Acromesomelic Dysplasia Grebe Type

Mendelian MONDO:0008703 Pathograph 6 Show in embeddings browser Skeletal Dysplasia

Grebe-type acromesomelic dysplasia is a severe autosomal recessive limb dysplasia caused by biallelic variants in GDF5 (formerly CDMP1), which encodes growth/differentiation factor 5, a bone morphogenetic protein family ligand that binds the type I BMP receptor BMPR1B with high affinity. Limb malformation follows a strict proximodistal severity gradient: the hands and feet are devastated while the femur and humerus are comparatively preserved, and the axial and craniofacial skeleton is spared. Fingers and toes are rudimentary or knob-like, with absent, fused, or malformed phalanges, metacarpals, metatarsals, carpals, and tarsals, and postaxial polydactyly occurs in some families. Two distinct molecular routes converge on this phenotype. Truncating alleles cause a simple loss of GDF5 signalling, whereas the classic mature-domain missense allele produces a protein that is retained inside the cell and, by heterodimerising with other BMP family members, blocks their secretion as well, a dominant-negative effect that explains the brachydactyly seen in heterozygous carriers. The Hunter-Thompson type, curated here as a subtype, is the allelic form in which the lower limbs and large joints bear the brunt of the disease; the 2023 ISDS nosology groups both under GDF5-related Grebe dysplasia.

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1
Inheritance
5
Pathophys.
8
Phenotypes
3
Hypotheses
3
Gaps
6
Pathograph
1
Genes
1
Medical Actions
2
Subtypes
4
Differentials
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Classifications

ISDS Skeletal Nosology
acromesomelic dysplasias
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Inheritance

1
Autosomal Recessive HP:0000007
The full Grebe phenotype requires biallelic GDF5 variants. Heterozygous carriers are not unaffected in the general sense: with the dominant-negative mature-domain alleles they may show brachydactyly type C or an unclassified brachydactyly, and non-penetrant carriers also occur in the same pedigree.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:9288098 SUPPORT Human Clinical
"Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder characterized by severe limb shortening and dysmorphogenesis."
States the recessive inheritance of the full Grebe phenotype.
PMID:33872773 SUPPORT Human Clinical
"with severe GTC associated with homozygosity, and with a wide phenotypic variability among heterozygous carriers, ranging from unaffected non-penetrant carriers, to classical BDC and to novel unclassified types of brachydactylies"
A six-generation pedigree documents the dosage relationship between homozygous Grebe disease and heterozygous brachydactyly.
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Subtypes

2
Grebe type (OMIM 200700)
The severe classical form, with marked micromelia and a proximodistal severity gradient in which the distal parts are the most affected. It carries no `subtype_term` deliberately: this entry's own `disease_term` is MONDO:0008703, the Grebe concept, so binding the same class again here would make the disease a subtype of itself and duplicate the identifier on export. The subtype is listed as a named clinical presentation so that it and Hunter-Thompson can be referred to symmetrically.
Show evidence (1 reference)
PMID:26275437 SUPPORT Human Clinical
"Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia characterized by severe dwarfism with marked micromelia and deformation of the upper and lower limbs, with a proximodistal gradient of severity."
Defines the classical Grebe presentation and its proximodistal gradient.
Hunter-Thompson type (OMIM 201250) MONDO:0008717
The allelic form in which the lower limbs are more severely affected than the upper, phalanges tend to be square, and joint dislocation is prominent. The 2023 ISDS nosology folds it into GDF5-related Grebe dysplasia rather than listing it as a separate group-16 entity.
Show evidence (3 references)
PMID:8589725 SUPPORT Human Clinical
"we now show that a mutation in hCDMP-1 is associated with a recessive human chondrodysplasia (acromesomelic chondrodysplasia, Hunter-Thompson type"
Establishes GDF5/CDMP1 as the cause of the Hunter-Thompson type.
PMID:34178199 SUPPORT Other
"In AMDH the lower limbs are more severely affected, phalanges tend to square and there may be a single phalangeal bone in the fifth digit. Ankle dislocation is common and radial head dislocation may be present"
Supplies the radiographic pattern that distinguishes the Hunter-Thompson subtype. Graded OTHER because it is a differential-diagnosis summary in a paper about NPR2-related disease.
PMID:26870132 SUPPORT Human Clinical
"Hind-limbs were more severely affected than fore-limbs."
A molecularly confirmed GDF5 family shows the lower-limb predominance that the Hunter-Thompson description emphasises, which is one reason the 2023 nosology folds the two together rather than separating them.
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Mechanistic Hypotheses

3
Simple Ligand-Loss Model
gdf5_null_loss_model CANONICAL
Evidence balance 1 support
Truncating GDF5 alleles remove the ligand, GDF5-BMPR1B signalling falls to near zero in the distal limb, and the condensations that build the digits fail. This accounts for the families in which the causative allele is a frameshift and the heterozygous parents are unaffected, and it is the model that carries over directly to the BMPR1B disorders, where the receptor rather than the ligand is removed.
Pathograph links
Biallelic GDF5 Mature-Domain Variants -> Loss of GDF5-BMPR1B Signaling in the Developing Limb DIRECT Truncating alleles remove the ligand outright, directly eliminating GDF5 input to its receptor without any dominant-negative intermediate.
Show evidence (1 reference)
PMID:12124730 SUPPORT Human Clinical
"The truncated CDMP1 protein in these subjects is predicted to cause a total loss of its signaling function."
A frameshift allele causing severe Grebe-type disease with unaffected carriers fits simple ligand loss.
Dominant-Negative BMP Sequestration Model
dominant_negative_bmp_sequestration ALTERNATIVE
Evidence balance 4 support
The archetypal Grebe missense allele does more than remove GDF5. The mutant protein is retained inside the cell and, because BMP family members dimerise, drags partner BMPs out of the secretory pathway with it, so the lesion is a broader withdrawal of BMP signalling than a GDF5 null produces. The clinical prediction that distinguishes the two models is carrier status: a null allele should leave heterozygotes unaffected, whereas a sequestering allele should give them a brachydactyly, and heterozygous brachydactyly is exactly what the reported families show. What has never been done is the comparison that would settle it, matching homozygous phenotype severity between a sequestering allele and a true null. A refinement worth noting is that the sequestration may not be a simple property of the mutant protein. For a prodomain GDF5 variant, inhibition of wild-type GDF5 secretion happened only when the latent TGF-beta binding proteins LTBP1 or LTBP2 were co-expressed. If the effect depends on the local abundance of such co-factors, dominant-negative penetrance is partly a property of the tissue environment rather than of the allele alone, which would be one way to explain why carriers of a single allele in one pedigree range from unaffected to frankly brachydactylous.
Pathograph links
Biallelic GDF5 Mature-Domain Variants -> Failed Secretion of GDF5 and Dominant-Negative Sequestration of BMP Partners DIRECT The classic Grebe missense allele directly produces an unsecreted, inactive protein that also traps other BMP family members.
Show evidence (4 references)
PMID:9288098 SUPPORT In Vitro
"It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers."
Establishes the sequestration mechanism that makes this allele more than a null.
PMID:33872773 SUPPORT Human Clinical
"with severe GTC associated with homozygosity, and with a wide phenotypic variability among heterozygous carriers, ranging from unaffected non-penetrant carriers, to classical BDC and to novel unclassified types of brachydactylies"
Carrier phenotypes vary within a single family carrying one frameshift allele, which complicates using carrier status alone to separate the two models.
PMID:23812741 SUPPORT In Vitro
"Finally, we demonstrated that secretion of Wt-GDF5 was inhibited by the Mut-GDF5, but only when LTBP (LTBP1 or LTBP2) was co-expressed."
Shows that dominant-negative inhibition of wild-type GDF5 secretion can be conditional on a co-factor. Support is partial because the allele tested is a prodomain variant, not the mature-domain cysteine substitution this group is built on.
+ 1 more reference
Precursor-Processing Failure Model
processing_failure_model EMERGING
Evidence balance 2 support
A third allele class acts before either of the above: p.Arg377Trp sits in the RRKRR recognition motif at the proteolytic processing site, so the lesion is failure to mature the GDF5 precursor into active ligand rather than failure of the mature protein to fold, be secreted, or bind. The functional consequence has been inferred from the motif rather than measured, and no processing assay has been run on this allele.
The three groups describe different allele classes rather than competing accounts of one allele, and a single entry can only be explained by one of them. They are curated together because the clinical phenotype does not distinguish them, so the mechanism operating in any given family is read from the variant rather than from the radiographs.
Pathograph links
Biallelic GDF5 Mature-Domain Variants -> Failed Secretion of GDF5 and Dominant-Negative Sequestration of BMP Partners DIRECT The classic Grebe missense allele directly produces an unsecreted, inactive protein that also traps other BMP family members.
Show evidence (2 references)
PMID:26275437 SUPPORT Human Clinical
"The p.Arg377Trp mutation is located within the recognition motif at the processing site of GDF5 where the sequence RRKRR changes to WRKRR."
Localises the allele to the processing motif. Support is partial because the pathogenic effect was established by in silico and structural prediction rather than by a processing assay.
PMID:26275437 SUPPORT Computational
"In silico and structural analyses predicted the p.Arg377Trp amino acid change to be pathogenic."
Records that the evidence for this allele class is predictive rather than experimental.
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Discussions and Knowledge Gaps

