Du Pan Syndrome

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Classifications

ISDS Skeletal Nosology

👪

Inheritance

2

Autosomal Recessive HP:0000007

The usual mode is autosomal recessive, with homozygous hypomorphic GDF5 or BMPR1B variants in consanguineous families and phenotypically normal heterozygous parents.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:12121354 SUPPORT Human Clinical

"The present authors have previously described a consanguineous Pakistani family with fibular hypoplasia and complex brachydactyly (DuPan syndrome) inherited as an autosomal recessive trait."

Establishes recessive transmission in the founding molecularly characterised kindred.

PMID:12121354 SUPPORT Human Clinical

"Obligate heterozygote parents were phenotypically normal."

Carrier parents are unaffected, consistent with a recessive rather than dominant-negative allele.

Autosomal Dominant (cis-allele exception) HP:0000006

One Polish family transmits du Pan syndrome dominantly. The affected allele carries three GDF5 variants in cis within the mature active domain, and the proposed explanation is that their combined effect on one allele reaches the threshold that normally requires two hit alleles. This is a single reported exception and should not be generalised.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:16222676 SUPPORT Human Clinical

"Three new heterozygous mutations clustered on one allele of the CDMP1 gene were identified in the affected individuals resulting in the first familial case with dominant Du Pan syndrome."

Documents the only reported dominantly transmitted du Pan kindred and its cis-allele basis.

PMID:16222676 SUPPORT Human Clinical

"A possible synergistic effect of the cis-acting mutations located in the active domain of the mature CDMP1 protein is likely to be responsible for the clinical expression of the disorder."

The proposed synergy of cis variants is the authors' interpretation rather than a functionally demonstrated mechanism, so this is recorded as partial support.

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Mechanistic Hypotheses

2

Residual GDF5-BMPR1B Signalling Dose Model

residual_signalling_dose_model CANONICAL

Evidence balance 2 support

The acromesomelic GDF5-BMPR1B disorders are one mechanism read at different doses. How much signalling an allele leaves, rather than which of the two genes it hits, determines whether the result is du Pan syndrome, Grebe dysplasia, or in the heterozygous state a brachydactyly. The strongest test is within BMPR1B, where the du Pan allele p.Arg31Cys and the Grebe allele p.Cys53Arg were assayed side by side and ranked in the order the phenotypes predict. The same logic holds for GDF5 p.Leu441Pro, which gives brachydactyly type A2 heterozygous and du Pan syndrome homozygous.

Show evidence (2 references)

PMID:26105076 SUPPORT In Vitro

"leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia"

Two alleles of one gene ranked by residual function match the severity order of the two diagnoses.

PMID:16127465 SUPPORT Human Clinical

"They cause brachydactyly type A2 (L441P) and symphalangism (R438L)"

Supplies the allele-dose half of the model: the du Pan GDF5 allele in one copy gives an isolated brachydactyly.

Receptor-Binding-Specificity Model

receptor_specificity_model ALTERNATIVE

Evidence balance 2 support

A competing reading of the same interface data is that what matters is not only how much receptor binding an allele leaves, but which receptor it binds. GDF5 p.Arg438Leu, one residue away from the du Pan allele, keeps normal BMPR1B binding but gains BMPR1A binding and causes symphalangism, a joint-fusion phenotype rather than a hypoplasia. On this view the du Pan and Grebe alleles sit at the loss end of a two-dimensional space whose other axis is receptor choice, and a purely quantitative dose model cannot predict the phenotype of an allele that redistributes binding rather than reducing it. This has not been tested against any acromesomelic allele.

Show evidence (2 references)

PMID:16127465 SUPPORT In Vitro

"whereas the R438L mutant showed normal binding to BMPR1B but increased binding to BMPR1A, the receptor normally activated by BMP2"

Documents an allele that changes receptor preference rather than overall binding strength.

PMID:16127465 SUPPORT In Vitro

"the symphalangism phenotype (R438L) is caused by a loss of receptor-binding specificity, resulting in a gain of function by the acquisition of BMP2-like properties"

States the specificity mechanism explicitly, as an alternative to a purely quantitative account of GDF5 allele effects.

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Discussions and Knowledge Gaps

3

What supportive, orthopaedic and rehabilitative management actually benefits du Pan syndrome?

KNOWLEDGE GAP OPEN no_disease_specific_management_literature

Attached to

treatments#

The treatments section is deliberately limited to genetic counselling, which is the one intervention the published literature for this disorder actually documents. Reconstructive and orthopaedic surgery, prosthetics, and physiotherapy are all plausible for a limb malformation of this severity and are presumably used in practice, but a search of the indexed literature returned no disease-specific management report for du Pan syndrome to cite. Curating them from general skeletal-dysplasia practice would be inference, not evidence, so the gap is recorded rather than filled. A case series reporting functional outcomes after surgical or prosthetic management would close it.

Is there any clinical or radiographic feature that separates GDF5-related from BMPR1B-related du Pan syndrome?

KNOWLEDGE GAP OPEN du_pan_gene_indistinguishability

Attached to

genetic#Biallelic Hypomorphic GDF5 Variants genetic#Biallelic Hypomorphic BMPR1B Variants

Polydactyly was the last candidate discriminator and it fell in 2024, when a BMPR1B case was reported with bilateral postaxial polydactyly. With so few published cases in either group, no feature is currently established as gene-specific, which is why this entry curates both aetiologies under one disease concept rather than splitting them.

Show evidence (1 reference)

PMID:39441036 SUPPORT Human Clinical

"Our case expands the phenotypical overlap between the different ACD types, du Pan and Grebe."

The authors frame their finding as widening, not narrowing, the phenotypic overlap.

Do the three cis GDF5 variants in the reported dominant du Pan family act synergistically, and is the dominant transmission reproducible?

KNOWLEDGE GAP OPEN dominant_du_pan_cis_allele

Attached to

inheritance#Autosomal Dominant (cis-allele exception)

A single Polish family transmits du Pan syndrome dominantly through one allele carrying three variants in the mature domain. The synergy is inferred from the pedigree, not measured, and no second dominant family has been reported in the twenty years since. Until it is functionally tested, this entry records the dominant inheritance block as an explicit exception rather than as an alternative mode of inheritance.

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Pathophysiology

3

Biallelic Hypomorphic Variants in GDF5 or BMPR1B

The initiating lesion is a partial, not complete, loss of function in either half of the GDF5-BMPR1B ligand-receptor pair. Reported du Pan alleles are missense changes that leave a folded protein with reduced activity rather than truncating alleles that remove it.

