Brachydactyly Type E1

Mendelian MONDO:0007223 Pathograph 12 Show in embeddings browser Limb Development Disorders

Brachydactyly type E1 is the HOXD13-related form of isolated brachydactyly type E: variable shortening of the metacarpals — classically the fourth, detected by the metacarpal sign — with phalanges of roughly normal length, though terminal phalanges are often short. Metatarsals may be involved, and affected people are often mildly short of stature. Radiographically it is indistinguishable from the hand of Albright hereditary osteodystrophy, and the differential is what most of the clinical work in BDE consists of: short metacarpals are a feature of Turner syndrome, of 2q37 deletion, and of several syndromes, so establishing that the brachydactyly is isolated is the diagnosis. Most isolated BDE remains molecularly unsolved; the HOXD13 form is defined by a handful of homeodomain missense and truncating alleles. This entry is deliberately scoped to the HOXD13 form, because the PTHLH-related type E2 is a separate disease that the ISDS nosology places in a different group.

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1
Inheritance
3
Pathophys.
8
Phenotypes
12
Pathograph
2
Genes
3
Medical Actions
3
References
🏷

Classifications

ISDS Skeletal Nosology
brachydactyly without extraskeletal manifestations
👪

Inheritance

1
Autosomal Dominant HP:0000006
Autosomal dominant with variable expressivity, variable involvement of metacarpals and metatarsals, and frequent bilateral asymmetry.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:18554391 SUPPORT Other
"As an isolated anomaly, type E brachydactyly is inherited as an autosomal dominant trait with variable expressivity"
States the inheritance pattern of isolated BDE.
PMID:22233338 SUPPORT Human Clinical
"We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the HOXD13 gene."
Father-to-daughter transmission of a heterozygous HOXD13 allele.
⚙

Pathophysiology

3
Altered HOXD13 Homeodomain Function
HOXD13, the most 5' gene of the HOXD cluster, encodes a homeodomain transcription factor that patterns the autopod. The alleles associated with isolated BDE are of two kinds: homeodomain missense substitutions, of which Ile314Leu at homeodomain position 47 has been shown to shift DNA-binding preference between related target sequences rather than abolish it, and truncating nonsense alleles such as p.E181X and p.R274X. Both classes are distinct from the polyalanine expansions and frameshifts that dominate the HOXD13 mutation spectrum and cause synpolydactyly — the same gene reaches a different limb phenotype through a different kind of lesion.
HOXD13 hgnc:5136 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HOXD13 (hgnc:5136). hgnc:5136 is a gene from the HUGO Gene Nomenclature Committee.
Regulation of Transcription by RNA Polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Regulation of Transcription by RNA Polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↕ DYSREGULATED
DNA-binding Transcription Factor Activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal DNA-binding Transcription Factor Activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Disturbed Metacarpal and Metatarsal Growth Specification Altered HOXD13 output changes how the length of the metacarpal and metatarsal segments is specified in the autopod.
Show evidence (4 references)
PMID:12649808 SUPPORT Human Clinical
"HOXD13, the most 5' gene of the HOXD cluster, encodes a homeodomain transcription factor with important functions in limb patterning and growth."
Establishes HOXD13's role in limb patterning.
PMID:12649808 SUPPORT Human Clinical
"Heterozygous mutations of human HOXD13, encoding polyalanine expansions or frameshifts, are believed to act by dominant negative or haploinsufficiency mechanisms and are predominantly associated with synpolydactyly phenotypes."
Contrasts the BDE allele class with the synpolydactyly allele class of the same gene.
PMID:12649808 SUPPORT In Vitro
"the Ile314Leu mutation (which resides at the 47th position of the homeodomain) exhibited increased affinity for a target containing the core recognition sequence 5'-TTAC-3' but decreased affinity for a 5'-TTAT-3' target"
Shows the missense allele rebalances rather than abolishes target-site selection.
+ 1 more reference
Disturbed Metacarpal and Metatarsal Growth Specification
The lesion acts on the metacarpal and metatarsal segments rather than on phalangeal segmentation, which is what separates type E from types A-C. Radiographs attribute the shortening to hypoplastic and partially fused metacarpal epiphyses, so as in type D the proximate abnormality is growth-plate behaviour in specific skeletal elements. Involvement is selective and asymmetric — most often the fourth ray, in variable combinations — and is postaxially weighted.
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.
Endochondral Ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Endochondral Ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology. ⚠ ABNORMAL Embryonic Digit Morphogenesis GO:0042733 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Embryonic Digit Morphogenesis (GO:0042733). GO:0042733 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Short Metacarpals with Preserved Phalangeal Length Selective metacarpal and metatarsal shortening produces small hands and feet with digits of near-normal proportion.
Show evidence (2 references)
PMID:18554391 SUPPORT Other
"This results from hypoplastic and partially fused metacarpal epiphyses"
Attributes the metacarpal shortening to hypoplastic, partially fused epiphyses.
PMID:22233338 SUPPORT Human Clinical
"Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb."
Establishes the postaxial, metacarpal-and-metatarsal distribution of the lesion.
Short Metacarpals with Preserved Phalangeal Length
The realised malformation: variable shortening of the metacarpals with phalanges of more or less normal length, terminal phalanges often short, metatarsals variably involved, hyperextensible hand joints, and mild short stature. The fourth metacarpal is the classic target and gives the metacarpal sign — a line touching the heads of the third and fifth metacarpals in the closed fist passes over, rather than through, the receding fourth.
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 E Brachydactyly
Short Fourth Metacarpal
Short Metacarpal
Short Metatarsal
Short Distal Phalanx of Finger
Short Broad Thumb (BDD Overlap)
Mild Short Stature
Round Face
Show evidence (2 references)
PMID:18554391 SUPPORT Other
"Variable shortening of the metacarpals with more or less normal length of phalanges"
Defines the cardinal BDE skeletal pattern.
PMID:18554391 SUPPORT Other
"Short 4th metacarpal can be diagnosed by a positive metacarpal sign."
Names the clinical sign that detects the characteristic fourth-ray shortening.
⬡

