Acromesomelic Dysplasia Demirhan Type

Mendelian MONDO:0012274 Pathograph 31 Show in embeddings browser Skeletal Dysplasia

An autosomal recessive acromesomelic skeletal dysplasia caused by biallelic BMPR1B variants, corresponding to Grebe dysplasia, BMPR1B-related in the 2023 skeletal nosology. Severe shortening and malformation of the middle and distal limbs include brachydactyly, fibular aplasia and carpal fusion. Tarsal fusion and genital abnormalities were documented in the founding patient but are not established as universal findings. That adolescent had primary amenorrhea, hypergonadotropic hypogonadism and a hypoplastic uterus; later young or male patients do not establish adult female penetrance. Truncating alleles are predicted to reduce receptor function, whereas the C53R missense allele has directly demonstrated defective GDF5-responsive signaling. The phenotype overlaps GDF5-related dysplasia without establishing complete equivalence of ligand and receptor loss.

Ask OpenScientist

Ask a research question about Acromesomelic Dysplasia Demirhan Type. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
22
Phenotypes
1
Hypotheses
3
Gaps
31
Pathograph
1
Genes
2
Medical Actions
3
Differentials
4
Models
🏷

Classifications

ISDS Skeletal Nosology
acromesomelic dysplasias
👪

Inheritance

1
Autosomal Recessive HP:0000007
Severe disease segregates with homozygous BMPR1B variants in the reported families. Heterozygous relatives range from apparently unaffected to mild brachydactyly. This differs from the severe recessive phenotype and does not imply that every BMPR1B missense variant is a recessive allele.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:24129431 SUPPORT Human Clinical
"A loss-of-function effect of both mutations causing recessive ACD-type Grebe is further supported by the mild brachydactyly or even non-penetrance of these mutations observed in the heterozygous parents."
The carrier phenotype in two consanguineous families supports recessive loss-of-function inheritance.
◈

Mechanistic Hypotheses

1
BMPR1B contribution to the reproductive phenotype
bmpr1b_reproductive_role EMERGING
Evidence balance 3 support
Loss of BMPR1B may contribute to the ovarian endocrine and uterine abnormalities documented in the founder. Null mice show impaired cumulus expansion, fertility and uterine gland formation but retain follicles and ovulation. These findings support reproductive involvement without reproducing human ovarian nonvisualization or proving a granulosa-cell-specific human pathway. A second genetic contributor in the consanguineous family remains an alternative.
Later reports include males and a two-year-old girl whose uterus was normal but ovaries were not assessable. These observations cannot estimate adult female penetrance. The sheep Q249R hyperprolific allele is not a model of complete receptor loss. In the null-mouse full text, aromatase mRNA reduction was not statistically significant and estradiol was not directly compared.
Pathograph links
Biallelic BMPR1B Variants -> Ovarian Endocrine Dysfunction INDIRECT UNKNOWN INTERMEDIATES A contribution of BMPR1B loss to the founding ovarian phenotype is plausible from the human case and null-mouse reproductive defects, but the human intermediate steps and tissue of action remain unresolved.
Biallelic BMPR1B Variants -> Impaired Uterine Development INDIRECT UNKNOWN INTERMEDIATES The founding uterine phenotype may reflect direct uterine receptor loss, secondary endocrine effects, or both. Null-mouse uterine histology supplies partial biological support.
Show evidence (3 references)
PMID:15805157 SUPPORT Human Clinical
"In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism."
The founding patient had both ovarian endocrine dysfunction and uterine hypoplasia; this case does not establish the intervening molecular mechanism.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants"
Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice"
Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
?

Discussions and Knowledge Gaps

3
What functional outcomes follow orthopedic, rehabilitative and endocrine care in severe BMPR1B-related acromesomelic dysplasia?
KNOWLEDGE GAP OPEN supportive_management_outcomes
Attached to
treatments#
Genetic counseling is discussed in the Moroccan report and hormone substitution is explicitly documented in the founding full text. The retrieved disease-specific sources do not supply the hormone regimen or response, or comparative outcomes for surgery, prostheses and rehabilitation. These are gaps in evidence, not an absence of all reported care.
Which BMPR1B-related reproductive defects recur in adequately assessed adult patients, and which tissues mediate them?
KNOWLEDGE GAP OPEN bmpr1b_genital_phenotype_mechanism
Attached to
pathophysiology#Ovarian Endocrine Dysfunction pathophysiology#Impaired Uterine Development
The founding human case and Bmpr1b-null mouse reproductive phenotypes support further investigation, but the mice retain follicles and ovulation and do not reproduce confirmed human ovarian agenesis. The mouse full text reports nonsignificant aromatase mRNA differences and no direct estradiol comparison. Direct uterine effects, ovarian endocrine effects, and a possible second genetic contributor in the founder remain unresolved. Males and a prepubertal girl with unassessable ovaries cannot establish adult female penetrance.
How well does residual signaling predict the BMPR1B acromesomelic phenotype across alleles?
KNOWLEDGE GAP OPEN residual_signaling_and_severity
Attached to
pathophysiology#Reduced BMPR1B-Mediated BMP Signaling
C53R and the milder Du Pan-associated R31C allele differ in reporter activity. This supports a proposed severity-function relationship for selected alleles, not exact equivalence of GDF5 and BMPR1B loss or a validated diagnostic functional threshold.
⚙