GDF5 hgnc:4220 BMPR1B hgnc:1077

Proteolytic maturation of the GDF5 precursor GO:0016485 ⚠ ABNORMAL

BMP receptor binding GO:0070700 ↓ DECREASED

Downstream

Partially Reduced GDF5-BMPR1B Signaling A hypomorphic allele in ligand or receptor directly lowers, without abolishing, signalling through the pair.

Show evidence (4 references)

PMID:16127465 SUPPORT In Vitro

"Biosensor interaction analyses revealed loss of binding to BMPR1A and BMPR1B ectodomains for the L441P mutant"

Identifies the initiating molecular lesion of the du Pan GDF5 allele as failure to engage the type I receptor ectodomains.

PMID:16127465 SUPPORT In Vitro

"The binding to NOGGIN was normal for both mutants."

Antagonist binding is preserved, so the lesion is specifically at the receptor interface rather than a general loss of ligand folding or of partner interactions.

PMID:26105076 SUPPORT Human Clinical

"The majority of patients with these disorders have biallelic loss-of-function mutations of GDF5."

Establishes biallelic GDF5 loss of function as the commonest route into the disorder.

+ 1 more reference

Partially Reduced GDF5-BMPR1B Signaling

GDF5 signals through BMPR1B, its preferred type I receptor. In du Pan syndrome this signalling is reduced but retained, which is the proposed explanation for why the same pathway lesion yields a mild rather than a devastating limb phenotype. This is a quantitative, dose-dependent claim about a normally regulated pathway, not a qualitative escape from regulation.

Chondrocyte CL:0000138

BMP signaling pathway GO:0030509 ↓ DECREASED Cell surface receptor protein serine/threonine kinase signaling pathway GO:0007178 ↓ DECREASED SMAD protein signal transduction GO:0060395 ↓ DECREASED Cartilage development GO:0051216 ⚠ ABNORMAL

BMP receptor activity GO:0098821 ↓ DECREASED BMP receptor binding GO:0070700 ↓ DECREASED

Downstream

Distal Limb Skeletal Element Hypoplasia with Preserved Growth Retained signalling permits the skeletal elements to form and grow, so the deficit is confined to the most signal-dependent structures of the distal limb and the fibula.

Show evidence (3 references)

PMID:26105076 SUPPORT Human Clinical

"GDF5 belongs to the bone morphogenetic protein (BMP) family and binds to the BMP receptors BMPR1A and BMPR1B, with a preference for BMPR1B"

Establishes the ligand-receptor relationship this node represents.

PMID:26105076 SUPPORT Human Clinical

"The phenotypic severity gradient of the clinically and radiologically related acromesomelic chondrodysplasia spectrum of skeletal disorders may be due to the extent of functional impairment of the ligand-receptor pair GDF5-BMPR1B."

States the dose-response model in which du Pan syndrome occupies the high-residual-signalling end.

PMID:17381068 SUPPORT In Vitro

"SMAD1/5/8 phosphorylation in nascent human mesenchymal stem cells (HMSCs) was stimulated weakly by rhGDF5 but strongly by rhBMP7."

Establishes SMAD1/5/8 phosphorylation as the transducer engaged by GDF5 in a human chondrogenic system, which is the basis for annotating SMAD signalling on this node. Support is partial, and deliberately so: GDF5's own SMAD stimulation is reported as weak, so SMAD phosphorylation may not be the whole of how GDF5 acts here.

Distal Limb Skeletal Element Hypoplasia with Preserved Growth

The output is a hand-and-foot malformation bundle - complex brachydactyly with hypoplastic or absent phalanges and metacarpals, and short deviated toes - accompanied by fibular hypoplasia, on a background of normal or near-normal stature. The bilateral hand-plus-foot pattern is the serially homologous signature of a limb patterning lesion.

Chondrocyte CL:0000138

Limb development GO:0060173 ⚠ ABNORMAL Cartilage development GO:0051216 ⚠ ABNORMAL Bone morphogenesis GO:0060349 ⚠ ABNORMAL Limb morphogenesis GO:0035108 ⚠ ABNORMAL

Show evidence (2 references)

PMID:39441036 SUPPORT Human Clinical

"The patient showed skeletal malformation of both hands and feet that included complex brachydactyly with the thumbs most severely affected, postaxial polydactyly of both hands, shortened toes as well as a bilateral hypoplasia of the fibula."

Documents the bilateral hand-and-foot malformation bundle with fibular hypoplasia.

PMID:12121354 SUPPORT Human Clinical

"All affected individuals showed either reductions or absence of bones in the limbs, and appendicular bone dysmorphogenesis with unaffected axial bones."

Confirms that the lesion is appendicular and spares the axial skeleton.

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Pathograph

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Phenotypes

7

Limbs 3

Complex Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:39441036 SUPPORT Human Clinical

"Radiological examination of the hands revealed bilateral hypoplastic metacarpal bones, especially very hypoplastic first metacarpals and absent proximal phalanges of the thumbs, malformed proximal phalanges of the other fingers, hypoplastic or absent and malformed middle phalanges"

Radiographs itemise the mixed element involvement that makes the brachydactyly complex.

Postaxial Polydactyly OCCASIONAL HP:0100259

Show evidence (1 reference)

PMID:39441036 SUPPORT Human Clinical

"However, this patient additionally shows a bilateral postaxial polydactyly of the hands-a novel clinical feature that has to date not been reported in BMPR1B-associated dysplasia patients in general."

Reports the finding and its novelty for BMPR1B, which is why it is curated as occasional rather than typical.

Syndactyly of the Toes OCCASIONAL HP:0001159

Show evidence (1 reference)

PMID:39441036 SUPPORT Human Clinical

"bilateral syndactyly between the second and third toes"

Documents toe syndactyly in a molecularly confirmed case.

Musculoskeletal 1

Camptodactyly OCCASIONAL HP:0012385

Show evidence (1 reference)

PMID:39441036 SUPPORT Human Clinical

"camptodactyly of the fourth fingers and ulnar deviation of the third fingers"

Documents camptodactyly in a molecularly confirmed case.

Other 3

Fibular Hypoplasia or Aplasia HP:0003038

Show evidence (2 references)

PMID:39441036 SUPPORT Human Clinical

"shortened toes as well as a bilateral hypoplasia of the fibula"

Documents bilateral fibular hypoplasia in a molecularly confirmed case.

PMID:26105076 SUPPORT Human Clinical

"milder limb involvement in du Pan dysplasia"

Places fibular hypoplasia within the milder limb involvement that characterises du Pan relative to Grebe dysplasia.