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 E1 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

8
Limbs 2
Short Fourth Metacarpal VERY_FREQUENT Short 4th metacarpal HP:0010044 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short 4th metacarpal (HP:0010044). HP:0010044 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"Short 4th metacarpal can be diagnosed by a positive metacarpal sign."
Establishes fourth-metacarpal shortening as the characteristic finding.
Short Metacarpal OBLIGATE HP:0010049 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short metacarpal (HP:0010049). HP:0010049 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"Variable shortening of the metacarpals with more or less normal length of phalanges"
Documents variable metacarpal involvement as the core lesion.
Other 6
Type E Brachydactyly OBLIGATE HP:0005863 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type E brachydactyly (HP:0005863). HP:0005863 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22233338 SUPPORT Human Clinical
"Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb."
Defines the cardinal BDE phenotype.
Short Metatarsal FREQUENT HP:0010743 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short metatarsal (HP:0010743). HP:0010743 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20170896 SUPPORT Human Clinical
"small hands and feet predominantly as a result of shortened metacarpals and metatarsals"
Documents metatarsal shortening as part of the BDE phenotype.
Mild Short Stature FREQUENT HP:0003502 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild short stature (HP:0003502). HP:0003502 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"Affected individuals are slightly short of stature."
Documents mild short stature as part of the isolated BDE phenotype.
Short Distal Phalanx of Finger FREQUENT HP:0009882 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short distal phalanx of finger (HP:0009882). HP:0009882 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"The terminal phalanges are often short."
Documents terminal-phalangeal shortening alongside the metacarpal lesion.
Short Broad Thumb (BDD Overlap) OCCASIONAL Short distal phalanx of the thumb HP:0009650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short distal phalanx of the thumb (HP:0009650). HP:0009650 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40589517 SUPPORT Human Clinical
"Some patients with HOXD13 gene variants present not only with BDE, but also with overlapping features of BDD, characterized by the shortening and broadening of thumbs"
States the BDD/BDE phenotypic overlap specific to HOXD13 carriers.
PMID:12649808 SUPPORT Human Clinical
"exhibiting overlap with brachydactyly types D and E"
The original HOXD13 report describes the same D/E overlap.
Round Face FREQUENT HP:0000311 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Round face (HP:0000311). HP:0000311 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"short of stature and have round facies but do not have ectopic calcification, mental retardation or cataract"
Documents round facies and, in the same sentence, the features whose absence distinguishes isolated BDE from pseudopseudohypoparathyroidism.
🧬

