP:0009464 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ulnar deviation of the 2nd finger (HP:0009464). HP:0009464 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22828468 SUPPORT Human Clinical
"ulnar deviation of the index finger"
Names index-finger ulnar deviation as a defining feature.
Angel-Shaped Phalanx OCCASIONAL HP:0032078 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Angel-shaped phalanx (HP:0032078). HP:0032078 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35502951 SUPPORT Human Clinical
"However, only 1 hand showed all the features of angel-shaped bony defect."
Quantifies how uncommon the complete angel-shaped picture is within a large BDC series.
PMID:22828468 SUPPORT Human Clinical
"An "angel-shaped phalanx" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias"
Establishes the angel-shaped phalanx as a recognised BDC radiographic sign.
🧬

Genetic Associations

1
GDF5 Loss-of-Function Variants (Causative)
Gene: GDF5 hgnc:4220 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GDF5 (hgnc:4220). hgnc:4220 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:12357473 SUPPORT Human Clinical
"Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12."
Resolves the apparent second locus and establishes locus homogeneity.
PMID:33872773 SUPPORT Human Clinical
"Different mutations in the Growth/Differentiation Factor 5 gene (GDF5) have been associated with varying types of skeletal dysplasia, including Grebe type chondrodysplasia (GTC), Hunter-Thompson syndrome, Du Pan Syndrome and Brachydactyly type C (BDC)."
Places BDC within the wider GDF5 allelic series.
PMID:33872773 SUPPORT Human Clinical
"Heterozygous pathogenic mutations exert milder effects, whereas homozygous mutations are known to manifest more severe phenotypes."
States the dosage relationship between BDC and the recessive GDF5 chondrodysplasias.
+ 1 more reference
💊

Medical Actions

4
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 with incomplete penetrance and wide expressivity, and — where both partners carry a GDF5 variant — for the severe biallelic phenotypes at the other end of the allelic series.
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:33872773 SUPPORT Human Clinical
"In this study, we report a GDF5 frameshift mutation (c.404delC) segregating over six generations in an extended consanguineous Pakistani family."
A consanguineous kindred in which the same allele produced both BDC and Grebe chondrodysplasia is the counseling scenario this covers.
Closing Wedge Osteotomy for Clinodactyly
Action: orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Where clinodactyly makes the digits overlap, a closing wedge osteotomy corrects the angulation. The largest reported series - 23 digits in Saudi children from 15 families, one surgeon, one technique - reports satisfactory midterm outcomes, with the authors themselves noting that long-term follow-up is lacking.
Show evidence (3 references)
PMID:35502951 SUPPORT Human Clinical
"Closing wedge osteotomy was done in a total of 23 digits with a satisfactory outcome."
Reports the outcome of the procedure across 23 operated digits.
PMID:35502951 SUPPORT Human Clinical
"Surgery for the clinodactyly defect was only done if there was finger overlap."
States the operative indication used in the series.
PMID:35502951 SUPPORT Human Clinical
"The closing wedge osteotomy used resulted in good midterm outcomes, although long-term follow-up is lacking."
Supports midterm benefit from closing wedge osteotomy, carrying the authors' own caveat that long-term follow-up is lacking, so nothing is established beyond the midterm horizon.
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 and is usually unnecessary.
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 digital shortening limits function.
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
Hand radiographs show brachymesophalangy of rays II, III, and V with hyperphalangy of rays II and III, a short first metacarpal, and a ring finger that is the longest digit. GDF5 sequencing confirms. Non-penetrant carriers are documented, so a negative family history and a negative examination in a parent do not exclude transmission.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Brachymesophalangy with hyperphalangy on hand radiographs and a heterozygous loss-of-function GDF5 variant.
Show evidence (2 references)
PMID:18554391 SUPPORT Other
"The ring finger is always the longest, longer than the index"
Gives the radiographic sign that discriminates BDC at the bedside.
PMID:12357473 SUPPORT Human Clinical
"show nonpenetrance in a mutation carrier"
Documented non-penetrance is why a normal parental examination does not exclude carriage.
📊

Prevalence

1
Reported pedigrees worldwide
Cases In Literature Unknown
No population-based estimate. BDC is described through family series; the defining mutational survey assembled ten probands or families.
Show evidence (2 references)
PMID:18554391 SUPPORT Other
"The various types of isolated brachydactyly are rare, except for types A3 and D."
Places isolated BDC among the rare brachydactylies.
PMID:12357473 SUPPORT Human Clinical
"We also describe heterozygous mutations in nine additional probands/families with BDC"
Illustrates the family-series basis of the BDC evidence base.
{ }