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

Show evidence (1 reference)

PMID:39441036 SUPPORT Human Clinical

"hypoplastic or absent and malformed middle phalanges"

Directly documents middle-phalangeal aplasia and hypoplasia.

Short Toes HP:0001831

Show evidence (1 reference)

PMID:39441036 SUPPORT Human Clinical

"The feet presented similarly with shortened toes with fibular deviation of the big toes, tibial deviation of the fifth toes and bilateral syndactyly between the second and third toes"

Documents the foot phenotype in a molecularly confirmed case.

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Genetic Associations

2

Biallelic Hypomorphic GDF5 Variants (Causative)

Gene: GDF5 hgnc:4220 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:12121354 SUPPORT Human Clinical

"Affected individuals were homozygous for a missense mutation, T1322C, in the coding region of the CDMP1 gene."

Establishes GDF5 as a cause of du Pan syndrome.

PMID:12121354 SUPPORT Human Clinical

"The T1322C change predicts a leu441pro substitution in the mature domain of the CDMP1 protein."

Localises the allele to the mature domain of the ligand.

PMID:16127465 SUPPORT In Vitro

"Biosensor interaction analyses revealed loss of binding to BMPR1A and BMPR1B ectodomains for the L441P mutant"

Direct binding measurement identifies the molecular defect of the du Pan GDF5 allele as loss of type I receptor engagement rather than a non-specific conformational change.

+ 1 more reference

Biallelic Hypomorphic BMPR1B Variants (Causative)

Gene: BMPR1B hgnc:1077 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:26105076 SUPPORT In Vitro

"We show that the homozygous c.91C>T, p.(Arg31Cys) mutation causing du Pan dysplasia leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia."

Functional assays quantify the du Pan allele as hypomorphic relative to the Grebe-causing allele in the same gene.

PMID:39441036 SUPPORT Human Clinical

"The analysis identified the biallelic variant NM_001203.3:c.821A > G;p.(Gln274Arg) in BMPR1B, a gene encoding bone morphogenetic protein receptor 1B."

Adds a second reported BMPR1B allele causing du Pan dysplasia.

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Medical Actions

1

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counselling for an autosomal recessive disorder, with the added complication that the causative GDF5 allele is not silent in carriers: p.Leu441Pro heterozygous causes brachydactyly type A2, so a "carrier" parent may have a visible hand phenotype of their own. One kindred also transmits the disorder dominantly through three cis variants on a single allele, which changes the recurrence risk entirely and is why counselling should follow the family's molecular result rather than the diagnosis label.

Show evidence (2 references)

PMID:37064338 SUPPORT Human Clinical

"GDF5 (NM_000557.5) sequencing identified a homozygous pathogenic variant c.1322T>C, p.(Leu441Pro) in the fetus and confirmed the carrier status in the mother."

Documents molecular confirmation of carrier status in a family, the step on which recurrence-risk counselling depends.

PMID:16222676 SUPPORT Human Clinical

"Three new heterozygous mutations clustered on one allele of the CDMP1 gene were identified in the affected individuals resulting in the first familial case with dominant Du Pan syndrome."

The dominantly transmitted kindred is the reason recurrence-risk counselling here has to follow the molecular result rather than an assumed recessive model.

🔬

Diagnosis

3

Gene Panel Covering the Acromesomelic Dysplasia Genes

Only three genes account for the isolated acromesomelic dysplasias in the GDF5-BMPR1B and NPR2 families, so a small targeted panel resolves most presentations; PRKG2 was added to that list after the review below was written.

Show evidence (1 reference)

PMID:26926249 SUPPORT Human Clinical

"Mutations in three genes (GDF5, NPR2, BMPR1B) have been reported to cause different forms of acromesomelic dysplasia."

Establishes the small gene set that a targeted panel needs to cover.

Prenatal Sonographic Diagnosis

Du Pan syndrome has been diagnosed prenatally on the combination of bilateral fibular agenesis with ball-shaped toes. The toes can be mistaken for preaxial polydactyly, which is the specific trap in reading the scan.

Show evidence (1 reference)

PMID:37064338 SUPPORT Human Clinical

"Here, we report the first prenatal diagnosis of Du Pan syndrome based on the sonographic findings of bilateral fibular agenesis and ball-shaped toes mimicking preaxial polydactyly accompanying subtle brachydactyly in the family."

Documents the prenatal sonographic pattern and the misreading it invites.

Sequential GDF5 then BMPR1B Sequencing

Because the two genes produce an overlapping phenotype, a du Pan-like presentation without a GDF5 variant should prompt BMPR1B sequencing. This is now explicitly recommended for cases that also show polydactyly, which was previously taken as evidence for a GDF5 aetiology.

Show evidence (1 reference)

PMID:39441036 SUPPORT Human Clinical

"individuals with du Pan acromesomelic dysplasia and polydactyly who do not carry pathogenic variants in GDF5, should be taken into account for BMPR1B sequencing"

States the recommended diagnostic escalation.

📊

Prevalence

1

Consanguineous kindreds, predominantly from Muslim-majority countries

Cases In Literature Ultra Rare

No population-based estimate exists. The reported case base is a small number of consanguineous families, with the ancestral concentration explicitly noted in the literature and a Caucasian family reported as an exception.

Show evidence (1 reference)

PMID:16222676 SUPPORT Human Clinical

"Du Pan syndrome is a rare acromesomelic dysplasia with characteristic clinical and radiographic findings. It is inherited as an autosomal recessive trait. Almost all the patients reported have been from Muslim countries."

Characterises the rarity and the ancestral distribution of reported cases.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Du Pan Syndrome:

Acromesomelic Dysplasia, Grebe Type MONDO:0008703

Overlapping Features The severe end of the same GDF5-BMPR1B spectrum, caused by alleles that abolish rather than reduce signalling.

Distinguishing Features

Grebe dysplasia causes severe dwarfism with rudimentary fingers and toes; stature and the long bones are preserved in du Pan syndrome.
The two are separated by residual pathway activity rather than by which gene is mutated, so the distinction is clinical and radiographic rather than molecular.

Show evidence (2 references)

PMID:26105076 SUPPORT Human Clinical

"While Grebe dysplasia is characterised by severe distal limb anomalies with rudimentary fingers and toes"

States the severe distal phenotype that separates Grebe dysplasia from du Pan syndrome.

PMID:26105076 SUPPORT In Vitro

"leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia"

Shows that the same gene gives either diagnosis according to residual receptor function.

Acromesomelic Dysplasia, Demirhan Type MONDO:0012274

Overlapping Features The BMPR1B-related Grebe-like disorder, which shares the receptor with BMPR1B-related du Pan syndrome but adds genital anomalies.