Pathophysiology

8
Biallelic BMPR1B Variants
Homozygous truncating or functionally disruptive missense BMPR1B alleles initiate severe acromesomelic disease. The molecular route depends on the allele.
BMPR1B contribution to the reproductive phenotype
BMPR1B hgnc:1077 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BMPR1B (hgnc:1077). hgnc:1077 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Predicted Loss of Functional BMPR1B Protein Truncating alleles are predicted to yield transcript degradation or a nonfunctional truncated receptor; neither route was directly measured in patient cells.
Reduced BMPR1B-Mediated BMP Signaling The C53R missense allele produces defective GDF5-responsive reporter signaling despite detectable membrane localization.
Ovarian Endocrine Dysfunction A contribution of BMPR1B loss to the founding ovarian phenotype is plausible from the human case and null-mouse reproductive defects, but the human intermediate steps and tissue of action remain unresolved. BMPR1B contribution to the reproductive phenotype
Impaired Uterine Development The founding uterine phenotype may reflect direct uterine receptor loss, secondary endocrine effects, or both. Null-mouse uterine histology supplies partial biological support. BMPR1B contribution to the reproductive phenotype
Show evidence (3 references)
PMID:15805157 SUPPORT Human Clinical
"Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function"
The founding report establishes a homozygous truncating BMPR1B allele as causative.
PMID:24129431 SUPPORT Human Clinical
"Here, we present two consanguineous families with missense (c.157T>C, p.(C53R)) or nonsense (c.657G>A, p.(W219*)) mutations in BMPR1B."
Extends the allelic spectrum to a missense and a second nonsense allele.
PMID:37524292 SUPPORT Human Clinical
"The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein."
Adds a further nonsense allele and states the predicted loss-of-function route.
Predicted Loss of Functional BMPR1B Protein
Frameshift and nonsense alleles are expected to reduce functional BMPR1B through premature truncation and/or nonsense-mediated RNA decay. The source studies predict these alternatives without demonstrating transcript decay or receptor abundance in patient tissue.
BMPR1B hgnc:1077 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BMPR1B (hgnc:1077). hgnc:1077 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced BMPR1B-Mediated BMP Signaling Predicted loss of a functional type I receptor reduces signaling capacity; the exact contribution of RNA decay versus truncated protein remains untested.
Show evidence (2 references)
PMID:37524292 SUPPORT Human Clinical
"The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein."
Adds a further nonsense allele and states the predicted loss-of-function route.
PMID:15805157 SUPPORT Human Clinical
"Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function"
The founding report establishes a homozygous truncating BMPR1B allele as causative.
Reduced BMPR1B-Mediated BMP Signaling
BMPR1B transduces BMP-family signals important in appendicular development. In the C53R expression model, GDF5 fails to induce a wild-type BMP-responsive luciferase signal. The receptor remains detectable at the membrane; impaired folding and ligand recognition are proposed explanations rather than directly assayed binding defects. Neither complete absence of receptor trafficking nor patient SMAD phosphorylation failure was established.
BMP signaling pathway GO:0030509 ↓ DECREASED 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.
Experimental models
C53R BMPR1B reporter and localization in NIH/3T3 cells CELL LINE The reporter resolves the C53R signaling defect and microscopy confirms retained surface localization.
Downstream
Reduced Digital Prechondrogenic Cell Proliferation Bmpr1b-null mice show reduced proliferation in the phalangeal region after normal initial digital-ray formation. This provides model-based support for a developmental consequence of impaired receptor signaling.
Impaired Digital Chondrocyte Differentiation Loss of Bmpr1b reduces phalangeal chondrocyte differentiation in mice; the human developmental mechanism is inferred from this perturbation model.
Show evidence (2 references)
PMID:24129431 SUPPORT In Vitro
"In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay."
GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/ SUPPORT In Vitro
"is processed and can translocate to the cell surface in our overexpression studies, the efficiency of these processes might be reduced."
The C53R construct retained surface localization; reduced processing or delivery was suggested from weaker extracellular staining, not directly measured.
Reduced Digital Prechondrogenic Cell Proliferation
In the Bmpr1b-null mouse, prechondrogenic cell proliferation in the phalangeal region is markedly reduced despite initially normal digital rays. The model supports deficient expansion of committed skeletal precursors, not failed initiation of all limb condensations.
Animal models
Bmpr1b-null mouse appendicular development Mus musculus partially recapitulates Null mice reproduce reduced precursor proliferation in the phalangeal region.
Downstream
Acromesomelic Appendicular Malformation Reduced expansion of digital precursors is a model-supported contributor to distal skeletal underdevelopment; it does not by itself explain every human fusion or fibular defect.
Show evidence (1 reference)
PMID:10631182 SUPPORT Model Organism
"Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced."
Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
Impaired Digital Chondrocyte Differentiation
Reduced chondrocyte differentiation in the phalangeal region is demonstrated in Bmpr1b-null mice. The C53R chick micromass experiment instead showed unchanged matrix under overexpression and tested for dominant-negative interference; it is not a demonstration of this developmental defect.
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.