Genetic Associations

2
HOXD13 Homeodomain and Truncating Variants (Causative)
Gene: HOXD13 hgnc:5136 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HOXD13 (hgnc:5136). hgnc:5136 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:22233338 SUPPORT Human Clinical
"Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the HOXD13 gene."
Establishes HOXD13 homeodomain missense variants as the original molecular cause of isolated BDE.
PMID:22233338 SUPPORT Human Clinical
"In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous HOXD13 mutation."
Extends the BDE allele class to truncating variants.
PTHLH Variants (Type E2, Not This Entry) (Causative for the separate type E2 entity)
Gene: PTHLH hgnc:9607 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PTHLH (hgnc:9607). hgnc:9607 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (2 references)
PMID:20170896 SUPPORT Human Clinical
"Thus, loss-of-function mutations in PTHLH cause BDE with short stature."
Establishes PTHLH as the cause of the separate short-stature BDE entity.
PMID:20170896 SUPPORT Human Clinical
"In a large pedigree with BDE, short stature, and learning disabilities, we detected a microdeletion of approximately 900 kb encompassing PTHLH, the gene coding for parathyroid hormone related protein (PTHRP)."
Describes the PTHLH deletion phenotype that distinguishes type E2 from isolated type E1.
💊

Medical Actions

3
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for autosomal dominant transmission with variable expressivity, once syndromic causes of short metacarpals have been excluded.
Show evidence (1 reference)
PMID:18554391 SUPPORT Other
"The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms."
Supports inheritance- and phenotype-specific counseling.
Function- or Cosmesis-Directed Hand Surgery
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgery is reserved for meaningful impairment of hand function or selected cosmetic indications and is usually unnecessary in isolated BDE.
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 metacarpal shortening limits grip.
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 and foot radiographs show variably shortened metacarpals and metatarsals with near-normal phalanges; the metacarpal sign detects fourth-ray shortening at the bedside. The diagnostic work is mostly exclusion: the same hand occurs in Albright hereditary osteodystrophy, in Turner syndrome, in 2q37 deletion, and with PTHLH mutations, so isolated BDE is a diagnosis reached after those are excluded. HOXD13 sequencing confirms the type E1 form when positive, but is negative in most isolated BDE.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Short metacarpals with preserved phalangeal length and a positive metacarpal sign, with a heterozygous HOXD13 variant when molecularly solved.
Show evidence (5 references)
PMID:18554391 SUPPORT Other
"Clinical and radiological evaluation of hand bones."
States the diagnostic method for BDE.
PMID:18554391 SUPPORT Other
"a useful example of genetic heterogeneity, because in addition to the autosomal dominant isolated type and Albright hereditary osteodystrophy, it also occurs with Turner syndrome."
Names the principal differential diagnoses that must be excluded.
PMID:22233338 SUPPORT Human Clinical
"Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved."
Explains why a negative HOXD13 result does not exclude isolated BDE.
+ 2 more references
📊