Distinguishing Features

Genital anomalies with hypergonadotrophic hypogonadism are present in the Demirhan type and absent in du Pan syndrome.
The Demirhan-type allele is truncating whereas the du Pan BMPR1B alleles are hypomorphic missense changes.

Show evidence (1 reference)

PMID:15805157 SUPPORT Human Clinical

"In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism."

Identifies the genital phenotype that separates the Demirhan type from du Pan syndrome.

Brachydactyly Type A2

Overlapping Features The heterozygous manifestation of the same GDF5 allele. A carrier parent or sibling of a du Pan proband may present with isolated index-finger brachydactyly rather than being unaffected, and BMPR1B brachydactyly type A2 is the dominant counterpart on the receptor side.

Distinguishing Features

Brachydactyly type A2 is dominant and confined to the digits, without the fibular deficiency that defines du Pan syndrome.
On the receptor side the mechanisms differ as well: brachydactyly type A2 arises from dominant-negative BMPR1B alleles, whereas du Pan syndrome arises from recessive hypomorphic ones.

Show evidence (2 references)

PMID:16127465 SUPPORT Human Clinical

"the brachydactyly type A2 phenotype (L441P) is caused by inhibition of the ligand-receptor interaction"

Identifies the heterozygous phenotype of the du Pan GDF5 allele and its mechanism.

PMID:14523231 SUPPORT Human Clinical

"These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner."

Establishes the dominant-negative mechanism that separates BDA2 from recessive BMPR1B du Pan syndrome.

Isolated Fibular Hemimelia

Overlapping Features Longitudinal fibular deficiency without the hand and foot malformation bundle. Du Pan syndrome should be considered when fibular hypoplasia is accompanied by bilateral complex brachydactyly, which is not a feature of isolated fibular hemimelia.

Distinguishing Features

Du Pan syndrome pairs the fibular deficiency with bilateral complex brachydactyly of hands and feet and is recessive with a molecular diagnosis in GDF5 or BMPR1B.

Show evidence (1 reference)

PMID:12121354 SUPPORT Human Clinical

"a consanguineous Pakistani family with fibular hypoplasia and complex brachydactyly (DuPan syndrome) inherited as an autosomal recessive trait"

The defining pairing of fibular hypoplasia with complex brachydactyly in a recessive kindred is what separates du Pan syndrome from an isolated fibular deficiency.