Source YAML

click to show 
name: Brachydactyly Type C
synonyms:
- BDC
- Brachydactyly with hyperphalangism, Haws type
- GDF5-related brachydactyly type C
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
description: >
  Brachydactyly type C (BDC) is an isolated hand malformation with an unusual
  signature: shortening of the middle phalanges of the index, middle, and little
  fingers combined with hyperphalangy — an extra, often triangular phalangeal
  segment — of the index and middle fingers, plus a short first metacarpal. The
  ring finger is spared and therefore ends up the longest digit, which is the
  single most useful bedside sign. BDC is caused by heterozygous loss-of-function
  variants in GDF5 (CDMP1), and the disease is locus homogeneous: the earlier
  suggestion of a second locus on chromosome 12 resolved to a GDF5 frameshift.
  Penetrance is incomplete and intra- and interfamilial variability is
  considerable, so an apparently skipped generation does not exclude the
  diagnosis. GDF5 dosage grades a whole allelic series — heterozygous
  loss-of-function gives BDC, while biallelic loss gives the far more severe
  Grebe type chondrodysplasia and Du Pan syndrome — and distinct GDF5 alleles
  that impair ligand processing or receptor affinity instead produce brachydactyly
  type A2 or A1.
disease_term:
  preferred_term: brachydactyly type C
  term:
    id: MONDO:0007221
    label: brachydactyly type C
parents:
- Limb Development Disorders
inheritance:
- name: Autosomal Dominant with Incomplete Penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant with demonstrated non-penetrance in mutation carriers and
    marked intra- and interfamilial variability. Rare families with an affected
    sibling pair born to unaffected consanguineous parents raised the possibility
    of a recessive form, and a semidominant pattern has been described in a
    consanguineous kindred in which homozygotes were more severely affected than
    heterozygotes.
  evidence:
  - reference: PMID:12357473
    reference_title: The mutational spectrum of brachydactyly type C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier."
    explanation: Documents both dominant transmission and non-penetrance within the same series.
  - reference: PMID:33872773
    reference_title: "A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with severe GTC associated with homozygosity, and with a wide phenotypic variability among heterozygous carriers, ranging from unaffected non-penetrant carriers, to classical BDC and to novel unclassified types of brachydactylies"
    explanation: A six-generation family shows the dosage effect and the full range of heterozygous expressivity.
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 C (GDF5; OMIM 113100). The biallelic GDF5 disorders —
      Grebe type chondrodysplasia, Hunter-Thompson and Du Pan syndrome — are
      acromesomelic dysplasias and belong to group 16, so the group follows the
      entity rather than the gene. The 2019 revision (PMID:31633310) placed type
      C 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. BDC is described through family series; the
    defining mutational survey assembled ten probands or families.
  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 BDC among the rare brachydactylies.
  - reference: PMID:12357473
    reference_title: The mutational spectrum of brachydactyly type C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also describe heterozygous mutations in nine additional probands/families with BDC"
    explanation: Illustrates the family-series basis of the BDC evidence base.
pathophysiology:
- name: GDF5 Functional Haploinsufficiency
  conforms_to: "limb_digit_patterning_serial_homology#Limb Patterning Signal Perturbation"
  role: trigger
  biological_scale: MOLECULAR
  description: >
    GDF5 (CDMP1) is a secreted BMP-family ligand that acts through BMPR1B to
    drive chondrocyte differentiation and joint formation. BDC alleles are
    heterozygous frameshift, nonsense, and active-domain missense variants.
    Truncating alleles simply remove a functional copy; the missense alleles
    reach the same endpoint by a different route, failing to form the
    disulfide-linked dimers that the mature growth factor requires. Both
    converge on functional haploinsufficiency — roughly half the normal GDF5
    activity — which distinguishes BDC from the dominant-negative BMPR1B alleles
    of type A2 and from the processing-site GDF5 allele that also causes A2.
  gene:
    preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  biological_processes:
  - preferred_term: BMP Signaling Pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DECREASED
  - preferred_term: SMAD Protein Signal Transduction
    term:
      id: GO:0060395
      label: SMAD protein signal transduction
    modifier: DECREASED
  evidence:
  - reference: PMID:12357473
    reference_title: The mutational spectrum of brachydactyly type C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC)."
    explanation: Establishes heterozygous GDF5 variants as the cause of BDC.
  - reference: PMID:12357473
    reference_title: The mutational spectrum of brachydactyly type C.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro."
    explanation: Explains how active-domain missense alleles lose function.
  - reference: PMID:12357473