chondrocyte differentiation GO:0002062 ↓ DECREASED 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.
Experimental models
C53R chick limb-bud micromass comparator assay PRIMARY CELL CULTURE This comparator assay tests whether C53R interferes with endogenous chondrogenesis in a dominant-negative manner.
Animal models
Bmpr1b-null mouse appendicular development Mus musculus partially recapitulates Null mice exhibit reduced phalangeal chondrocyte differentiation.
Downstream
Acromesomelic Appendicular Malformation Deficient digital chondrocyte differentiation offers a partial developmental explanation for the human distal-limb malformations. Precise routes to individual skeletal abnormalities remain unresolved.
Show evidence (2 references)
PMID:10631182 SUPPORT Model Organism
"Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced."
Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/ SUPPORT In Vitro
"When comparing the degree of chondrogenic differentiation of micromass cultures expressing ... with control cultures, no significant differences were observed."
C53R, wild-type and ligand-binding-domain-deletion overexpression gave similar cartilage matrix to empty-virus controls; the experiment did not demonstrate failed differentiation.
Acromesomelic Appendicular Malformation
Middle and distal appendicular segments are disproportionately short and malformed. Severe brachydactyly, absent or shortened phalanges, fibular aplasia and carpal fusion occur in reported BMPR1B-related Grebe families. Tarsal fusion was present in the founder but absent from the three new patients tabulated in the C53R/W219* report.
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 development GO:0060173 ⚠ ABNORMAL 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. bone morphogenesis GO:0060349 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal bone morphogenesis (GO:0060349). GO:0060349 is a biological process from the Gene Ontology.
Downstream
Fibular Aplasia This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Severe Brachydactyly This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Ulnar Deviation of the Hands This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Carpal Synostosis This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Tarsal Synostosis This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Short Stature This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Radial Deviation of Fingers This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Short First Metacarpals This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Short Ulna This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Clubfoot This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Short Toes This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Short Femoral Necks This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
Absent Proximal Thumb Phalanges This absent skeletal element is part of the founding appendicular malformation pattern.
Absent Proximal Index Phalanges This absent skeletal element is part of the founding appendicular malformation pattern.
Show evidence (2 references)
PMID:24129431 SUPPORT Human Clinical
"Acromesomelic chondrodysplasias (ACDs) are characterized by disproportionate shortening of the appendicular skeleton, predominantly affecting the middle (forearms and forelegs) and distal segments (hands and feet)."
Defines the appendicular pattern that this node represents.
PMID:15805157 SUPPORT Human Clinical
"showed a severe form of limb malformation consisting of aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones"
Itemises the malformation in the index patient.
Ovarian Endocrine Dysfunction
The founding adolescent had primary amenorrhea, high gonadotropins and low estradiol, with ovaries not visualized on ultrasound. These establish her endocrine phenotype but not histological ovarian agenesis or a granulosa-cell-specific mechanism. Bmpr1b-null mice have impaired cumulus expansion and fertility despite preserved developing follicles, a partial and biologically distinct reproductive phenotype.
Animal models
Bmpr1b-null female reproductive model Mus musculus partially recapitulates The model supports a reproductive requirement for BMPR1B but differs substantially from the founding human ovarian phenotype.
Downstream
Hypergonadotrophic Hypogonadism The founding clinical and endocrine assessment documents this manifestation of ovarian dysfunction.
Primary Amenorrhea The founding clinical and endocrine assessment documents this manifestation of ovarian dysfunction.
Show evidence (2 references)
PMID:15805157 SUPPORT Human Clinical
"In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism."
The founding patient had both ovarian endocrine dysfunction and uterine hypoplasia; this case does not establish the intervening molecular mechanism.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice"
Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
Impaired Uterine Development
Uterine hypoplasia was observed in the founding adolescent. Null-mouse thin uterine linings and underdeveloped glands support a role for BMPR1B in reproductive tissues, while direct uterine versus secondary endocrine causation remains unresolved.
Animal models
Bmpr1b-null female reproductive model Mus musculus partially recapitulates Thin uterine linings and impaired endometrial gland development supply partial correspondence to human uterine hypoplasia.
Downstream
Uterine Hypoplasia The uterine developmental endpoint was documented by ultrasound in the founder.
Show evidence (2 references)
PMID:15805157 SUPPORT Human Clinical
"In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism."
The founding patient had both ovarian endocrine dysfunction and uterine hypoplasia; this case does not establish the intervening molecular mechanism.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants"
Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
⬡