3
What supportive, orthopaedic and rehabilitative management actually benefits Grebe dysplasia?
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 Grebe dysplasia 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.
Do the Grebe and Hunter-Thompson types reflect distinct GDF5 allele classes, or are they two descriptions of one continuum?
KNOWLEDGE GAP OPEN grebe_hunter_thompson_lumping
Attached to
has_subtypes#Grebe has_subtypes#Hunter-Thompson
The 2023 ISDS nosology folds Hunter-Thompson into GDF5-related Grebe dysplasia, and OMIM and MONDO keep them as separate entities. The published radiographic distinction is real (lower-limb predominance and joint dislocation in Hunter-Thompson), but no study has systematically related those features to allele class or residual signalling. This entry curates them as subtypes of one disease pending such a study.
Does the dominant-negative Grebe missense allele produce a more severe homozygous phenotype than a GDF5 null allele?
KNOWLEDGE GAP OPEN dominant_negative_vs_null_severity
Attached to
pathophysiology#Failed Secretion of GDF5 and Dominant-Negative Sequestration of BMP Partners mechanistic_hypotheses#gdf5_null_loss_model mechanistic_hypotheses#dominant_negative_bmp_sequestration
The mature-domain missense allele sequesters other BMP family members and so should remove more BMP signalling than a simple null, which predicts a more severe homozygous phenotype. Reported truncating alleles nonetheless produce severe Grebe-like disease, and no series has compared the two allele classes with matched phenotyping. Resolving this bears on genetic counselling for carriers, who are affected only with the dominant-negative alleles.
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Pathophysiology

5
Biallelic GDF5 Mature-Domain Variants
Pathogenic variants on both GDF5 alleles disrupt the mature, secreted domain of the ligand. Truncating variants abolish the protein, while missense variants in the mature active domain or at the RRKRR processing motif yield a full-length but functionally defective product.
Dominant-Negative BMP Sequestration Model Precursor-Processing Failure Model Simple Ligand-Loss Model
GDF5 hgnc:4220 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GDF5 (hgnc:4220). hgnc:4220 is a gene from the HUGO Gene Nomenclature Committee.
Proteolytic maturation of the GDF5 precursor GO:0016485 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Proteolytic maturation of the GDF5 precursor, annotated with protein processing (GO:0016485). GO:0016485 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Failed Secretion of GDF5 and Dominant-Negative Sequestration of BMP Partners The classic Grebe missense allele directly produces an unsecreted, inactive protein that also traps other BMP family members. Dominant-Negative BMP Sequestration Model Precursor-Processing Failure Model
Loss of GDF5-BMPR1B Signaling in the Developing Limb Truncating alleles remove the ligand outright, directly eliminating GDF5 input to its receptor without any dominant-negative intermediate. Simple Ligand-Loss Model
Show evidence (1 reference)
PMID:26275437 SUPPORT Human Clinical
"Homozygous mutations in the mature domain of GDF5 result in severe limb malformations such as the Grebe type or the Hunter-Thompson type of acromesomelic chondrodysplasia."
Localises the causative alleles to the mature domain and ties them to both phenotypes curated here.
Failed Secretion of GDF5 and Dominant-Negative Sequestration of BMP Partners
The archetypal Grebe allele substitutes a tyrosine for the first of seven conserved cysteines of the mature active domain. The resulting protein is retained inside the cell, and because BMP family members dimerise, it drags related BMPs out of the secretory pathway with it. This is why the Grebe allele is more than a null: heterozygotes carry a brachydactyly phenotype that a simple loss-of-function allele would not produce.
Protein secretion GO:0009306 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Protein secretion (GO:0009306). GO:0009306 is a biological process from the Gene Ontology. ↓ DECREASED
BMP receptor binding GO:0070700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased BMP receptor binding (GO:0070700). GO:0070700 is a molecular function from the Gene Ontology. ↓ DECREASED Heterodimerization with partner BMP ligands GO:0046982 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal Heterodimerization with partner BMP ligands, annotated with protein heterodimerization activity (GO:0046982). GO:0046982 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Loss of GDF5-BMPR1B Signaling in the Developing Limb Withdrawal of GDF5 and of its co-sequestered BMP partners from the extracellular space directly deprives BMPR1B of ligand.
Show evidence (2 references)
PMID:9288098 SUPPORT Human Clinical
"The mutation substitutes a tyrosine for the first of seven highly conserved cysteine residues in the mature active domain of the protein."
Identifies the specific residue change behind the dominant-negative Grebe allele.
PMID:9288098 SUPPORT In Vitro
"It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers."
Establishes heterodimer-mediated sequestration as the dominant-negative mechanism.
Loss of GDF5-BMPR1B Signaling in the Developing Limb
GDF5 is a BMP-family ligand with high affinity for the type I receptor BMPR1B. This node is the shared central effector of the whole acromesomelic GDF5/BMPR1B spectrum: disabling the ligand and disabling the receptor produce overlapping disease, and the severity of the resulting phenotype tracks the degree of functional impairment of the ligand-receptor pair.
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.
BMP signaling pathway GO:0030509 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased BMP signaling pathway (GO:0030509). GO:0030509 is a biological process from the Gene Ontology. ↓ DECREASED Cell surface receptor protein serine/threonine kinase signaling pathway GO:0007178 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Cell surface receptor protein serine/threonine kinase signaling pathway (GO:0007178). GO:0007178 is a biological process from the Gene Ontology. ↓ DECREASED SMAD protein signal transduction GO:0060395 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased SMAD protein signal transduction (GO:0060395). GO:0060395 is a biological process from the Gene Ontology. ↓ DECREASED
BMP receptor activity GO:0098821 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased BMP receptor activity (GO:0098821). GO:0098821 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Failed Chondrogenic Condensation and Joint Specification in the Distal Limb GDF5-BMPR1B signalling directly governs the condensation, differentiation and maturation steps that build appendicular skeletal elements and their joints.
Show evidence (3 references)
PMID:39441036 SUPPORT Human Clinical
"Both genes encode members of the same pathway: The GDF5 ligand belongs to the bone morphogenetic protein (BMP) family and binds with a high affinity to the BMP receptor BMPR1B"
Establishes the ligand-receptor pair that 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-dependent relationship between residual GDF5-BMPR1B signalling and phenotype severity across the spectrum.
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.
Failed Chondrogenic Condensation and Joint Specification in the Distal Limb
GDF5 is expressed at sites of skeletal morphogenesis, particularly in the interzones that prefigure joints and in the condensations that prefigure individual skeletal elements. Without GDF5-BMPR1B signalling these condensations fail to form, segment, or separate correctly, which is why the phenotype is one of missing, fused and malformed elements rather than of uniformly short but well-formed bones.
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. Condensing limb mesenchyme CL:0000134 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Condensing limb mesenchyme, annotated with mesenchymal stem cell (CL:0000134). CL:0000134 is a cell type from the Cell Ontology.
Cartilage condensation GO:0001502 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cartilage condensation (GO:0001502). GO:0001502 is a biological process from the Gene Ontology. ⚠ ABNORMAL Embryonic skeletal joint morphogenesis GO:0060272 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Embryonic skeletal joint morphogenesis (GO:0060272). GO:0060272 is a biological process from the Gene Ontology. ⚠ ABNORMAL Chondrocyte differentiation GO:0002062 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Chondrocyte differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology. ↓ DECREASED Cartilage development GO:0051216 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cartilage development (GO:0051216). GO:0051216 is a biological process from the Gene Ontology. ⚠ ABNORMAL Extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Proximodistally Graded Appendicular Skeletal Malformation Failure of condensation and segmentation directly yields absent, fused and rudimentary appendicular elements, most severely at the distal end of the limb.
Show evidence (3 references)
PMID:8589725 SUPPORT Human Clinical
"CDMP-1 is predominantly expressed at sites of skeletal morphogenesis (3), and we now show that a mutation in hCDMP-1 is associated with a recessive human chondrodysplasia"
Ties GDF5 expression at sites of skeletal morphogenesis to the human disease.
PMID:8589725 SUPPORT Human Clinical
"The disorder, characterized by skeletal abnormalities restricted to the limbs andlimb joints"
Records that the lesion is restricted to limb skeletal elements and limb joints, the structures this node concerns.
PMID:14523231 SUPPORT In Vitro
"Functional analyses with a micromass culture system revealed a strong inhibition of chondrogenesis by both mutant receptors."
Micromass culture shows that blocking this ligand-receptor pair inhibits chondrogenesis itself, which is the basis for annotating chondrocyte differentiation as decreased at this node.
Proximodistally Graded Appendicular Skeletal Malformation
The malformation is graded along the proximodistal axis and is repeated in both fore- and hindlimb autopods, the hallmark of a lesion in a limb patterning signal that is serially reused. Distal elements are the most severely affected, the axial and craniofacial skeleton is spared, and the graded pattern is the feature that separates this spectrum from generalised chondrodysplasias.
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.
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 Limb development GO:0060173 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Limb development (GO:0060173). GO:0060173 is a biological process from the Gene Ontology. ⚠ ABNORMAL 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
Show evidence (2 references)
PMID:26275437 SUPPORT Human Clinical
"severe shortening of the forearms with an acromesomelic pattern following a proximodistal gradient, with distal parts more severely affected than medial parts"
Directly documents the proximodistal severity gradient in a molecularly confirmed case.
PMID:12124730 SUPPORT Human Clinical
"all affected patients had a similar phenotype with unaffected axial and craniofacial bones"
Confirms that the malformation spares the axial and craniofacial skeleton.
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Pathograph