    reference_title: The mutational spectrum of brachydactyly type C.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5."
    explanation: States the inferred mechanism for BDC.
  downstream:
  - target: Reduced GDF5-BMPR1B Signaling in the Digital Ray and Interzone
    description: >-
      Halved GDF5 activity lowers signalling through BMPR1B in the condensing
      digital ray and at the forming interphalangeal joints.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12357473
      reference_title: The mutational spectrum of brachydactyly type C.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5."
      explanation: Ties the allele class to a quantitative reduction in GDF5 signalling.
- name: Reduced GDF5-BMPR1B Signaling in the Digital Ray and Interzone
  conforms_to: "limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification"
  role: central_effector
  biological_scale: CELLULAR
  description: >
    GDF5 is expressed in the joint interzone and controls both chondrocyte
    differentiation in the digital ray and the segmentation that separates
    phalanges. Lowering it disturbs the segmentation program in two directions at
    once, which is why BDC uniquely pairs missing middle-phalangeal length with
    supernumerary phalangeal segments: some interzones fail to make a normal
    segment, while others produce an extra, malformed one. GDF5 is also the BDA2
    and (in semidominant families) the BDA1 gene, so the type of brachydactyly
    tracks the allele's specific effect on ligand maturation and receptor
    affinity rather than the identity of the gene.
  biological_processes:
  - preferred_term: Chondrocyte Differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: DECREASED
  - 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:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GDF5, the most prominent member of the GDFs, was shown to play a vital role in the differentiation of chondrocytes and the formation of joints"
    explanation: Establishes GDF5's dual role in chondrocyte differentiation and joint formation.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BDC is characterized by brachymesophalangia of the second, third, and fifth fingers, sometimes together with hyperphalangia, usually of the second and third fingers."
    explanation: Describes the paired shortening-plus-extra-segment pattern that the segmentation defect produces.
  - reference: PMID:19790289
    reference_title: "The brachydactylies: a molecular disease family."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As a consequence of the close interactions within the network, overlapping phenotypes are generated that are, nevertheless, characterized by specific recognizable patterns."
    explanation: >-
      Supports the reading that the distinct brachydactyly patterns arise from
      graded perturbations of one shared regulatory network.
  downstream:
  - target: Brachymesophalangy with Hyperphalangy of the Radial Digits
    description: >-
      The disturbed segmentation program yields short middle phalanges in rays
      II, III, and V and an extra phalangeal segment in rays II and III.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22828468
      reference_title: A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brachydactyly type C (BDC), a well-recognized autosomal dominant hand malformation, displays brachymesophalangy of the second, third, and fifth fingers, a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger."
      explanation: Names the realised digital pattern that follows from the segmentation defect.
- name: Brachymesophalangy with Hyperphalangy of the Radial Digits
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  role: consequence
  biological_scale: TISSUE
  description: >
    The realised malformation: short middle phalanges of the index, middle, and
    little fingers; an extra phalangeal segment in the index and middle fingers,
    often with an anomalous proximal-phalanx configuration that deviates the
    index finger ulnarly; and a short first metacarpal. Because the ring finger
    is spared it becomes the longest digit. Feet are normal or show only ordinary
    brachydactyly, so unlike most brachydactylies the hand carries nearly all of
    the phenotype. The "angel-shaped phalanx" is a distinctive radiographic
    variant within the same CDMP1 spectrum.
  biological_processes:
  - preferred_term: Limb Morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22828468
    reference_title: A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An \"angel-shaped phalanx\" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias"
    explanation: Records the angel-shaped phalanx as a recognised BDC radiographic sign.
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The ring finger is always the longest, longer than the index"
    explanation: States the ring-finger sign that distinguishes BDC clinically.
  downstream:
  - target: Type C Brachydactyly
    causal_link_type: DIRECT
  - target: Finger Hyperphalangy
    causal_link_type: DIRECT
  - target: Short Middle Phalanx of Finger
    causal_link_type: DIRECT
  - target: Short First Metacarpal
    causal_link_type: DIRECT
  - target: Ulnar Deviation of the Index Finger
    causal_link_type: DIRECT
  - target: Clinodactyly of the Index or Middle Finger
    causal_link_type: DIRECT