{ }

Source YAML

click to show

name: Du Pan Syndrome
synonyms:
- Fibular hypoplasia and complex brachydactyly
- Acromesomelic dysplasia 2B
- du Pan dysplasia
- Du Pan acromesomelic dysplasia
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Du Pan syndrome is the mild end of the acromesomelic GDF5-BMPR1B spectrum: an
  autosomal recessive limb malformation combining fibular hypoplasia or aplasia
  with complex brachydactyly and short, ball-shaped toes, while stature and the
  major long bones are largely preserved. It is caused by biallelic hypomorphic
  variants in either partner of the same ligand-receptor pair, GDF5 (the ligand,
  formerly CDMP1) or BMPR1B (its high-affinity type I receptor. The disorder is
  therefore best understood not as a separate mechanism from Grebe dysplasia but
  as the same mechanism operating at a higher level of residual signalling:
  alleles that leave partial GDF5-BMPR1B function produce du Pan syndrome,
  whereas alleles that abolish it produce Grebe dysplasia. Postaxial polydactyly,
  long regarded as a GDF5-specific finding, has now also been reported in a
  BMPR1B-related case, further blurring the boundary between the two genes'
  phenotypes. A single Polish kindred with three GDF5 variants in cis on one
  allele shows dominant transmission, the only reported exception to the
  recessive rule.
disease_term:
  preferred_term: du Pan syndrome
  term:
    id: MONDO:0009231
    label: acromesomelic dysplasia 2B
parents:
- Skeletal Dysplasia
classifications:
  isds_skeletal_category:
  - classification_value: acromesomelic_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 16 "Acromesomelic dysplasias". The revision lists the
      GDF5-related and BMPR1B-related forms of "Fibular hypoplasia and complex
      brachydactyly (Du Pan)" as two rows; this entry curates both under the
      single MONDO concept MONDO:0009231, so it carries one group value. Du Pan
      syndrome was in group 16 of the 2019 revision (PMID:31633310) as well.
    evidence:
    - reference: PMID:39441036
      reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        To date, four disease genes and seven distinct ACD subtypes with varying
        severity are recognised according to the 2023 revision of the nosology
        and classification of genetic skeletal disorders
      explanation: >-
        This is the sentence that ties the enumeration below to the 2023 ISDS
        nosology revision. It is quoted separately because the enumeration
        itself names diseases and OMIM numbers without repeating the nosology
        attribution, so on its own it would not support a group assignment.
    - reference: PMID:39441036
      reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        whereas pathogenic variants in BMPR1B can cause a Grebe dysplasia-like
        phenotype (OMIM #609441), as well as BMPR1B-related du Pan dysplasia
      explanation: >-
        A 2024 report enumerating the acromesomelic chondrodysplasia types of the
        2023 nosology revision records both a GDF5-related and a BMPR1B-related
        du Pan entity inside that group.
prevalence:
- population: Consanguineous kindreds, predominantly from Muslim-majority countries
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based estimate exists. The reported case base is a small number
    of consanguineous families, with the ancestral concentration explicitly noted
    in the literature and a Caucasian family reported as an exception.
  evidence:
  - reference: PMID:16222676
    reference_title: Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Du Pan syndrome is a rare acromesomelic dysplasia with characteristic
      clinical and radiographic findings. It is inherited as an autosomal
      recessive trait. Almost all the patients reported have been from Muslim
      countries.
    explanation: Characterises the rarity and the ancestral distribution of reported cases.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The usual mode is autosomal recessive, with homozygous hypomorphic GDF5 or
    BMPR1B variants in consanguineous families and phenotypically normal
    heterozygous parents.
  evidence:
  - reference: PMID:12121354
    reference_title: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present authors have previously described a consanguineous Pakistani
      family with fibular hypoplasia and complex brachydactyly (DuPan syndrome)
      inherited as an autosomal recessive trait.
    explanation: Establishes recessive transmission in the founding molecularly characterised kindred.
  - reference: PMID:12121354
    reference_title: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Obligate heterozygote parents were phenotypically normal.
    explanation: Carrier parents are unaffected, consistent with a recessive rather than dominant-negative allele.
- name: Autosomal Dominant (cis-allele exception)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    One Polish family transmits du Pan syndrome dominantly. The affected allele
    carries three GDF5 variants in cis within the mature active domain, and the
    proposed explanation is that their combined effect on one allele reaches the
    threshold that normally requires two hit alleles. This is a single reported
    exception and should not be generalised.
  evidence:
  - reference: PMID:16222676
    reference_title: Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three new heterozygous mutations clustered on one allele of the CDMP1 gene
      were identified in the affected individuals resulting in the first familial
      case with dominant Du Pan syndrome.
    explanation: Documents the only reported dominantly transmitted du Pan kindred and its cis-allele basis.
  - reference: PMID:16222676
    reference_title: Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A possible synergistic effect of the cis-acting mutations located in the
      active domain of the mature CDMP1 protein is likely to be responsible for
      the clinical expression of the disorder.
    explanation: >-
      The proposed synergy of cis variants is the authors' interpretation rather
      than a functionally demonstrated mechanism, so this is recorded as partial support.
genetic:
- name: Biallelic Hypomorphic GDF5 Variants
  gene_term:
    preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    The founding kindred is homozygous for a missense variant in the mature
    domain, T1322C predicting p.Leu441Pro. The 2002 report inferred a
    conformational change; direct biosensor measurement three years later showed
    the specific defect, which is loss of binding to the type I BMP receptor
    ectodomains. The same allele in the heterozygous state causes brachydactyly
    type A2, so p.Leu441Pro is a dosage series in one variant rather than two
    separate alleles.
  evidence:
  - reference: PMID:12121354
    reference_title: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals were homozygous for a missense mutation, T1322C, in
      the coding region of the CDMP1 gene.
    explanation: Establishes GDF5 as a cause of du Pan syndrome.
  - reference: PMID:12121354
    reference_title: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The T1322C change predicts a leu441pro substitution in the mature domain
      of the CDMP1 protein.
    explanation: Localises the allele to the mature domain of the ligand.
  - reference: PMID:16127465
    reference_title: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Biosensor interaction analyses revealed loss of binding to BMPR1A and
      BMPR1B ectodomains for the L441P mutant
    explanation: >-
      Direct binding measurement identifies the molecular defect of the du Pan
      GDF5 allele as loss of type I receptor engagement rather than a
      non-specific conformational change.
  - reference: PMID:16127465
    reference_title: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They cause brachydactyly type A2 (L441P) and symphalangism (R438L)
    explanation: >-
      The same p.Leu441Pro allele produces brachydactyly type A2 in the
      heterozygous state, establishing the dosage relationship with homozygous
      du Pan syndrome.
- name: Biallelic Hypomorphic BMPR1B Variants
  gene_term:
    preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported alleles are homozygous missense variants that reduce but do not
    abolish receptor function: p.Arg31Cys, functionally characterised as
    hypomorphic relative to the Grebe-causing p.Cys53Arg, and p.Gln274Arg in the
    protein kinase domain.
  evidence:
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that the homozygous c.91C>T, p.(Arg31Cys) mutation causing du Pan
      dysplasia leads to a significant loss of BMPR1B function, but to a lesser
      extent than the previously reported p.Cys53Arg mutation that results in the
      more severe Grebe dysplasia.
    explanation: >-
      Functional assays quantify the du Pan allele as hypomorphic relative to the
      Grebe-causing allele in the same gene.