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

8
Limbs 5
Severe Micromelia HP:0002983 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micromelia (HP:0002983). HP:0002983 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:26275437 SUPPORT Human Clinical
"Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia characterized by severe dwarfism with marked micromelia and deformation of the upper and lower limbs, with a proximodistal gradient of severity."
A molecularly confirmed Grebe case report documents marked micromelia directly.
PMID:26870132 SUPPORT Human Clinical
"Patients were observed with short and deformed limbs having a proximo-distal gradient of severity."
An independent molecularly confirmed family reproduces the finding.
PMID:34178199 SUPPORT Other
"AMDG is characterized by severe micromelia."
A radiology review of a different disorder names severe micromelia as the defining Grebe feature in its differential-diagnosis discussion. Graded OTHER because the paper reports no Grebe patient of its own.
Carpal Synostosis HP:0009702 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carpal synostosis (HP:0009702). HP:0009702 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34178199 SUPPORT Other
"Fusion of the carpals and/or metacarpals and tarsals and/or metatarsals maybe present."
Documents carpal fusion in Grebe type. Graded OTHER because the statement comes from a differential-diagnosis paragraph in a case report about NPR2-related disease, not from a Grebe patient this paper examined.
Postaxial Polydactyly HP:0100259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postaxial polydactyly (HP:0100259). HP:0100259 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34178199 SUPPORT Other
"Postaxial polydactyly has also been reported."
Records postaxial polydactyly among reported Grebe findings. Graded OTHER: the sentence is itself a citation of other reports.
PMID:39441036 SUPPORT Other
"polydactyly is a known finding in Grebe dysplasia caused by biallelic variants in GDF5"
Independently confirms polydactyly as an established GDF5-related Grebe finding. Graded OTHER for the same reason: this is a BMPR1B case report summarising the GDF5 literature rather than observing it.
Femoral, Tibial and Fibular Hypoplasia Short femur HP:0003097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short femur (HP:0003097). HP:0003097 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26275437 SUPPORT Human Clinical
"severe hypoplastic tibial/femoral zones in both limbs"
Radiographs of a molecularly confirmed Grebe case document the femoral and tibial hypoplasia directly.
PMID:34178199 SUPPORT Other
"Significant femoral shortening is present in AMDG, as well as absent tibial and fibular diaphysis, hypoplasia of the ulna and a malformed radial head"
Adds the fibular and forearm detail. Graded OTHER because it is a differential-diagnosis statement rather than this paper's own observation.
Ulnar Hypoplasia and Malformed Radial Head Hypoplasia of the ulna HP:0003022 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the ulna (HP:0003022). HP:0003022 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34178199 SUPPORT Other
"as well as absent tibial and fibular diaphysis, hypoplasia of the ulna and a malformed radial head"
Documents forearm involvement. This is the only source in the entry for the forearm findings and it is a secondary one, so it is graded OTHER and the phenotype should be re-sourced when a primary description is available.
Musculoskeletal 1
Joint Dislocation HP:0001373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint dislocation (HP:0001373). HP:0001373 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34178199 SUPPORT Other
"Ankle dislocation is common and radial head dislocation may be present"
Records the joint dislocations characteristic of the Hunter-Thompson subtype. Graded OTHER because the statement is a differential-diagnosis summary, not an observation of a Hunter-Thompson patient by this paper.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26275437 SUPPORT Human Clinical
"characterized by severe dwarfism with marked micromelia"
States the severe short stature of Grebe type.
Other 1
Absent or Fused Hand and Foot Bones Aplasia/hypoplasia involving bones of the hand HP:0005927 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/hypoplasia involving bones of the hand (HP:0005927). HP:0005927 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:27577507 SUPPORT Human Clinical
"Acromesomelic dysplasia Grebe type (AMDG) is characterized by severe knob like non-functional fingers and short acromesomelic limbs"
Two molecularly confirmed consanguineous families document the knob-like non-functional digits that the underlying element loss produces.
PMID:26870132 SUPPORT Human Clinical
"Digits on autopods were very short and nonfunctional."
An independent family reproduces the digit phenotype.
PMID:34178199 SUPPORT Other
"Fusion of the carpals and/or metacarpals and tarsals and/or metatarsals maybe present. Metacarpal, metatarsal or proximal and/or middle phalanges may be absent."
Supplies the element-by-element radiographic detail, which the primary case reports above do not itemise. Graded OTHER because this is a differential-diagnosis paragraph in a paper about a different disorder.
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Genetic Associations

1
Biallelic GDF5 Variants (Causative)
Gene: GDF5 hgnc:4220 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GDF5 (hgnc:4220). hgnc:4220 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:12124730 SUPPORT Human Clinical
"In affected subjects, an insertion of a C at nucleotide 297 of the coding sequence was discovered. This insertion produced a shift in the reading frame at amino acid residue 99, causing premature termination of the polypeptide six amino acids downstream."
Documents a truncating GDF5 allele causing severe Grebe-type disease.
PMID:26275437 SUPPORT Human Clinical
"The p.Arg377Trp mutation is located within the recognition motif at the processing site of GDF5 where the sequence RRKRR changes to WRKRR."
Documents a missense allele disrupting proteolytic processing of the GDF5 precursor.
PMID:26275437 SUPPORT Human Clinical
"Of the 34 mutations described in the CDMP1 gene, four different missense mutations have been associated with Grebe syndrome."
Summarises the GDF5 allelic spectrum and the missense subset tied to the Grebe phenotype.
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Medical Actions

1
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
Counselling for an autosomal recessive disorder with a one-in-four recurrence risk in an affected sibship. It is not routine here: with the dominant-negative mature-domain alleles, heterozygous carriers are not reliably unaffected, and within a single pedigree carrier phenotypes have ranged from normal through classical brachydactyly type C to unclassified brachydactylies. Molecular confirmation of the family's allele is what makes the counselling accurate.
Show evidence (2 references)
PMID:26275437 SUPPORT Human Clinical
"The genotype-phenotype correlation allowed not only confirmation of the clinical diagnosis but also appropriate genetic counselling to be offered to this family."
Documents genetic counselling as the management step that molecular confirmation enables.
PMID:33872773 SUPPORT Human Clinical
"with a wide phenotypic variability among heterozygous carriers, ranging from unaffected non-penetrant carriers, to classical BDC and to novel unclassified types of brachydactylies"
Carrier phenotypes vary within one pedigree, which is what makes counselling for this disorder harder than a standard recessive recurrence-risk conversation.
🔬