Prevalence

3
Reported families worldwide
Cases In Literature Unknown
Isolated BDE is rare and the HOXD13-related form is rarer still: at the time of the fourth reported allele, only four HOXD13 mutations had been associated with typical isolated BDE.
Show evidence (2 references)
PMID:22233338 SUPPORT Human Clinical
"Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved."
States both the rarity of isolated BDE and its largely unresolved molecular basis.
PMID:22233338 SUPPORT Human Clinical
"The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE."
Quantifies how few HOXD13 alleles had been linked to isolated BDE.
Jirel ethnic group, eastern Nepal
Point Prevalence 390.0 per 100,000 >1 in 1,000
0.39% of a 2,130-person radiographically phenotyped community sample. This counts the BDE phenotype irrespective of molecular cause, so it is an upper bound on the HOXD13-related form rather than an estimate of it, and it describes a single ethnic group.
Show evidence (1 reference)
PMID:24022874 SUPPORT Human Clinical
"BDD was present in 3.55%, and BDE was present in 0.39%, of the study sample."
Gives a population frequency for the BDE phenotype. The cohort was phenotyped radiographically without molecular subtyping, so the figure bounds rather than measures the HOXD13-related form.
Chinese children attending a paediatric hospital
Point Prevalence 223.0 per 100,000 >1 in 1,000
135 BDE cases identified among 60,650 consecutive left-hand wrist radiographs (0.22%). This is a radiographic case-finding rate in children referred for hand films, not a general-population prevalence, and it counts the BDE pattern irrespective of cause - most of these children were not molecularly solved.
Show evidence (1 reference)
PMID:40589517 SUPPORT Human Clinical
"From 60,650 films, 135 BDE cases were identified, and their comprehensive phenotypes were collected."
Gives the numerator and denominator for the radiographic case-finding rate. The cohort is hospital-referred and molecularly unsubtyped, so this is a case-finding rate rather than a general-population prevalence.
{ }