  - target: Angel-Shaped Phalanx
    causal_link_type: DIRECT
phenotypes:
- category: Skeletal
  name: Type C Brachydactyly
  description: >
    The defining pattern of brachymesophalangy in rays II, III, and V with
    hyperphalangy of rays II and III and a short first metacarpal.
  phenotype_term:
    preferred_term: Type C brachydactyly
    term:
      id: HP:0009373
      label: Type C brachydactyly
  frequency: OBLIGATE
  evidence:
  - reference: PMID:22828468
    reference_title: A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type C (BDC), a well-recognized autosomal dominant hand malformation, displays brachymesophalangy of the second, third, and fifth fingers, a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger."
    explanation: Defines the cardinal BDC digital pattern.
- category: Skeletal
  name: Finger Hyperphalangy
  description: >
    A supernumerary phalangeal segment, usually in the index and middle fingers,
    is the feature that separates BDC from the other brachymesophalangies.
  phenotype_term:
    preferred_term: Finger hyperphalangy
    term:
      id: HP:0030367
      label: Finger hyperphalangy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BDC is characterized by brachymesophalangia of the second, third, and fifth fingers, sometimes together with hyperphalangia, usually of the second and third fingers."
    explanation: Places hyperphalangy in rays II and III as part of the defining description.
- category: Skeletal
  name: Short Middle Phalanx of Finger
  description: >
    Shortening of the middle phalanges of the index, middle, and little fingers.
  phenotype_term:
    preferred_term: Short middle phalanx of finger
    term:
      id: HP:0005819
      label: Short middle phalanx of finger
  frequency: OBLIGATE
  evidence:
  - reference: PMID:22828468
    reference_title: A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "displays brachymesophalangy of the second, third, and fifth fingers"
    explanation: Names the affected rays.
- category: Skeletal
  name: Short First Metacarpal
  description: >
    Shortening of the first metacarpal is part of the classic BDC hand.
  phenotype_term:
    preferred_term: Short 1st metacarpal
    term:
      id: HP:0010034
      label: Short 1st metacarpal
  frequency: FREQUENT
  evidence:
  - reference: PMID:22828468
    reference_title: A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger"
    explanation: Lists the short first metacarpal among the defining features.
- category: Skeletal
  name: Ulnar Deviation of the Index Finger
  description: >
    An anomalous configuration of the index proximal phalanx deflects the finger
    ulnarly.
  phenotype_term:
    preferred_term: Ulnar deviation of the 2nd finger
    term:
      id: HP:0009464
      label: Ulnar deviation of the 2nd finger
  frequency: FREQUENT
  evidence:
  - reference: PMID:22828468
    reference_title: A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ulnar deviation of the index finger"
    explanation: Names index-finger ulnar deviation as a defining feature.
- category: Skeletal
  name: Clinodactyly of the Index or Middle Finger
  description: >
    Clinodactyly is the feature that turns BDC from a radiographic curiosity
    into a surgical problem: in the largest reported series it fell mostly on
    the index or middle fingers and was operated on when it caused the digits to
    overlap.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  frequency: FREQUENT
  evidence:
  - reference: PMID:35502951
    reference_title: "Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinodactyly defect was mostly observed in the index or middle fingers."
    explanation: Localises the clinodactyly to the radial digits in 42 affected children.
  - reference: PMID:35502951
    reference_title: "Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some of the affected children have severe clinodactyly requiring surgery."
    explanation: Establishes clinodactyly as the clinically consequential component of BDC.
- category: Skeletal
  name: Angel-Shaped Phalanx
  description: >
    A distinctive radiographic sign within the CDMP1 spectrum, though far from
    universal - in a 42-child series only a single hand showed the complete
    picture.
  phenotype_term:
    preferred_term: Angel-shaped phalanx
    term:
      id: HP:0032078
      label: Angel-shaped phalanx
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35502951
    reference_title: "Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, only 1 hand showed all the features of angel-shaped bony defect."
    explanation: Quantifies how uncommon the complete angel-shaped picture is within a large BDC series.
  - reference: PMID:22828468
    reference_title: A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An \"angel-shaped phalanx\" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias"
    explanation: Establishes the angel-shaped phalanx as a recognised BDC radiographic sign.
genetic:
- name: GDF5 Loss-of-Function Variants
  gene_term:
    preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Heterozygous frameshift, nonsense, and active-domain missense variants in
    GDF5 (CDMP1) on chromosome 20. BDC is locus homogeneous. The same gene in
    the biallelic state gives Grebe type chondrodysplasia and Du Pan syndrome,
    and distinct heterozygous alleles that impair precursor processing or