Diagnosis

3
Radiographic Pattern Recognition
The combination of severe distal-predominant limb malformation with a normal axial and craniofacial skeleton, in a child of consanguineous parents, is the pattern that directs testing to the GDF5/BMPR1B spectrum rather than to a generalised chondrodysplasia.
Show evidence (1 reference)
PMID:26275437 SUPPORT Human Clinical
"Radiographic imaging revealed features typical of Grebe syndrome: severe shortening of the forearms with an acromesomelic pattern following a proximodistal gradient"
Radiographs established the clinical diagnosis before molecular confirmation in this case.
Prenatal Sonographic Diagnosis
The limb phenotype is severe enough to be recognised on second-trimester ultrasound, with the globular fingers and toes as the distinguishing feature. This matters for counselling in an at-risk sibship, and the prognostic point that goes with it is that the condition is not lethal and intelligence is normal.
Show evidence (2 references)
PMID:27677752 SUPPORT Human Clinical
"Rendered 3-D ultrasound images of the fetal limbs, particularly of the characteristic tiny and globular-looking fingers and toes, were instrumental in accurately characterizing the phenotype prenatally."
Documents prenatal recognition of the phenotype and the finding that carried the diagnosis.
PMID:27677752 SUPPORT Human Clinical
"Despite the severe skeletal deformities, the condition is not lethal and surviving individuals can have normal intelligence."
The prognostic statement that accompanies a prenatal diagnosis and is central to counselling.
Molecular Confirmation of Biallelic GDF5 Variants
Sequencing GDF5 confirms the diagnosis and, because the GDF5 and BMPR1B phenotypes overlap, a negative GDF5 result should be followed by BMPR1B sequencing rather than closing the workup.
Show evidence (2 references)
PMID:26275437 SUPPORT Human Clinical
"The genotype-phenotype correlation allowed not only confirmation of the clinical diagnosis but also appropriate genetic counselling to be offered to this family."
Molecular confirmation is what converts the radiographic impression into a counselled diagnosis.
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"
Supports escalating to BMPR1B when GDF5 sequencing is negative in an overlapping phenotype.
📊

Prevalence

1
Consanguineous kindreds, predominantly South Asian, Middle Eastern and Brazilian
Cases In Literature Ultra Rare
No population-based estimate exists. Published Grebe dysplasia is overwhelmingly reported as large consanguineous pedigrees, and the entity is characterised in the literature as very rare.
Show evidence (2 references)
PMID:26275437 SUPPORT Human Clinical
"Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia characterized by severe dwarfism with marked micromelia"
Characterises the disorder as very rare.
PMID:12124730 SUPPORT Human Clinical
"Here we report a family with seven males and six females who inherited the disorder in an autosomal recessive fashion."
Illustrates that the published case base consists of extended consanguineous families.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Acromesomelic Dysplasia Grebe Type:

Du Pan Syndrome MONDO:0009231
Overlapping Features The mild end of the same GDF5/BMPR1B spectrum, with fibular hypoplasia and complex brachydactyly but preserved stature and largely intact long bones.
Distinguishing Features
  • Stature and the long bones are preserved in du Pan syndrome, whereas Grebe type causes severe dwarfism with absent or fused distal elements.
  • The distinction reflects residual signalling, with hypomorphic alleles giving du Pan and severe loss-of-function alleles giving Grebe.
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-limb phenotype at the Grebe end of the spectrum.
PMID:26105076 SUPPORT Human Clinical
"We extend the genotype-phenotype correlation in the acromesomelic chondrodysplasias by showing that the milder du Pan dysplasia can be caused by a hypomorphic BMPR1B mutation."
States that du Pan is the milder phenotype and that it maps onto a hypomorphic rather than a severe loss-of-function allele.
Acromesomelic Dysplasia, Demirhan Type MONDO:0012274
Overlapping Features The BMPR1B-related Grebe-like phenotype, which the 2023 nosology lists as a separate group-16 entity and which adds genital anomalies to a very similar limb picture.
Distinguishing Features
  • Hypoplasia of the uterus with ovarian dysfunction and hypergonadotrophic hypogonadism is present in the BMPR1B-related disorder and absent in GDF5-related Grebe dysplasia.
  • Biallelic BMPR1B rather than biallelic GDF5 variants establish the diagnosis.
Show evidence (1 reference)
PMID:15805157 SUPPORT Human Clinical
"However, the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype."
The founding report states exactly how the BMPR1B disorder differs from the GDF5 disorders.
Acromesomelic Dysplasia, Maroteaux Type MONDO:0011275
Overlapping Features The NPR2-related acromesomelic dysplasia, in the same nosology group but a different signalling pathway.
Distinguishing Features
  • The craniofacial and axial skeleton are affected in AMDM and unaffected in Grebe and Hunter-Thompson types.
  • All skeletal elements are present but abnormally grown in AMDM, whereas Grebe type shows absent and fused elements.
Show evidence (2 references)
PMID:34178199 SUPPORT Other
"Unlike AMDM, in both acromesomelic dysplasia, Hunter-Thompson type (AMDH) and Grebe type (AMDG) the craniofacial and axial skeleton is unaffected"
States the axial and craniofacial contrast that separates AMDM from this entry. Graded OTHER because the comparison is drawn in discussion; the paper observed an AMDM patient, not a Grebe one.
PMID:26870132 SUPPORT Human Clinical
"However, symptoms in the craniofacial and axial skeleton were minimal."
A molecularly confirmed Grebe family supplies the axial-sparing half of the contrast from the Grebe side, which is the side this entry is about.
Brachydactyly Type C
Overlapping Features The heterozygous manifestation of GDF5 alleles in the same families. It is a differential in the sense that a carrier relative of a Grebe proband may present with isolated brachydactyly rather than being unaffected.
Distinguishing Features
  • Brachydactyly type C arises in heterozygous carriers; the full Grebe phenotype requires homozygosity.
Show evidence (1 reference)
PMID:33872773 SUPPORT Human Clinical
"The family confirmed that both GTC and BDC are part of the GDF5 mutational spectrum, with severe GTC associated with homozygosity"
Establishes that both phenotypes arise from the same allele at different dosage.
{ }