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The analysis identified the biallelic variant NM_001203.3:c.821A >
      G;p.(Gln274Arg) in BMPR1B, a gene encoding bone morphogenetic protein
      receptor 1B.
    explanation: Adds a second reported BMPR1B allele causing du Pan dysplasia.
pathophysiology:
- name: Biallelic Hypomorphic Variants in GDF5 or BMPR1B
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion is a partial, not complete, loss of function in either
    half of the GDF5-BMPR1B ligand-receptor pair. Reported du Pan alleles are
    missense changes that leave a folded protein with reduced activity rather
    than truncating alleles that remove it.
  genes:
  - preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  - preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  molecular_functions:
  - preferred_term: BMP receptor binding
    term:
      id: GO:0070700
      label: BMP receptor binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: Proteolytic maturation of the GDF5 precursor
    term:
      id: GO:0016485
      label: protein processing
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16127465
    reference_title: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Biosensor interaction analyses revealed loss of binding to BMPR1A and
      BMPR1B ectodomains for the L441P mutant
    explanation: >-
      Identifies the initiating molecular lesion of the du Pan GDF5 allele as
      failure to engage the type I receptor ectodomains.
  - reference: PMID:16127465
    reference_title: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The binding to NOGGIN was normal for both mutants.
    explanation: >-
      Antagonist binding is preserved, so the lesion is specifically at the
      receptor interface rather than a general loss of ligand folding or of
      partner interactions.
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients with these disorders have biallelic
      loss-of-function mutations of GDF5.
    explanation: Establishes biallelic GDF5 loss of function as the commonest route into the disorder.
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ACD cannot only be caused by GDF5 mutations, but in rare cases also by
      loss-of-function BMPR1B mutations.
    explanation: Establishes the receptor as the alternative locus for the same disorder.
  downstream:
  - target: Partially Reduced GDF5-BMPR1B Signaling
    causal_link_type: DIRECT
    description: >-
      A hypomorphic allele in ligand or receptor directly lowers, without
      abolishing, signalling through the pair.
    evidence:
    - reference: PMID:26105076
      reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        p.(Arg31Cys) mutation causing du Pan dysplasia leads to a significant
        loss of BMPR1B function, but to a lesser extent than the previously
        reported p.Cys53Arg mutation
      explanation: Reporter assays show a graded, partial reduction of receptor function.
- name: Partially Reduced GDF5-BMPR1B Signaling
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    GDF5 signals through BMPR1B, its preferred type I receptor. In du Pan
    syndrome this signalling is reduced but retained, which is the proposed
    explanation for why the same pathway lesion yields a mild rather than a
    devastating limb phenotype. This is a quantitative, dose-dependent claim
    about a normally regulated pathway, not a qualitative escape from regulation.
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DECREASED
  - preferred_term: Cell surface receptor protein serine/threonine kinase signaling pathway
    term:
      id: GO:0007178
      label: cell surface receptor protein serine/threonine kinase signaling pathway
    modifier: DECREASED
  - preferred_term: SMAD protein signal transduction
    term:
      id: GO:0060395
      label: SMAD protein signal transduction
    modifier: DECREASED
  - preferred_term: Cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  molecular_functions:
  - preferred_term: BMP receptor activity
    term:
      id: GO:0098821
      label: BMP receptor activity
    modifier: DECREASED
  - preferred_term: BMP receptor binding
    term:
      id: GO:0070700
      label: BMP receptor binding
    modifier: DECREASED
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GDF5 belongs to the bone morphogenetic protein (BMP) family and binds to
      the BMP receptors BMPR1A and BMPR1B, with a preference for BMPR1B
    explanation: Establishes the ligand-receptor relationship this node represents.
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypic severity gradient of the clinically and radiologically
      related acromesomelic chondrodysplasia spectrum of skeletal disorders may
      be due to the extent of functional impairment of the ligand-receptor pair
      GDF5-BMPR1B.
    explanation: >-
      States the dose-response model in which du Pan syndrome occupies the
      high-residual-signalling end.
  - reference: PMID:17381068
    reference_title: Potential involvement of BMP receptor type IB activation in a synergistic effect of chondrogenic promotion between rhTGFbeta3 and rhGDF5 or rhBMP7 in human mesenchymal stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SMAD1/5/8 phosphorylation in nascent human mesenchymal stem cells (HMSCs)
      was stimulated weakly by rhGDF5 but strongly by rhBMP7.
    explanation: >-
      Establishes SMAD1/5/8 phosphorylation as the transducer engaged by GDF5 in
      a human chondrogenic system, which is the basis for annotating SMAD
      signalling on this node. Support is partial, and deliberately so: GDF5's
      own SMAD stimulation is reported as weak, so SMAD phosphorylation may not
      be the whole of how GDF5 acts here.
  downstream:
  - target: Distal Limb Skeletal Element Hypoplasia with Preserved Growth
    causal_link_type: DIRECT
    description: >-
      Retained signalling permits the skeletal elements to form and grow, so the
      deficit is confined to the most signal-dependent structures of the distal
      limb and the fibula.
    evidence:
    - reference: PMID:39441036
      reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our patient shows du Pan dysplasia with a mild phenotype. He has a normal
        height as well as no short femur, tibia, humerus, ulna or radius.
      explanation: Documents preserved long-bone growth alongside the distal malformation.
- name: Distal Limb Skeletal Element Hypoplasia with Preserved Growth
  role: consequence
  biological_scale: TISSUE
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  description: >-
    The output is a hand-and-foot malformation bundle - complex brachydactyly
    with hypoplastic or absent phalanges and metacarpals, and short deviated toes
    - accompanied by fibular hypoplasia, on a background of normal or near-normal
    stature. The bilateral hand-plus-foot pattern is the serially homologous
    signature of a limb patterning lesion.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Limb development
    term:
      id: GO:0060173
      label: limb development
    modifier: ABNORMAL
  - preferred_term: Cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  - preferred_term: Bone morphogenesis
    term:
      id: GO:0060349
      label: bone morphogenesis
    modifier: ABNORMAL
  - preferred_term: Limb morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient showed skeletal malformation of both hands and feet that
      included complex brachydactyly with the thumbs most severely affected,
      postaxial polydactyly of both hands, shortened toes as well as a bilateral
      hypoplasia of the fibula.
    explanation: Documents the bilateral hand-and-foot malformation bundle with fibular hypoplasia.
  - reference: PMID:12121354
    reference_title: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals showed either reductions or absence of bones in
      the limbs, and appendicular bone dysmorphogenesis with unaffected axial
      bones.
    explanation: Confirms that the lesion is appendicular and spares the axial skeleton.
mechanistic_hypotheses:
- hypothesis_group_id: residual_signalling_dose_model
  hypothesis_label: Residual GDF5-BMPR1B Signalling Dose Model
  status: CANONICAL
  description: >-
    The acromesomelic GDF5-BMPR1B disorders are one mechanism read at different
    doses. How much signalling an allele leaves, rather than which of the two
    genes it hits, determines whether the result is du Pan syndrome, Grebe
    dysplasia, or in the heterozygous state a brachydactyly. The strongest test
    is within BMPR1B, where the du Pan allele p.Arg31Cys and the Grebe allele
    p.Cys53Arg were assayed side by side and ranked in the order the phenotypes
    predict. The same logic holds for GDF5 p.Leu441Pro, which gives
    brachydactyly type A2 heterozygous and du Pan syndrome homozygous.
  evidence:
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      leads to a significant loss of BMPR1B function, but to a lesser extent