Source YAML

click to show 
name: Brachydactyly Type E1
synonyms:
- BDE1
- HOXD13-related brachydactyly type E
- Isolated brachydactyly type E
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
description: >
  Brachydactyly type E1 is the HOXD13-related form of isolated brachydactyly type
  E: variable shortening of the metacarpals — classically the fourth, detected by
  the metacarpal sign — with phalanges of roughly normal length, though terminal
  phalanges are often short. Metatarsals may be involved, and affected people are
  often mildly short of stature. Radiographically it is indistinguishable from the
  hand of Albright hereditary osteodystrophy, and the differential is what most of
  the clinical work in BDE consists of: short metacarpals are a feature of Turner
  syndrome, of 2q37 deletion, and of several syndromes, so establishing that the
  brachydactyly is isolated is the diagnosis. Most isolated BDE remains
  molecularly unsolved; the HOXD13 form is defined by a handful of homeodomain
  missense and truncating alleles. This entry is deliberately scoped to the
  HOXD13 form, because the PTHLH-related type E2 is a separate disease that the
  ISDS nosology places in a different group.
disease_term:
  preferred_term: brachydactyly type E1
  term:
    id: MONDO:0007223
    label: brachydactyly type E1
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 expressivity, variable involvement of
    metacarpals and metatarsals, and frequent bilateral asymmetry.
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As an isolated anomaly, type E brachydactyly is inherited as an autosomal dominant trait with variable expressivity"
    explanation: States the inheritance pattern of isolated BDE.
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the HOXD13 gene."
    explanation: Father-to-daughter transmission of a heterozygous HOXD13 allele.
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 E (HOXD13; OMIM 113300 = type E1). The PTHLH-related
      type E2 is placed in the separate 2023 group 28, skeletal disorders of the
      parathyroid hormone signaling cascade, which is why this entry is scoped to
      the HOXD13 form rather than to the umbrella MONDO:0019677 "brachydactyly
      type E" — an umbrella entry would straddle two nosology groups and break
      the committee's one-group-per-disorder rule. Albright hereditary
      osteodystrophy, radiographically the closest mimic, is in group 17
      (acromelic dysplasias). The 2019 revision (PMID:31633310) placed type E 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 families worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Isolated BDE is rare and the HOXD13-related form is rarer still: at the time
    of the fourth reported allele, only four HOXD13 mutations had been associated
    with typical isolated BDE.
  evidence:
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved."
    explanation: States both the rarity of isolated BDE and its largely unresolved molecular basis.
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE."
    explanation: Quantifies how few HOXD13 alleles had been linked to isolated BDE.
- population: Jirel ethnic group, eastern Nepal
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 390.0
  notes: >-
    0.39% of a 2,130-person radiographically phenotyped community sample. This
    counts the BDE phenotype irrespective of molecular cause, so it is an upper
    bound on the HOXD13-related form rather than an estimate of it, and it
    describes a single ethnic group.
  evidence:
  - reference: PMID:24022874
    reference_title: Nonsyndromic brachydactyly type D and type E mapped to 7p15 in healthy children and adults from the Jirel ethnic group in eastern Nepal.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BDD was present in 3.55%, and BDE was present in 0.39%, of the study sample."
    explanation: >-
      Gives a population frequency for the BDE phenotype. The cohort was
      phenotyped radiographically without molecular subtyping, so the figure
      bounds rather than measures the HOXD13-related form.
- population: Chinese children attending a paediatric hospital
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 223.0
  notes: >-
    135 BDE cases identified among 60,650 consecutive left-hand wrist
    radiographs (0.22%). This is a radiographic case-finding rate in children
    referred for hand films, not a general-population prevalence, and it counts
    the BDE pattern irrespective of cause - most of these children were not
    molecularly solved.
  evidence:
  - reference: PMID:40589517
    reference_title: Establishing an algorithm for molecular genetic diagnostics in Chinese children with brachydactyly type E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From 60,650 films, 135 BDE cases were identified, and their comprehensive phenotypes were collected."
    explanation: >-
      Gives the numerator and denominator for the radiographic case-finding
      rate. The cohort is hospital-referred and molecularly unsubtyped, so this
      is a case-finding rate rather than a general-population prevalence.
pathophysiology:
- name: Altered HOXD13 Homeodomain Function
  conforms_to: "limb_digit_patterning_serial_homology#Limb Patterning Signal Perturbation"
  role: trigger
  biological_scale: MOLECULAR
  description: >
    HOXD13, the most 5' gene of the HOXD cluster, encodes a homeodomain
    transcription factor that patterns the autopod. The alleles associated with
    isolated BDE are of two kinds: homeodomain missense substitutions, of which
    Ile314Leu at homeodomain position 47 has been shown to shift DNA-binding
    preference between related target sequences rather than abolish it, and
    truncating nonsense alleles such as p.E181X and p.R274X. Both classes are