Source YAML

click to show 
name: Acromesomelic Dysplasia Grebe Type
synonyms:
- Grebe dysplasia
- Grebe chondrodysplasia
- Grebe dysplasia, GDF5-related
- Acromesomelic dysplasia 2A
- AMDG
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Grebe-type acromesomelic dysplasia is a severe autosomal recessive limb
  dysplasia caused by biallelic variants in GDF5 (formerly CDMP1), which encodes
  growth/differentiation factor 5, a bone morphogenetic protein family ligand
  that binds the type I BMP receptor BMPR1B with high affinity. Limb malformation
  follows a strict proximodistal severity gradient: the hands and feet are
  devastated while the femur and humerus are comparatively preserved, and the
  axial and craniofacial skeleton is spared. Fingers and toes are rudimentary or
  knob-like, with absent, fused, or malformed phalanges, metacarpals,
  metatarsals, carpals, and tarsals, and postaxial polydactyly occurs in some
  families. Two distinct molecular routes converge on this phenotype. Truncating
  alleles cause a simple loss of GDF5 signalling, whereas the classic
  mature-domain missense allele produces a protein that is retained inside the
  cell and, by heterodimerising with other BMP family members, blocks their
  secretion as well, a dominant-negative effect that explains the brachydactyly
  seen in heterozygous carriers. The Hunter-Thompson type, curated here as a
  subtype, is the allelic form in which the lower limbs and large joints bear the
  brunt of the disease; the 2023 ISDS nosology groups both under GDF5-related
  Grebe dysplasia.
disease_term:
  preferred_term: acromesomelic dysplasia, Grebe type
  term:
    id: MONDO:0008703
    label: acromesomelic dysplasia 2A
parents:
- Skeletal Dysplasia
has_subtypes:
- name: Grebe
  display_name: Grebe type (OMIM 200700)
  description: >-
    The severe classical form, with marked micromelia and a proximodistal
    severity gradient in which the distal parts are the most affected. It
    carries no `subtype_term` deliberately: this entry's own `disease_term` is
    MONDO:0008703, the Grebe concept, so binding the same class again here would
    make the disease a subtype of itself and duplicate the identifier on export.
    The subtype is listed as a named clinical presentation so that it and
    Hunter-Thompson can be referred to symmetrically.
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia
      characterized by severe dwarfism with marked micromelia and deformation of
      the upper and lower limbs, with a proximodistal gradient of severity.
    explanation: Defines the classical Grebe presentation and its proximodistal gradient.
- name: Hunter-Thompson
  display_name: Hunter-Thompson type (OMIM 201250)
  subtype_term:
    preferred_term: acromesomelic dysplasia, Hunter-Thompson type
    term:
      id: MONDO:0008717
      label: acromesomelic dysplasia 2C, Hunter-Thompson type
  description: >-
    The allelic form in which the lower limbs are more severely affected than the
    upper, phalanges tend to be square, and joint dislocation is prominent. The
    2023 ISDS nosology folds it into GDF5-related Grebe dysplasia rather than
    listing it as a separate group-16 entity.
  evidence:
  - reference: PMID:8589725
    reference_title: A human chondrodysplasia due to a mutation in a TGF-beta superfamily member.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we now show that a mutation in hCDMP-1 is associated with a recessive human
      chondrodysplasia (acromesomelic chondrodysplasia, Hunter-Thompson type
    explanation: Establishes GDF5/CDMP1 as the cause of the Hunter-Thompson type.
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In AMDH the lower limbs are more severely affected, phalanges tend to
      square and there may be a single phalangeal bone in the fifth digit. Ankle
      dislocation is common and radial head dislocation may be present
    explanation: >-
      Supplies the radiographic pattern that distinguishes the Hunter-Thompson
      subtype. Graded OTHER because it is a differential-diagnosis summary in a
      paper about NPR2-related disease.
  - reference: PMID:26870132
    reference_title: "Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hind-limbs were more severely affected than fore-limbs.
    explanation: >-
      A molecularly confirmed GDF5 family shows the lower-limb predominance that
      the Hunter-Thompson description emphasises, which is one reason the 2023
      nosology folds the two together rather than separating them.
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"; listed as "Grebe
      dysplasia, GDF5-related", which the revision treats as covering both the
      Grebe (OMIM 200700) and Hunter-Thompson (OMIM 201250) types. This entry
      therefore carries the single group value even though it lumps two OMIM
      entities. The 2019 revision (PMID:31633310) placed Grebe dysplasia in the
      same group 16.
    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: >-
        Pathogenic GDF5 variants underlie the severe Grebe dysplasia (including
        Grebe (OMIM #200700) and Hunter-Thompson (OMIM #201250) types) and the
        milder du Pan dysplasia (OMIM #228900)
      explanation: >-
        A 2024 report enumerating the acromesomelic chondrodysplasia types of the
        2023 nosology revision states that the GDF5-related Grebe entity covers
        both the Grebe and Hunter-Thompson types.
prevalence:
- population: Consanguineous kindreds, predominantly South Asian, Middle Eastern and Brazilian
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based estimate exists. Published Grebe dysplasia is
    overwhelmingly reported as large consanguineous pedigrees, and the entity is
    characterised in the literature as very rare.
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia
      characterized by severe dwarfism with marked micromelia
    explanation: Characterises the disorder as very rare.
  - reference: PMID:12124730
    reference_title: Frameshift mutation in the cartilage-derived morphogenetic protein 1 (CDMP1) gene and severe acromesomelic chondrodysplasia resembling Grebe-type chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a family with seven males and six females who inherited the
      disorder in an autosomal recessive fashion.
    explanation: Illustrates that the published case base consists of extended consanguineous families.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The full Grebe phenotype requires biallelic GDF5 variants. Heterozygous
    carriers are not unaffected in the general sense: with the dominant-negative
    mature-domain alleles they may show brachydactyly type C or an unclassified
    brachydactyly, and non-penetrant carriers also occur in the same pedigree.
  evidence:
  - reference: PMID:9288098
    reference_title: Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder
      characterized by severe limb shortening and dysmorphogenesis.
    explanation: States the recessive inheritance of the full Grebe phenotype.
  - reference: PMID:33872773
    reference_title: "A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with severe GTC associated with homozygosity, and with a wide phenotypic
      variability among heterozygous carriers, ranging from unaffected
      non-penetrant carriers, to classical BDC and to novel unclassified types of
      brachydactylies
    explanation: >-
      A six-generation pedigree documents the dosage relationship between
      homozygous Grebe disease and heterozygous brachydactyly.
genetic:
- name: Biallelic GDF5 Variants
  gene_term:
    preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported causative alleles include frameshift and other truncating variants
    in the mature region, and missense variants in the mature active domain.
    Missense alleles at the conserved cysteines or at the RRKRR processing
    recognition motif behave differently from truncating alleles: they yield a
    retained, dominant-negative protein rather than simple absence.
  evidence:
  - reference: PMID:12124730
    reference_title: Frameshift mutation in the cartilage-derived morphogenetic protein 1 (CDMP1) gene and severe acromesomelic chondrodysplasia resembling Grebe-type chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In affected subjects, an insertion of a C at nucleotide 297 of the coding
      sequence was discovered. This insertion produced a shift in the reading
      frame at amino acid residue 99, causing premature termination of the
      polypeptide six amino acids downstream.
    explanation: Documents a truncating GDF5 allele causing severe Grebe-type disease.
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The p.Arg377Trp mutation is located within the recognition motif at the
      processing site of GDF5 where the sequence RRKRR changes to WRKRR.
    explanation: Documents a missense allele disrupting proteolytic processing of the GDF5 precursor.
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 34 mutations described in the CDMP1 gene, four different missense
      mutations have been associated with Grebe syndrome.
    explanation: Summarises the GDF5 allelic spectrum and the missense subset tied to the Grebe phenotype.
pathophysiology:
- name: Biallelic GDF5 Mature-Domain Variants
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Pathogenic variants on both GDF5 alleles disrupt the mature, secreted domain
    of the ligand. Truncating variants abolish the protein, while missense
    variants in the mature active domain or at the RRKRR processing motif yield a
    full-length but functionally defective product.
  genes:
  - preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  biological_processes:
  - preferred_term: Proteolytic maturation of the GDF5 precursor
    term:
      id: GO:0016485
      label: protein processing
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous mutations in the mature domain of GDF5 result in severe limb
      malformations such as the Grebe type or the Hunter-Thompson type of
      acromesomelic chondrodysplasia.
    explanation: Localises the causative alleles to the mature domain and ties them to both phenotypes curated here.
  downstream:
  - target: Failed Secretion of GDF5 and Dominant-Negative Sequestration of BMP Partners
    causal_link_type: DIRECT
    hypothesis_groups:
    - dominant_negative_bmp_sequestration
    - processing_failure_model
    description: >-
      The classic Grebe missense allele directly produces an unsecreted,
      inactive protein that also traps other BMP family members.
    evidence:
    - reference: PMID:9288098
      reference_title: Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We demonstrate that the mutation results in a protein that is not
        secreted and is inactive in vitro.
      explanation: Functional assays show the mutant protein is neither secreted nor active.
  - target: Loss of GDF5-BMPR1B Signaling in the Developing Limb
    causal_link_type: DIRECT
    hypothesis_groups:
    - gdf5_null_loss_model
    description: >-
      Truncating alleles remove the ligand outright, directly eliminating
      GDF5 input to its receptor without any dominant-negative intermediate.
    evidence:
    - reference: PMID:12124730