      than the previously reported p.Cys53Arg mutation that results in the more
      severe Grebe dysplasia
    explanation: Two alleles of one gene ranked by residual function match the severity order of the two diagnoses.
  - reference: PMID:16127465
    reference_title: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They cause brachydactyly type A2 (L441P) and symphalangism (R438L)
    explanation: >-
      Supplies the allele-dose half of the model: the du Pan GDF5 allele in one
      copy gives an isolated brachydactyly.
- hypothesis_group_id: receptor_specificity_model
  hypothesis_label: Receptor-Binding-Specificity Model
  status: ALTERNATIVE
  description: >-
    A competing reading of the same interface data is that what matters is not
    only how much receptor binding an allele leaves, but which receptor it
    binds. GDF5 p.Arg438Leu, one residue away from the du Pan allele, keeps
    normal BMPR1B binding but gains BMPR1A binding and causes symphalangism, a
    joint-fusion phenotype rather than a hypoplasia. On this view the du Pan and
    Grebe alleles sit at the loss end of a two-dimensional space whose other
    axis is receptor choice, and a purely quantitative dose model cannot predict
    the phenotype of an allele that redistributes binding rather than reducing
    it. This has not been tested against any acromesomelic allele.
  evidence:
  - reference: PMID:16127465
    reference_title: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      whereas the R438L mutant showed normal binding to BMPR1B but increased
      binding to BMPR1A, the receptor normally activated by BMP2
    explanation: Documents an allele that changes receptor preference rather than overall binding strength.
  - reference: PMID:16127465
    reference_title: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the symphalangism phenotype (R438L) is caused by a loss of receptor-binding
      specificity, resulting in a gain of function by the acquisition of
      BMP2-like properties
    explanation: >-
      States the specificity mechanism explicitly, as an alternative to a purely
      quantitative account of GDF5 allele effects.
phenotypes:
- category: Skeletal
  name: Fibular Hypoplasia or Aplasia
  description: >-
    Hypoplasia of the fibula is the defining lower-limb feature and gives the
    disorder its descriptive name; complete aplasia occurs in more severe cases.
  phenotype_term:
    preferred_term: Fibular hypoplasia
    term:
      id: HP:0003038
      label: Fibular hypoplasia
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      shortened toes as well as a bilateral hypoplasia of the fibula
    explanation: Documents bilateral fibular hypoplasia in a molecularly confirmed case.
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      milder limb involvement in du Pan dysplasia
    explanation: >-
      Places fibular hypoplasia within the milder limb involvement that
      characterises du Pan relative to Grebe dysplasia.
- category: Skeletal
  name: Complex Brachydactyly
  description: >-
    Brachydactyly involving multiple element classes at once - hypoplastic
    metacarpals, absent or malformed proximal phalanges, hypoplastic or absent
    middle phalanges - rather than uniform shortening of one segment.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological examination of the hands revealed bilateral hypoplastic
      metacarpal bones, especially very hypoplastic first metacarpals and absent
      proximal phalanges of the thumbs, malformed proximal phalanges of the other
      fingers, hypoplastic or absent and malformed middle phalanges
    explanation: Radiographs itemise the mixed element involvement that makes the brachydactyly complex.
- category: Skeletal
  name: Hypoplastic or Absent Middle Phalanges of the Hand
  description: Middle phalanges are hypoplastic, malformed, or absent.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the middle phalanges of the hand
    term:
      id: HP:0009843
      label: Aplasia/Hypoplasia of the middle phalanges of the hand
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypoplastic or absent and malformed middle phalanges
    explanation: Directly documents middle-phalangeal aplasia and hypoplasia.
- category: Skeletal
  name: Short Toes
  description: >-
    Shortened toes with deviation, and severe hypoplasia of the proximal and
    distal phalanges of the foot.
  phenotype_term:
    preferred_term: Short toe
    term:
      id: HP:0001831
      label: Short toe
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The feet presented similarly with shortened toes with fibular deviation of
      the big toes, tibial deviation of the fifth toes and bilateral syndactyly
      between the second and third toes
    explanation: Documents the foot phenotype in a molecularly confirmed case.
- category: Skeletal
  name: Postaxial Polydactyly
  frequency: OCCASIONAL
  description: >-
    Bilateral postaxial polydactyly of the hands was reported in 2024 in a
    BMPR1B-related case. Until then polydactyly had been considered a
    GDF5-specific finding, so this feature does not distinguish the two genes.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, this patient additionally shows a bilateral postaxial polydactyly
      of the hands-a novel clinical feature that has to date not been reported in
      BMPR1B-associated dysplasia patients in general.
    explanation: >-
      Reports the finding and its novelty for BMPR1B, which is why it is curated
      as occasional rather than typical.
- category: Skeletal
  name: Syndactyly of the Toes
  frequency: OCCASIONAL
  description: Bilateral syndactyly between the second and third toes.
  phenotype_term:
    preferred_term: Syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: bilateral syndactyly between the second and third toes
    explanation: Documents toe syndactyly in a molecularly confirmed case.
- category: Skeletal
  name: Camptodactyly
  frequency: OCCASIONAL
  description: Flexion deformity of the fourth fingers, with deviation of other digits.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      camptodactyly of the fourth fingers and ulnar deviation of the third
      fingers
    explanation: Documents camptodactyly in a molecularly confirmed case.
diagnosis:
- name: Gene Panel Covering the Acromesomelic Dysplasia Genes
  description: >-
    Only three genes account for the isolated acromesomelic dysplasias in the
    GDF5-BMPR1B and NPR2 families, so a small targeted panel resolves most
    presentations; PRKG2 was added to that list after the review below was
    written.
  evidence:
  - reference: PMID:26926249
    reference_title: Genetics of human isolated acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in three genes (GDF5, NPR2, BMPR1B) have been reported to cause
      different forms of acromesomelic dysplasia.
    explanation: Establishes the small gene set that a targeted panel needs to cover.
- name: Prenatal Sonographic Diagnosis
  description: >-
    Du Pan syndrome has been diagnosed prenatally on the combination of
    bilateral fibular agenesis with ball-shaped toes. The toes can be mistaken
    for preaxial polydactyly, which is the specific trap in reading the scan.
  evidence:
  - reference: PMID:37064338
    reference_title: "Fibular Agenesis and Ball-Like Toes Mimicking Preaxial Polydactyly: Prenatal Presentation of Du Pan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the first prenatal diagnosis of Du Pan syndrome based on
      the sonographic findings of bilateral fibular agenesis and ball-shaped toes
      mimicking preaxial polydactyly accompanying subtle brachydactyly in the
      family.
    explanation: Documents the prenatal sonographic pattern and the misreading it invites.
- name: Sequential GDF5 then BMPR1B Sequencing
  description: >-
    Because the two genes produce an overlapping phenotype, a du Pan-like
    presentation without a GDF5 variant should prompt BMPR1B sequencing. This is
    now explicitly recommended for cases that also show polydactyly, which was
    previously taken as evidence for a GDF5 aetiology.
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      individuals with du Pan acromesomelic dysplasia and polydactyly who do not
      carry pathogenic variants in GDF5, should be taken into account for BMPR1B
      sequencing
    explanation: States the recommended diagnostic escalation.
treatments:
- name: Genetic Counseling
  description: >-
    Counselling for an autosomal recessive disorder, with the added complication
    that the causative GDF5 allele is not silent in carriers: p.Leu441Pro
    heterozygous causes brachydactyly type A2, so a "carrier" parent may have a
    visible hand phenotype of their own. One kindred also transmits the disorder
    dominantly through three cis variants on a single allele, which changes the
    recurrence risk entirely and is why counselling should follow the family's