    distinct from the polyalanine expansions and frameshifts that dominate the
    HOXD13 mutation spectrum and cause synpolydactyly — the same gene reaches a
    different limb phenotype through a different kind of lesion.
  gene:
    preferred_term: HOXD13
    term:
      id: hgnc:5136
      label: HOXD13
  biological_processes:
  - preferred_term: Regulation of Transcription by RNA Polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: DNA-binding Transcription Factor Activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12649808
    reference_title: Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HOXD13, the most 5' gene of the HOXD cluster, encodes a homeodomain transcription factor with important functions in limb patterning and growth."
    explanation: Establishes HOXD13's role in limb patterning.
  - reference: PMID:12649808
    reference_title: Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous mutations of human HOXD13, encoding polyalanine expansions or frameshifts, are believed to act by dominant negative or haploinsufficiency mechanisms and are predominantly associated with synpolydactyly phenotypes."
    explanation: Contrasts the BDE allele class with the synpolydactyly allele class of the same gene.
  - reference: PMID:12649808
    reference_title: Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the Ile314Leu mutation (which resides at the 47th position of the homeodomain) exhibited increased affinity for a target containing the core recognition sequence 5'-TTAC-3' but decreased affinity for a 5'-TTAT-3' target"
    explanation: Shows the missense allele rebalances rather than abolishes target-site selection.
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "So far, only two missense HOXD13 substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE."
    explanation: Enumerates the BDE-associated HOXD13 allele set before the reported case.
  downstream:
  - target: Disturbed Metacarpal and Metatarsal Growth Specification
    description: >-
      Altered HOXD13 output changes how the length of the metacarpal and
      metatarsal segments is specified in the autopod.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12649808
      reference_title: Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both are associated with distinctive limb phenotypes in which brachydactyly of specific metacarpals, metatarsals, and phalangeal bones is the most constant feature, exhibiting overlap with brachydactyly types D and E."
      explanation: Links the HOXD13 alleles to selective metacarpal and metatarsal shortening.
- name: Disturbed Metacarpal and Metatarsal Growth Specification
  conforms_to: "limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification"
  role: central_effector
  biological_scale: TISSUE
  description: >
    The lesion acts on the metacarpal and metatarsal segments rather than on
    phalangeal segmentation, which is what separates type E from types A-C.
    Radiographs attribute the shortening to hypoplastic and partially fused
    metacarpal epiphyses, so as in type D the proximate abnormality is
    growth-plate behaviour in specific skeletal elements. Involvement is
    selective and asymmetric — most often the fourth ray, in variable
    combinations — and is postaxially weighted.
  biological_processes:
  - preferred_term: Endochondral Ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: ABNORMAL
  - preferred_term: Embryonic Digit Morphogenesis
    term:
      id: GO:0042733
      label: embryonic digit morphogenesis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This results from hypoplastic and partially fused metacarpal epiphyses"
    explanation: Attributes the metacarpal shortening to hypoplastic, partially fused epiphyses.
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb."
    explanation: Establishes the postaxial, metacarpal-and-metatarsal distribution of the lesion.
  downstream:
  - target: Short Metacarpals with Preserved Phalangeal Length
    description: >-
      Selective metacarpal and metatarsal shortening produces small hands and
      feet with digits of near-normal proportion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20170896
      reference_title: Deletion and point mutations of PTHLH cause brachydactyly type E.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal-dominant brachydactyly type E (BDE) is a congenital limb malformation characterized by small hands and feet predominantly as a result of shortened metacarpals and metatarsals."
      explanation: States the realised hand and foot morphology of BDE.
- name: Short Metacarpals with Preserved Phalangeal Length
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  role: consequence
  biological_scale: TISSUE
  description: >
    The realised malformation: variable shortening of the metacarpals with
    phalanges of more or less normal length, terminal phalanges often short,
    metatarsals variably involved, hyperextensible hand joints, and mild short
    stature. The fourth metacarpal is the classic target and gives the metacarpal
    sign — a line touching the heads of the third and fifth metacarpals in the
    closed fist passes over, rather than through, the receding fourth.
  biological_processes:
  - preferred_term: Limb Morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Variable shortening of the metacarpals with more or less normal length of phalanges"
    explanation: Defines the cardinal BDE skeletal pattern.
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Short 4th metacarpal can be diagnosed by a positive metacarpal sign."
    explanation: Names the clinical sign that detects the characteristic fourth-ray shortening.
  downstream:
  - target: Type E Brachydactyly
    causal_link_type: DIRECT
  - target: Short Fourth Metacarpal
    causal_link_type: DIRECT
  - target: Short Metacarpal