      reference_title: Frameshift mutation in the cartilage-derived morphogenetic protein 1 (CDMP1) gene and severe acromesomelic chondrodysplasia resembling Grebe-type chondrodysplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The truncated CDMP1 protein in these subjects is predicted to cause a
        total loss of its signaling function.
      explanation: A frameshift allele is inferred to abolish GDF5 signalling directly.
- name: Failed Secretion of GDF5 and Dominant-Negative Sequestration of BMP Partners
  role: intermediate
  biological_scale: MOLECULAR
  description: >-
    The archetypal Grebe allele substitutes a tyrosine for the first of seven
    conserved cysteines of the mature active domain. The resulting protein is
    retained inside the cell, and because BMP family members dimerise, it drags
    related BMPs out of the secretory pathway with it. This is why the Grebe
    allele is more than a null: heterozygotes carry a brachydactyly phenotype
    that a simple loss-of-function allele would not produce.
  molecular_functions:
  - preferred_term: BMP receptor binding
    term:
      id: GO:0070700
      label: BMP receptor binding
    modifier: DECREASED
  - preferred_term: Heterodimerization with partner BMP ligands
    term:
      id: GO:0046982
      label: protein heterodimerization activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: Protein secretion
    term:
      id: GO:0009306
      label: protein secretion
    modifier: DECREASED
  evidence:
  - reference: PMID:9288098
    reference_title: Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation substitutes a tyrosine for the first of seven highly
      conserved cysteine residues in the mature active domain of the protein.
    explanation: Identifies the specific residue change behind the dominant-negative Grebe allele.
  - reference: PMID:9288098
    reference_title: Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It produces a dominant negative effect by preventing the secretion of
      other, related BMP family members. We present evidence that this may occur
      through the formation of heterodimers.
    explanation: Establishes heterodimer-mediated sequestration as the dominant-negative mechanism.
  downstream:
  - target: Loss of GDF5-BMPR1B Signaling in the Developing Limb
    causal_link_type: DIRECT
    description: >-
      Withdrawal of GDF5 and of its co-sequestered BMP partners from the
      extracellular space directly deprives BMPR1B of ligand.
    evidence:
    - reference: PMID:9288098
      reference_title: Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        It produces a dominant negative effect by preventing the secretion of
        other, related BMP family members.
      explanation: Loss of secreted BMP ligands is the direct consequence for receptor signalling.
- name: Loss of GDF5-BMPR1B Signaling in the Developing Limb
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    GDF5 is a BMP-family ligand with high affinity for the type I receptor
    BMPR1B. This node is the shared central effector of the whole acromesomelic
    GDF5/BMPR1B spectrum: disabling the ligand and disabling the receptor produce
    overlapping disease, and the severity of the resulting phenotype tracks the
    degree of functional impairment of the ligand-receptor pair.
  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
  molecular_functions:
  - preferred_term: BMP receptor activity
    term:
      id: GO:0098821
      label: BMP receptor activity
    modifier: DECREASED
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  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: >-
      Both genes encode members of the same pathway: The GDF5 ligand belongs to
      the bone morphogenetic protein (BMP) family and binds with a high affinity
      to the BMP receptor BMPR1B
    explanation: Establishes the ligand-receptor pair that 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-dependent relationship between residual GDF5-BMPR1B
      signalling and phenotype severity across the spectrum.
  - 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: Failed Chondrogenic Condensation and Joint Specification in the Distal Limb
    causal_link_type: DIRECT
    description: >-
      GDF5-BMPR1B signalling directly governs the condensation, differentiation
      and maturation steps that build appendicular skeletal elements and their
      joints.
    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 interaction between GDF5 and BMPR1B is a critical aspect of bone
        development by regulating the differentiation and maturation of cells
        involved in bone formation, from chondrogenesis to osteogenesis
      explanation: Links the ligand-receptor interaction to the chondrogenic and osteogenic steps of bone formation.
- name: Failed Chondrogenic Condensation and Joint Specification in the Distal Limb
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    GDF5 is expressed at sites of skeletal morphogenesis, particularly in the
    interzones that prefigure joints and in the condensations that prefigure
    individual skeletal elements. Without GDF5-BMPR1B signalling these
    condensations fail to form, segment, or separate correctly, which is why the
    phenotype is one of missing, fused and malformed elements rather than of
    uniformly short but well-formed bones.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Condensing limb mesenchyme
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  biological_processes:
  - preferred_term: Cartilage condensation
    term:
      id: GO:0001502
      label: cartilage condensation
    modifier: ABNORMAL
  - preferred_term: Embryonic skeletal joint morphogenesis
    term:
      id: GO:0060272
      label: embryonic skeletal joint morphogenesis
    modifier: ABNORMAL
  - preferred_term: Chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: DECREASED
  - preferred_term: Cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:8589725
    reference_title: A human chondrodysplasia due to a mutation in a TGF-beta superfamily member.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDMP-1 is predominantly expressed at sites of skeletal morphogenesis (3),
      and we now show that a mutation in hCDMP-1 is associated with a recessive
      human chondrodysplasia
    explanation: Ties GDF5 expression at sites of skeletal morphogenesis to the human disease.
  - reference: PMID:8589725
    reference_title: A human chondrodysplasia due to a mutation in a TGF-beta superfamily member.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disorder, characterized by skeletal abnormalities restricted to the
      limbs andlimb joints
    explanation: >-
      Records that the lesion is restricted to limb skeletal elements and limb
      joints, the structures this node concerns.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analyses with a micromass culture system revealed a strong
      inhibition of chondrogenesis by both mutant receptors.
    explanation: >-
      Micromass culture shows that blocking this ligand-receptor pair inhibits
      chondrogenesis itself, which is the basis for annotating chondrocyte
      differentiation as decreased at this node.
  downstream:
  - target: Proximodistally Graded Appendicular Skeletal Malformation
    causal_link_type: DIRECT
    description: >-
      Failure of condensation and segmentation directly yields absent, fused and
      rudimentary appendicular elements, most severely at the distal end of the
      limb.
    evidence:
    - reference: PMID:26275437
      reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hypoplastic hands, with the phalangeal zone more affected than the
        metacarpal zone; and severe hypoplastic tibial/femoral zones in both
        limbs
      explanation: Documents the graded element-by-element hypoplasia produced downstream.
- name: Proximodistally Graded Appendicular Skeletal Malformation
  role: consequence
  biological_scale: TISSUE
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  description: >-
    The malformation is graded along the proximodistal axis and is repeated in
    both fore- and hindlimb autopods, the hallmark of a lesion in a limb
    patterning signal that is serially reused. Distal elements are the most
    severely affected, the axial and craniofacial skeleton is spared, and the
    graded pattern is the feature that separates this spectrum from generalised
    chondrodysplasias.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Limb morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  - preferred_term: Limb development
    term:
      id: GO:0060173
      label: limb development
    modifier: ABNORMAL
  - preferred_term: Endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe shortening of the forearms with an acromesomelic pattern following
      a proximodistal gradient, with distal parts more severely affected than
      medial parts
    explanation: Directly documents the proximodistal severity gradient in a molecularly confirmed case.
  - reference: PMID:12124730
    reference_title: Frameshift mutation in the cartilage-derived morphogenetic protein 1 (CDMP1) gene and severe acromesomelic chondrodysplasia resembling Grebe-type chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all affected patients had a similar phenotype with unaffected axial and
      craniofacial bones
    explanation: Confirms that the malformation spares the axial and craniofacial skeleton.
mechanistic_hypotheses:
- hypothesis_group_id: gdf5_null_loss_model
  hypothesis_label: Simple Ligand-Loss Model
  status: CANONICAL
  description: >-
    Truncating GDF5 alleles remove the ligand, GDF5-BMPR1B signalling falls to
    near zero in the distal limb, and the condensations that build the digits
    fail. This accounts for the families in which the causative allele is a
    frameshift and the heterozygous parents are unaffected, and it is the model
    that carries over directly to the BMPR1B disorders, where the receptor
    rather than the ligand is removed.
  evidence:
  - reference: PMID:12124730
    reference_title: Frameshift mutation in the cartilage-derived morphogenetic protein 1 (CDMP1) gene and severe acromesomelic chondrodysplasia resembling Grebe-type chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The truncated CDMP1 protein in these subjects is predicted to cause a
      total loss of its signaling function.
    explanation: A frameshift allele causing severe Grebe-type disease with unaffected carriers fits simple ligand loss.
- hypothesis_group_id: dominant_negative_bmp_sequestration
  hypothesis_label: Dominant-Negative BMP Sequestration Model
  status: ALTERNATIVE
  description: >-
    The archetypal Grebe missense allele does more than remove GDF5. The mutant
    protein is retained inside the cell and, because BMP family members
    dimerise, drags partner BMPs out of the secretory pathway with it, so the
    lesion is a broader withdrawal of BMP signalling than a GDF5 null produces.
    The clinical prediction that distinguishes the two models is carrier status:
    a null allele should leave heterozygotes unaffected, whereas a sequestering
    allele should give them a brachydactyly, and heterozygous brachydactyly is
    exactly what the reported families show. What has never been done is the
    comparison that would settle it, matching homozygous phenotype severity
    between a sequestering allele and a true null.