    receptor affinity give brachydactyly type A2 — so the allele, not the gene,
    determines the phenotype.
  evidence:
  - reference: PMID:12357473
    reference_title: The mutational spectrum of brachydactyly type C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12."
    explanation: Resolves the apparent second locus and establishes locus homogeneity.
  - reference: PMID:33872773
    reference_title: "A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Different mutations in the Growth/Differentiation Factor 5 gene (GDF5) have been associated with varying types of skeletal dysplasia, including Grebe type chondrodysplasia (GTC), Hunter-Thompson syndrome, Du Pan Syndrome and Brachydactyly type C (BDC)."
    explanation: Places BDC within the wider GDF5 allelic series.
  - reference: PMID:33872773
    reference_title: "A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous pathogenic mutations exert milder effects, whereas homozygous mutations are known to manifest more severe phenotypes."
    explanation: States the dosage relationship between BDC and the recessive GDF5 chondrodysplasias.
  - reference: PMID:35502951
    reference_title: "Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis was done in 6 families and confirmed the presence of 2 novel missense mutations (p.Met173Val in 3 families and p.Thr203Asn in 3 families) in the GDF5 gene."
    explanation: >-
      Adds two recurrent missense alleles to the BDC spectrum from a
      contemporary multi-family series.
diagnosis:
- name: Clinical-radiographic and molecular diagnosis
  description: >-
    Hand radiographs show brachymesophalangy of rays II, III, and V with
    hyperphalangy of rays II and III, a short first metacarpal, and a ring finger
    that is the longest digit. GDF5 sequencing confirms. Non-penetrant carriers
    are documented, so a negative family history and a negative examination in a
    parent do not exclude transmission.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Brachymesophalangy with hyperphalangy on hand radiographs and a heterozygous
    loss-of-function GDF5 variant.
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The ring finger is always the longest, longer than the index"
    explanation: Gives the radiographic sign that discriminates BDC at the bedside.
  - reference: PMID:12357473
    reference_title: The mutational spectrum of brachydactyly type C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "show nonpenetrance in a mutation carrier"
    explanation: Documented non-penetrance is why a normal parental examination does not exclude carriage.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for autosomal dominant transmission with incomplete penetrance
    and wide expressivity, and — where both partners carry a GDF5 variant — for
    the severe biallelic phenotypes at the other end of the allelic series.
  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:33872773
    reference_title: "A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we report a GDF5 frameshift mutation (c.404delC) segregating over six generations in an extended consanguineous Pakistani family."
    explanation: >-
      A consanguineous kindred in which the same allele produced both BDC and
      Grebe chondrodysplasia is the counseling scenario this covers.
- name: Closing Wedge Osteotomy for Clinodactyly
  description: >-
    Where clinodactyly makes the digits overlap, a closing wedge osteotomy
    corrects the angulation. The largest reported series - 23 digits in Saudi
    children from 15 families, one surgeon, one technique - reports satisfactory
    midterm outcomes, with the authors themselves noting that long-term
    follow-up is lacking.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:35502951
    reference_title: "Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Closing wedge osteotomy was done in a total of 23 digits with a satisfactory outcome."
    explanation: Reports the outcome of the procedure across 23 operated digits.
  - reference: PMID:35502951
    reference_title: "Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgery for the clinodactyly defect was only done if there was finger overlap."
    explanation: States the operative indication used in the series.
  - reference: PMID:35502951
    reference_title: "Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The closing wedge osteotomy used resulted in good midterm outcomes, although long-term follow-up is lacking."
    explanation: >-
      Supports midterm benefit from closing wedge osteotomy, carrying the
      authors' own caveat that long-term follow-up is lacking, so nothing is
      established beyond the midterm horizon.
- name: Function- or Cosmesis-Directed Hand Surgery
  description: >-
    Surgery is reserved for meaningful impairment of hand function or selected
    cosmetic indications and is usually unnecessary.
  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 digital shortening limits function.
  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.
- reference: PMID:9288091
  title: Mutations in CDMP1 cause autosomal dominant brachydactyly type C.
📚

References & Deep Research

References

3
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.
PMID:9288091
Mutations in CDMP1 cause autosomal dominant brachydactyly type C.
No top-level findings curated for this source.