    molecular result rather than the diagnosis label.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37064338
    reference_title: "Fibular Agenesis and Ball-Like Toes Mimicking Preaxial Polydactyly: Prenatal Presentation of Du Pan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GDF5 (NM_000557.5) sequencing identified a homozygous pathogenic variant
      c.1322T>C, p.(Leu441Pro) in the fetus and confirmed the carrier status in
      the mother.
    explanation: >-
      Documents molecular confirmation of carrier status in a family, the step on
      which recurrence-risk counselling depends.
  - reference: PMID:16222676
    reference_title: Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three new heterozygous mutations clustered on one allele of the CDMP1 gene
      were identified in the affected individuals resulting in the first familial
      case with dominant Du Pan syndrome.
    explanation: >-
      The dominantly transmitted kindred is the reason recurrence-risk counselling
      here has to follow the molecular result rather than an assumed recessive
      model.
differential_diagnoses:
- name: Acromesomelic Dysplasia, Grebe Type
  disease_term:
    preferred_term: acromesomelic dysplasia, Grebe type
    term:
      id: MONDO:0008703
      label: acromesomelic dysplasia 2A
  description: >-
    The severe end of the same GDF5-BMPR1B spectrum, caused by alleles that
    abolish rather than reduce signalling.
  distinguishing_features:
  - Grebe dysplasia causes severe dwarfism with rudimentary fingers and toes; stature and the long bones are preserved in du Pan syndrome.
  - >-
    The two are separated by residual pathway activity rather than by which gene
    is mutated, so the distinction is clinical and radiographic rather than
    molecular.
  evidence:
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While Grebe dysplasia is characterised by severe distal limb anomalies
      with rudimentary fingers and toes
    explanation: States the severe distal phenotype that separates Grebe dysplasia from du Pan syndrome.
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      leads to a significant loss of BMPR1B function, but to a lesser extent
      than the previously reported p.Cys53Arg mutation that results in the more
      severe Grebe dysplasia
    explanation: Shows that the same gene gives either diagnosis according to residual receptor function.
- name: Acromesomelic Dysplasia, Demirhan Type
  disease_term:
    preferred_term: acromesomelic dysplasia, Demirhan type
    term:
      id: MONDO:0012274
      label: acromesomelic dysplasia 3
  description: >-
    The BMPR1B-related Grebe-like disorder, which shares the receptor with
    BMPR1B-related du Pan syndrome but adds genital anomalies.
  distinguishing_features:
  - Genital anomalies with hypergonadotrophic hypogonadism are present in the Demirhan type and absent in du Pan syndrome.
  - The Demirhan-type allele is truncating whereas the du Pan BMPR1B alleles are hypomorphic missense changes.
  evidence:
  - reference: PMID:15805157
    reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, she presented with hypoplasia of the uterus and ovarian
      dysfunction resulting in hypergonadotrophic hypogonadism.
    explanation: Identifies the genital phenotype that separates the Demirhan type from du Pan syndrome.
- name: Brachydactyly Type A2
  description: >-
    The heterozygous manifestation of the same GDF5 allele. A carrier parent or
    sibling of a du Pan proband may present with isolated index-finger
    brachydactyly rather than being unaffected, and BMPR1B brachydactyly type A2
    is the dominant counterpart on the receptor side.
  distinguishing_features:
  - >-
    Brachydactyly type A2 is dominant and confined to the digits, without the
    fibular deficiency that defines du Pan syndrome.
  - >-
    On the receptor side the mechanisms differ as well: brachydactyly type A2
    arises from dominant-negative BMPR1B alleles, whereas du Pan syndrome arises
    from recessive hypomorphic ones.
  evidence:
  - reference: PMID:16127465
    reference_title: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the brachydactyly type A2 phenotype (L441P) is caused by inhibition of the
      ligand-receptor interaction
    explanation: Identifies the heterozygous phenotype of the du Pan GDF5 allele and its mechanism.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings imply that both mutations identified in human BMPR1B affect
      cartilage formation in a dominant-negative manner.
    explanation: Establishes the dominant-negative mechanism that separates BDA2 from recessive BMPR1B du Pan syndrome.
- name: Isolated Fibular Hemimelia
  description: >-
    Longitudinal fibular deficiency without the hand and foot malformation
    bundle. Du Pan syndrome should be considered when fibular hypoplasia is
    accompanied by bilateral complex brachydactyly, which is not a feature of
    isolated fibular hemimelia.
  distinguishing_features:
  - >-
    Du Pan syndrome pairs the fibular deficiency with bilateral complex
    brachydactyly of hands and feet and is recessive with a molecular diagnosis
    in GDF5 or BMPR1B.
  evidence:
  - reference: PMID:12121354
    reference_title: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a consanguineous Pakistani family with fibular hypoplasia and complex
      brachydactyly (DuPan syndrome) inherited as an autosomal recessive trait
    explanation: >-
      The defining pairing of fibular hypoplasia with complex brachydactyly in a
      recessive kindred is what separates du Pan syndrome from an isolated
      fibular deficiency.
discussions:
- discussion_id: no_disease_specific_management_literature
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#
  prompt: >-
    What supportive, orthopaedic and rehabilitative management actually benefits
    du Pan syndrome?
  rationale: >-
    The treatments section is deliberately limited to genetic counselling, which
    is the one intervention the published literature for this disorder actually
    documents. Reconstructive and orthopaedic surgery, prosthetics, and
    physiotherapy are all plausible for a limb malformation of this severity and
    are presumably used in practice, but a search of the indexed literature
    returned no disease-specific management report for du Pan syndrome to cite. Curating
    them from general skeletal-dysplasia practice would be inference, not
    evidence, so the gap is recorded rather than filled. A case series reporting
    functional outcomes after surgical or prosthetic management would close it.
- discussion_id: du_pan_gene_indistinguishability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there any clinical or radiographic feature that separates GDF5-related
    from BMPR1B-related du Pan syndrome?
  rationale: >-
    Polydactyly was the last candidate discriminator and it fell in 2024, when a
    BMPR1B case was reported with bilateral postaxial polydactyly. With so few
    published cases in either group, no feature is currently established as
    gene-specific, which is why this entry curates both aetiologies under one
    disease concept rather than splitting them.
  attaches_to:
  - genetic#Biallelic Hypomorphic GDF5 Variants
  - genetic#Biallelic Hypomorphic BMPR1B Variants
  evidence:
  - reference: PMID:39441036
    reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case expands the phenotypical overlap between the different ACD types,
      du Pan and Grebe.
    explanation: The authors frame their finding as widening, not narrowing, the phenotypic overlap.
- discussion_id: dominant_du_pan_cis_allele
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do the three cis GDF5 variants in the reported dominant du Pan family act
    synergistically, and is the dominant transmission reproducible?
  rationale: >-
    A single Polish family transmits du Pan syndrome dominantly through one
    allele carrying three variants in the mature domain. The synergy is inferred
    from the pedigree, not measured, and no second dominant family has been
    reported in the twenty years since. Until it is functionally tested, this
    entry records the dominant inheritance block as an explicit exception rather
    than as an alternative mode of inheritance.
  attaches_to:
  - inheritance#Autosomal Dominant (cis-allele exception)
notes: >-
  Curated as part of a review of ISDS 2023 nosology group 16 (acromesomelic
  dysplasias). The 2023 revision lists GDF5-related and BMPR1B-related du Pan
  dysplasia as two rows, but MONDO carries a single concept (MONDO:0009231) and
  no published feature distinguishes them clinically, so they are curated as one
  entry with two causative genes. No Orphanet structured record was cited: the
  pinned Orphadata snapshot in data/orphadata/MANIFEST.yaml no longer matches
  upstream, and re-pinning it would rewrite every ORPHA cache file in the
  repository.

Du Pan Syndrome

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