    A refinement worth noting is that the sequestration may not be a simple
    property of the mutant protein. For a prodomain GDF5 variant, inhibition of
    wild-type GDF5 secretion happened only when the latent TGF-beta binding
    proteins LTBP1 or LTBP2 were co-expressed. If the effect depends on the
    local abundance of such co-factors, dominant-negative penetrance is partly a
    property of the tissue environment rather than of the allele alone, which
    would be one way to explain why carriers of a single allele in one pedigree
    range from unaffected to frankly brachydactylous.
  evidence:
  - reference: PMID:9288098
    reference_title: Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It produces a dominant negative effect by preventing the secretion of
      other, related BMP family members. We present evidence that this may occur
      through the formation of heterodimers.
    explanation: Establishes the sequestration mechanism that makes this allele more than a null.
  - reference: PMID:33872773
    reference_title: "A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with severe GTC associated with homozygosity, and with a wide phenotypic
      variability among heterozygous carriers, ranging from unaffected
      non-penetrant carriers, to classical BDC and to novel unclassified types
      of brachydactylies
    explanation: >-
      Carrier phenotypes vary within a single family carrying one frameshift
      allele, which complicates using carrier status alone to separate the two
      models.
  - reference: PMID:23812741
    reference_title: "Characterization of a novel missense mutation in the prodomain of GDF5, which underlies brachydactyly type C and mild Grebe type chondrodysplasia in a large Pakistani family."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, we demonstrated that secretion of Wt-GDF5 was inhibited by the
      Mut-GDF5, but only when LTBP (LTBP1 or LTBP2) was co-expressed.
    explanation: >-
      Shows that dominant-negative inhibition of wild-type GDF5 secretion can be
      conditional on a co-factor. Support is partial because the allele tested is
      a prodomain variant, not the mature-domain cysteine substitution this group
      is built on.
  - reference: PMID:23812741
    reference_title: "Characterization of a novel missense mutation in the prodomain of GDF5, which underlies brachydactyly type C and mild Grebe type chondrodysplasia in a large Pakistani family."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we suggest a novel model, where the dosage of secretory co-factors or
      stabilizing proteins like LTBP1 and LTBP2 in the microenvironment may
      affect the extent of GDF5 secretion and thereby function as modifiers in
      phenotypes caused by GDF5 mutations
    explanation: >-
      States the co-factor-modifier model, a candidate explanation for the
      carrier variability this entry records, offered by its authors as a
      proposal rather than a demonstrated mechanism.
- hypothesis_group_id: processing_failure_model
  hypothesis_label: Precursor-Processing Failure Model
  status: EMERGING
  description: >-
    A third allele class acts before either of the above: p.Arg377Trp sits in
    the RRKRR recognition motif at the proteolytic processing site, so the
    lesion is failure to mature the GDF5 precursor into active ligand rather
    than failure of the mature protein to fold, be secreted, or bind. The
    functional consequence has been inferred from the motif rather than
    measured, and no processing assay has been run on this allele.
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The p.Arg377Trp mutation is located within the recognition motif at the
      processing site of GDF5 where the sequence RRKRR changes to WRKRR.
    explanation: >-
      Localises the allele to the processing motif. Support is partial because
      the pathogenic effect was established by in silico and structural
      prediction rather than by a processing assay.
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      In silico and structural analyses predicted the p.Arg377Trp amino acid
      change to be pathogenic.
    explanation: Records that the evidence for this allele class is predictive rather than experimental.
  notes: >-
    The three groups describe different allele classes rather than competing
    accounts of one allele, and a single entry can only be explained by one of
    them. They are curated together because the clinical phenotype does not
    distinguish them, so the mechanism operating in any given family is read
    from the variant rather than from the radiographs.
phenotypes:
- category: Skeletal
  name: Severe Micromelia
  description: >-
    Marked shortening and deformation of all four limbs, with the distal
    segments most severely affected.
  phenotype_term:
    preferred_term: Micromelia
    term:
      id: HP:0002983
      label: Micromelia
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acromesomelic dysplasia, Grebe type is a very rare skeletal dysplasia
      characterized by severe dwarfism with marked micromelia and deformation of
      the upper and lower limbs, with a proximodistal gradient of severity.
    explanation: A molecularly confirmed Grebe case report documents marked micromelia directly.
  - reference: PMID:26870132
    reference_title: "Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients were observed with short and deformed limbs having a proximo-distal
      gradient of severity.
    explanation: An independent molecularly confirmed family reproduces the finding.
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: AMDG is characterized by severe micromelia.
    explanation: >-
      A radiology review of a different disorder names severe micromelia as the
      defining Grebe feature in its differential-diagnosis discussion. Graded
      OTHER because the paper reports no Grebe patient of its own.
- category: Skeletal
  name: Absent or Fused Hand and Foot Bones
  description: >-
    Carpals and metacarpals, and tarsals and metatarsals, may be fused; the
    metacarpal, metatarsal, proximal or middle phalanges may be missing
    altogether, producing rudimentary knob-like digits.
  phenotype_term:
    preferred_term: Aplasia/hypoplasia involving bones of the hand
    term:
      id: HP:0005927
      label: Aplasia/hypoplasia involving bones of the hand
  evidence:
  - reference: PMID:27577507
    reference_title: Novel homozygous sequence variants in the GDF5 gene underlie acromesomelic dysplasia type-grebe in consanguineous families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acromesomelic dysplasia Grebe type (AMDG) is characterized by severe knob
      like non-functional fingers and short acromesomelic limbs
    explanation: >-
      Two molecularly confirmed consanguineous families document the knob-like
      non-functional digits that the underlying element loss produces.
  - reference: PMID:26870132
    reference_title: "Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Digits on autopods were very short and nonfunctional.
    explanation: An independent family reproduces the digit phenotype.
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fusion of the carpals and/or metacarpals and tarsals and/or metatarsals
      maybe present. Metacarpal, metatarsal or proximal and/or middle phalanges
      may be absent.
    explanation: >-
      Supplies the element-by-element radiographic detail, which the primary case
      reports above do not itemise. Graded OTHER because this is a
      differential-diagnosis paragraph in a paper about a different disorder.
- category: Skeletal
  name: Carpal Synostosis
  description: Fusion of carpal bones, part of the distal-limb dysmorphogenesis.
  phenotype_term:
    preferred_term: Carpal synostosis
    term:
      id: HP:0009702
      label: Carpal synostosis
  evidence:
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Fusion of the carpals and/or metacarpals and tarsals and/or metatarsals maybe present.
    explanation: >-
      Documents carpal fusion in Grebe type. Graded OTHER because the statement
      comes from a differential-diagnosis paragraph in a case report about
      NPR2-related disease, not from a Grebe patient this paper examined.
- category: Skeletal
  name: Postaxial Polydactyly
  description: >-
    Supernumerary postaxial digits occur in a subset of GDF5-related Grebe
    families, and are the feature that later prompted recognition of the same
    finding in BMPR1B-related disease.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Postaxial polydactyly has also been reported.
    explanation: >-
      Records postaxial polydactyly among reported Grebe findings. Graded OTHER:
      the sentence is itself a citation of other reports.
  - 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: >-
      polydactyly is a known finding in Grebe dysplasia caused by biallelic
      variants in GDF5
    explanation: >-
      Independently confirms polydactyly as an established GDF5-related Grebe
      finding. Graded OTHER for the same reason: this is a BMPR1B case report
      summarising the GDF5 literature rather than observing it.
- category: Skeletal
  name: Femoral, Tibial and Fibular Hypoplasia
  description: >-
    Significant femoral shortening with absent tibial and fibular diaphyses in
    the most severe cases.
  phenotype_term:
    preferred_term: Short femur
    term:
      id: HP:0003097
      label: Short femur
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe hypoplastic tibial/femoral zones in both limbs
    explanation: Radiographs of a molecularly confirmed Grebe case document the femoral and tibial hypoplasia directly.
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Significant femoral shortening is present in AMDG, as well as absent
      tibial and fibular diaphysis, hypoplasia of the ulna and a malformed radial
      head
    explanation: >-
      Adds the fibular and forearm detail. Graded OTHER because it is a
      differential-diagnosis statement rather than this paper's own observation.
- category: Skeletal
  name: Ulnar Hypoplasia and Malformed Radial Head
  description: Hypoplasia of the ulna with a malformed radial head in the forearm.
  phenotype_term:
    preferred_term: Hypoplasia of the ulna
    term:
      id: HP:0003022
      label: Hypoplasia of the ulna
  evidence:
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      as well as absent tibial and fibular diaphysis, hypoplasia of the ulna and
      a malformed radial head
    explanation: >-
      Documents forearm involvement. This is the only source in the entry for
      the forearm findings and it is a secondary one, so it is graded OTHER and
      the phenotype should be re-sourced when a primary description is
      available.
- category: Skeletal
  name: Joint Dislocation
  subtype: Hunter-Thompson
  description: >-
    Ankle dislocation is common and radial head dislocation may be present in the
    Hunter-Thompson subtype, consistent with GDF5's role at the joint interzone.
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ankle dislocation is common and radial head dislocation may be present
    explanation: >-
      Records the joint dislocations characteristic of the Hunter-Thompson
      subtype. Graded OTHER because the statement is a differential-diagnosis