    causal_link_type: DIRECT
  - target: Short Metatarsal
    causal_link_type: DIRECT
  - target: Short Distal Phalanx of Finger
    causal_link_type: DIRECT
  - target: Short Broad Thumb (BDD Overlap)
    causal_link_type: DIRECT
  - target: Mild Short Stature
    causal_link_type: DIRECT
  - target: Round Face
    causal_link_type: DIRECT
phenotypes:
- category: Skeletal
  name: Type E Brachydactyly
  description: >
    The defining pattern of shortened metacarpals and metatarsals with relatively
    preserved phalangeal length.
  phenotype_term:
    preferred_term: Type E brachydactyly
    term:
      id: HP:0005863
      label: Type E brachydactyly
  frequency: OBLIGATE
  evidence:
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb."
    explanation: Defines the cardinal BDE phenotype.
- category: Skeletal
  name: Short Fourth Metacarpal
  description: >
    Shortening limited to or most pronounced in the fourth metacarpal is the
    classic presentation and the basis of the metacarpal sign.
  phenotype_term:
    preferred_term: Short 4th metacarpal
    term:
      id: HP:0010044
      label: Short 4th metacarpal
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Short 4th metacarpal can be diagnosed by a positive metacarpal sign."
    explanation: Establishes fourth-metacarpal shortening as the characteristic finding.
- category: Skeletal
  name: Short Metacarpal
  description: >
    Variable combinations of metacarpals are shortened, with frequent bilateral
    asymmetry.
  phenotype_term:
    preferred_term: Short metacarpal
    term:
      id: HP:0010049
      label: Short metacarpal
  frequency: OBLIGATE
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Variable shortening of the metacarpals with more or less normal length of phalanges"
    explanation: Documents variable metacarpal involvement as the core lesion.
- category: Skeletal
  name: Short Metatarsal
  description: >
    Metatarsals are involved in a proportion of affected individuals, the
    hindlimb counterpart of the metacarpal lesion.
  phenotype_term:
    preferred_term: Short metatarsal
    term:
      id: HP:0010743
      label: Short metatarsal
  frequency: FREQUENT
  evidence:
  - reference: PMID:20170896
    reference_title: Deletion and point mutations of PTHLH cause brachydactyly type E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "small hands and feet predominantly as a result of shortened metacarpals and metatarsals"
    explanation: Documents metatarsal shortening as part of the BDE phenotype.
- category: Growth
  name: Mild Short Stature
  description: >
    Affected individuals are often slightly short of stature; this is milder than
    in the PTHLH-related type E2, where short stature is a defining feature.
  phenotype_term:
    preferred_term: Mild short stature
    term:
      id: HP:0003502
      label: Mild short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Affected individuals are slightly short of stature."
    explanation: Documents mild short stature as part of the isolated BDE phenotype.
- category: Skeletal
  name: Short Distal Phalanx of Finger
  description: >
    Although type E is defined by metacarpal rather than phalangeal shortening,
    the terminal phalanges are often short as well.
  phenotype_term:
    preferred_term: Short distal phalanx of finger
    term:
      id: HP:0009882
      label: Short distal phalanx of finger
  frequency: FREQUENT
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The terminal phalanges are often short."
    explanation: Documents terminal-phalangeal shortening alongside the metacarpal lesion.
- category: Skeletal
  name: Short Broad Thumb (BDD Overlap)
  description: >
    Some HOXD13 carriers show the type D thumb - short and broad - on top of the
    type E metacarpal pattern. This overlap is the phenotypic counterpart of the
    shared gene, and it is why a single family can be reported under either
    heading.
  phenotype_term:
    preferred_term: Short distal phalanx of the thumb
    term:
      id: HP:0009650
      label: Short distal phalanx of the thumb
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40589517
    reference_title: Establishing an algorithm for molecular genetic diagnostics in Chinese children with brachydactyly type E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some patients with HOXD13 gene variants present not only with BDE, but also with overlapping features of BDD, characterized by the shortening and broadening of thumbs"
    explanation: States the BDD/BDE phenotypic overlap specific to HOXD13 carriers.
  - reference: PMID:12649808
    reference_title: Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exhibiting overlap with brachydactyly types D and E"
    explanation: The original HOXD13 report describes the same D/E overlap.
- category: Craniofacial
  name: Round Face
  description: >
    A round facies accompanies the mild short stature. It is the feature that
    makes isolated BDE resemble pseudopseudohypoparathyroidism, from which it is
    separated by the absence of ectopic calcification, intellectual disability,
    and cataract.
  phenotype_term:
    preferred_term: Round face
    term:
      id: HP:0000311
      label: Round face
  frequency: FREQUENT
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "short of stature and have round facies but do not have ectopic calcification, mental retardation or cataract"
    explanation: >-
      Documents round facies and, in the same sentence, the features whose
      absence distinguishes isolated BDE from pseudopseudohypoparathyroidism.
genetic:
- name: HOXD13 Homeodomain and Truncating Variants
  gene_term:
    preferred_term: HOXD13
    term:
      id: hgnc:5136
      label: HOXD13
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Heterozygous homeodomain missense substitutions (p.S308C, p.I314L) and
    truncating nonsense alleles (p.E181X, p.R274X). Only four HOXD13 alleles had
    been reported in typical isolated BDE as of the most recent case series, and
    the majority of isolated BDE has no identified molecular cause.
  evidence:
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the HOXD13 gene."
    explanation: Establishes HOXD13 homeodomain missense variants as the original molecular cause of isolated BDE.
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous HOXD13 mutation."
    explanation: Extends the BDE allele class to truncating variants.
- name: PTHLH Variants (Type E2, Not This Entry)
  gene_term:
    preferred_term: PTHLH
    term:
      id: hgnc:9607
      label: PTHLH
  association: Causative for the separate type E2 entity
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >-
    Recorded here only to mark the boundary of this entry. Loss-of-function
    PTHLH deletions and point mutations cause brachydactyly type E with short
    stature (type E2, MONDO:0013244, OMIM 613382), which the ISDS nosology places
    in the parathyroid hormone signaling cascade group rather than the
    brachydactyly group. PTHLH is not a cause of the HOXD13-related type E1
    curated here; `relationship_type: DISPUTED` flags that this row is a
    boundary marker rather than a gene-disease assertion for this entry.
  evidence:
  - reference: PMID:20170896
    reference_title: Deletion and point mutations of PTHLH cause brachydactyly type E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, loss-of-function mutations in PTHLH cause BDE with short stature."
    explanation: Establishes PTHLH as the cause of the separate short-stature BDE entity.
  - reference: PMID:20170896
    reference_title: Deletion and point mutations of PTHLH cause brachydactyly type E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a large pedigree with BDE, short stature, and learning disabilities, we detected a microdeletion of approximately 900 kb encompassing PTHLH, the gene coding for parathyroid hormone related protein (PTHRP)."
    explanation: Describes the PTHLH deletion phenotype that distinguishes type E2 from isolated type E1.
diagnosis:
- name: Clinical-radiographic and molecular diagnosis
  description: >-
    Hand and foot radiographs show variably shortened metacarpals and metatarsals
    with near-normal phalanges; the metacarpal sign detects fourth-ray shortening
    at the bedside. The diagnostic work is mostly exclusion: the same hand occurs
    in Albright hereditary osteodystrophy, in Turner syndrome, in 2q37 deletion,
    and with PTHLH mutations, so isolated BDE is a diagnosis reached after those
    are excluded. HOXD13 sequencing confirms the type E1 form when positive, but
    is negative in most isolated BDE.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Short metacarpals with preserved phalangeal length and a positive metacarpal
    sign, with a heterozygous HOXD13 variant when molecularly solved.
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical and radiological evaluation of hand bones."
    explanation: States the diagnostic method for BDE.
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a useful example of genetic heterogeneity, because in addition to the autosomal dominant isolated type and Albright hereditary osteodystrophy, it also occurs with Turner syndrome."
    explanation: Names the principal differential diagnoses that must be excluded.
  - reference: PMID:22233338
    reference_title: "Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved."
    explanation: Explains why a negative HOXD13 result does not exclude isolated BDE.
  - reference: PMID:40589517
    reference_title: Establishing an algorithm for molecular genetic diagnostics in Chinese children with brachydactyly type E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnostic yield was 19.1% in patients with isolated brachydactyly; 75% in patients with brachydactyly combined with short stature; 77.8% in patients with brachydactyly combined with facial dysmorphism; 83.3% in patients with brachydactyly combined with intellectual disability."
    explanation: >-
      Quantifies the payoff of sequencing by phenotype: isolated BDE is mostly
      unsolved, while any accompanying feature quadruples the yield - which is
      what makes "is this brachydactyly really isolated?" the decisive question.
  - reference: PMID:40589517
    reference_title: Establishing an algorithm for molecular genetic diagnostics in Chinese children with brachydactyly type E.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GNAS mutations were the leading cause (four cases), followed by EXT1 and ACAN defects."
    explanation: >-
      In an unselected radiographic BDE cohort the solved cases were mostly
      syndromic genes, not HOXD13 - so a BDE hand is more often a clue to
      another diagnosis than to isolated type E1.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for autosomal dominant transmission with variable expressivity,
    once syndromic causes of short metacarpals have been excluded.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms."
    explanation: Supports inheritance- and phenotype-specific counseling.
- name: Function- or Cosmesis-Directed Hand Surgery
  description: >-
    Surgery is reserved for meaningful impairment of hand function or selected
    cosmetic indications and is usually unnecessary in isolated BDE.
  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 metacarpal shortening limits grip.
  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:26698251
  title: "Concomitance of types D and E brachydactyly: a case report."
📚

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:26698251
Concomitance of types D and E brachydactyly: a case report.
No top-level findings curated for this source.