      summary, not an observation of a Hunter-Thompson patient by this paper.
- category: Skeletal
  name: Short Stature
  description: >-
    Severe dwarfism results from the appendicular shortening; the trunk is
    comparatively preserved because the axial skeleton is unaffected.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characterized by severe dwarfism with marked micromelia
    explanation: States the severe short stature of Grebe type.
diagnosis:
- name: Radiographic Pattern Recognition
  description: >-
    The combination of severe distal-predominant limb malformation with a
    normal axial and craniofacial skeleton, in a child of consanguineous
    parents, is the pattern that directs testing to the GDF5/BMPR1B spectrum
    rather than to a generalised chondrodysplasia.
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic imaging revealed features typical of Grebe syndrome: severe
      shortening of the forearms with an acromesomelic pattern following a
      proximodistal gradient
    explanation: Radiographs established the clinical diagnosis before molecular confirmation in this case.
- name: Prenatal Sonographic Diagnosis
  description: >-
    The limb phenotype is severe enough to be recognised on second-trimester
    ultrasound, with the globular fingers and toes as the distinguishing
    feature. This matters for counselling in an at-risk sibship, and the
    prognostic point that goes with it is that the condition is not lethal and
    intelligence is normal.
  evidence:
  - reference: PMID:27677752
    reference_title: Grebe dysplasia - prenatal diagnosis based on rendered 3-D ultrasound images of fetal limbs.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rendered 3-D ultrasound images of the fetal limbs, particularly of the
      characteristic tiny and globular-looking fingers and toes, were
      instrumental in accurately characterizing the phenotype prenatally.
    explanation: Documents prenatal recognition of the phenotype and the finding that carried the diagnosis.
  - reference: PMID:27677752
    reference_title: Grebe dysplasia - prenatal diagnosis based on rendered 3-D ultrasound images of fetal limbs.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite the severe skeletal deformities, the condition is not lethal and
      surviving individuals can have normal intelligence.
    explanation: >-
      The prognostic statement that accompanies a prenatal diagnosis and is
      central to counselling.
- name: Molecular Confirmation of Biallelic GDF5 Variants
  description: >-
    Sequencing GDF5 confirms the diagnosis and, because the GDF5 and BMPR1B
    phenotypes overlap, a negative GDF5 result should be followed by BMPR1B
    sequencing rather than closing the workup.
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genotype-phenotype correlation allowed not only confirmation of the
      clinical diagnosis but also appropriate genetic counselling to be offered
      to this family.
    explanation: Molecular confirmation is what converts the radiographic impression into a counselled diagnosis.
  - 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: Supports escalating to BMPR1B when GDF5 sequencing is negative in an overlapping phenotype.
treatments:
- name: Genetic Counseling
  description: >-
    Counselling for an autosomal recessive disorder with a one-in-four
    recurrence risk in an affected sibship. It is not routine here: with the
    dominant-negative mature-domain alleles, heterozygous carriers are not
    reliably unaffected, and within a single pedigree carrier phenotypes have
    ranged from normal through classical brachydactyly type C to unclassified
    brachydactylies. Molecular confirmation of the family's allele is what makes
    the counselling accurate.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26275437
    reference_title: "Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genotype-phenotype correlation allowed not only confirmation of the
      clinical diagnosis but also appropriate genetic counselling to be offered
      to this family.
    explanation: Documents genetic counselling as the management step that molecular confirmation enables.
  - reference: PMID:33872773
    reference_title: "A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with a wide phenotypic variability among heterozygous carriers, ranging
      from unaffected non-penetrant carriers, to classical BDC and to novel
      unclassified types of brachydactylies
    explanation: >-
      Carrier phenotypes vary within one pedigree, which is what makes
      counselling for this disorder harder than a standard recessive
      recurrence-risk conversation.
differential_diagnoses:
- name: Du Pan Syndrome
  disease_term:
    preferred_term: du Pan syndrome
    term:
      id: MONDO:0009231
      label: acromesomelic dysplasia 2B
  description: >-
    The mild end of the same GDF5/BMPR1B spectrum, with fibular hypoplasia and
    complex brachydactyly but preserved stature and largely intact long bones.
  distinguishing_features:
  - Stature and the long bones are preserved in du Pan syndrome, whereas Grebe type causes severe dwarfism with absent or fused distal elements.
  - >-
      The distinction reflects residual signalling, with hypomorphic alleles
      giving du Pan and severe loss-of-function alleles giving Grebe.
  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-limb phenotype at the Grebe end of the spectrum.
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We extend the genotype-phenotype correlation in the acromesomelic
      chondrodysplasias by showing that the milder du Pan dysplasia can be
      caused by a hypomorphic BMPR1B mutation.
    explanation: >-
      States that du Pan is the milder phenotype and that it maps onto a
      hypomorphic rather than a severe loss-of-function allele.
- 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 phenotype, which the 2023 nosology lists as a
    separate group-16 entity and which adds genital anomalies to a very similar
    limb picture.
  distinguishing_features:
  - Hypoplasia of the uterus with ovarian dysfunction and hypergonadotrophic hypogonadism is present in the BMPR1B-related disorder and absent in GDF5-related Grebe dysplasia.
  - Biallelic BMPR1B rather than biallelic GDF5 variants establish the diagnosis.
  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: >-
      However, the phenotype described here differs from GDF5 associated
      chondrodysplasias because of the additional presence of genital anomalies
      and the distinct limb phenotype.
    explanation: The founding report states exactly how the BMPR1B disorder differs from the GDF5 disorders.
- name: Acromesomelic Dysplasia, Maroteaux Type
  disease_term:
    preferred_term: acromesomelic dysplasia, Maroteaux type
    term:
      id: MONDO:0011275
      label: acromesomelic dysplasia 1, Maroteaux type
  description: >-
    The NPR2-related acromesomelic dysplasia, in the same nosology group but a
    different signalling pathway.
  distinguishing_features:
  - The craniofacial and axial skeleton are affected in AMDM and unaffected in Grebe and Hunter-Thompson types.
  - All skeletal elements are present but abnormally grown in AMDM, whereas Grebe type shows absent and fused elements.
  evidence:
  - reference: PMID:34178199
    reference_title: "A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Unlike AMDM, in both acromesomelic dysplasia, Hunter-Thompson type (AMDH)
      and Grebe type (AMDG) the craniofacial and axial skeleton is unaffected
    explanation: >-
      States the axial and craniofacial contrast that separates AMDM from this
      entry. Graded OTHER because the comparison is drawn in discussion; the
      paper observed an AMDM patient, not a Grebe one.
  - reference: PMID:26870132
    reference_title: "Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, symptoms in the craniofacial and axial skeleton were minimal.
    explanation: >-
      A molecularly confirmed Grebe family supplies the axial-sparing half of the
      contrast from the Grebe side, which is the side this entry is about.
- name: Brachydactyly Type C
  description: >-
    The heterozygous manifestation of GDF5 alleles in the same families. It is a
    differential in the sense that a carrier relative of a Grebe proband may
    present with isolated brachydactyly rather than being unaffected.
  distinguishing_features:
  - Brachydactyly type C arises in heterozygous carriers; the full Grebe phenotype requires homozygosity.
  evidence:
  - reference: PMID:33872773
    reference_title: "A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and brachydactyly type C+ in a 6 generations family: Clinical report and mini review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family confirmed that both GTC and BDC are part of the GDF5 mutational
      spectrum, with severe GTC associated with homozygosity
    explanation: Establishes that both phenotypes arise from the same allele at different dosage.
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
    Grebe dysplasia?
  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 Grebe dysplasia 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: grebe_hunter_thompson_lumping
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do the Grebe and Hunter-Thompson types reflect distinct GDF5 allele classes,
    or are they two descriptions of one continuum?
  rationale: >-
    The 2023 ISDS nosology folds Hunter-Thompson into GDF5-related Grebe
    dysplasia, and OMIM and MONDO keep them as separate entities. The published
    radiographic distinction is real (lower-limb predominance and joint
    dislocation in Hunter-Thompson), but no study has systematically related
    those features to allele class or residual signalling. This entry curates
    them as subtypes of one disease pending such a study.
  attaches_to:
  - has_subtypes#Grebe
  - has_subtypes#Hunter-Thompson
- discussion_id: dominant_negative_vs_null_severity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does the dominant-negative Grebe missense allele produce a more severe
    homozygous phenotype than a GDF5 null allele?
  rationale: >-
    The mature-domain missense allele sequesters other BMP family members and so
    should remove more BMP signalling than a simple null, which predicts a more
    severe homozygous phenotype. Reported truncating alleles nonetheless produce
    severe Grebe-like disease, and no series has compared the two allele classes
    with matched phenotyping. Resolving this bears on genetic counselling for
    carriers, who are affected only with the dominant-negative alleles.
  attaches_to:
  - pathophysiology#Failed Secretion of GDF5 and Dominant-Negative Sequestration of BMP Partners
  - mechanistic_hypotheses#gdf5_null_loss_model
  - mechanistic_hypotheses#dominant_negative_bmp_sequestration
notes: >-
  Curated as part of a review of ISDS 2023 nosology group 16 (acromesomelic
  dysplasias). Hunter-Thompson type is curated here as a subtype rather than as
  its own entry because the 2023 revision treats "Grebe dysplasia, GDF5-related"
  as covering both OMIM 200700 and OMIM 201250; the separate MONDO term is
  retained on the subtype so the concept remains resolvable. 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.