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 Demirhan 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.
●

Phenotypes

22
Endocrine 1
Hypergonadotrophic Hypogonadism Hypergonadotropic hypogonadism HP:0000815 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergonadotropic hypogonadism (HP:0000815). HP:0000815 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15805157 SUPPORT Human Clinical
"ovarian dysfunction resulting in hypergonadotrophic hypogonadism"
Documents the endocrine phenotype in the index patient.
Genitourinary 2
Uterine Hypoplasia Hypoplasia of the uterus HP:0000013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the uterus (HP:0000013). HP:0000013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15805157 SUPPORT Human Clinical
"In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism."
Documents uterine hypoplasia in the index patient.
Primary Amenorrhea HP:0000786 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary amenorrhea (HP:0000786). HP:0000786 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"In addition to the skeletal phenotype, the patient presented with genital anomalies and primary amenorrhea."
Primary amenorrhea was present at age 16 in the founder.
Integument 1
Single Transverse Palmar Crease HP:0000954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Single transverse palmar crease (HP:0000954). HP:0000954 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37524292 SUPPORT Human Clinical
"the affected individuals showed additional features including bilateral simian creases"
Documents the palmar crease finding among the newly reported features.
Limbs 14
Fibular Aplasia HP:0002990 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fibular aplasia (HP:0002990). HP:0002990 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15805157 SUPPORT Human Clinical
"a severe form of limb malformation consisting of aplasia of the fibula"
Documents fibular aplasia in the founding case.
Severe Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156), qualified as severity severe. HP:0001156 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:15805157 SUPPORT Human Clinical
"aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands"
Documents severe brachydactyly in the founding case.
Ulnar Deviation of the Hands HP:0009487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ulnar deviation of the hand (HP:0009487). HP:0009487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15805157 SUPPORT Human Clinical
"severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones"
Documents ulnar deviation in the founding case.
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:15805157 SUPPORT Human Clinical
"ulnar deviation of the hands, and fusion of carpal/tarsal bones"
Documents carpal and tarsal fusion in the founding case.
Tarsal Synostosis HP:0008368 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tarsal synostosis (HP:0008368). HP:0008368 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15805157 SUPPORT Human Clinical
"and fusion of carpal/tarsal bones"
Documents tarsal fusion in the founding case.
Hip Dislocation HP:0002827 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip dislocation (HP:0002827). HP:0002827 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37524292 SUPPORT Human Clinical
"the affected individuals showed additional features including bilateral simian creases, lumbar hyperlordosis, as well as lower limb length inequality and dislocated hips in one of them, which were never reported previously for AMD Grebe type patients"
Observed in one affected sibling in the Moroccan report. A case count does not establish a population frequency.
Radial Deviation of Fingers HP:0009466 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Radial deviation of finger (HP:0009466). HP:0009466 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"Her hands (fig 2B) showed severe brachydactyly and radially deviated fingers. All fingernails were present."
The founder’s clinical body describes radial deviation of the fingers, separately from ulnar hand deviation in the abstract.
Short First Metacarpals Short 1st metacarpal HP:0010034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short 1st metacarpal (HP:0010034). HP:0010034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"The metacarpals II–V were of normal length, but metacarpals I were rudimentary."
The founder had rudimentary first metacarpals while metacarpals II–V were normal in length.
Short Ulna 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)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"The ulna was short and the radius appeared broad with an expanded distal epiphysis."
The founder’s ulna was short, with a broad radius and expanded distal radial epiphysis.
Clubfoot Talipes equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"The feet showed a bilateral clubfoot deformity with small broad feet and short toes that appeared constricted at their bases"
Bilateral clubfoot deformity was reported in the founder with fibular aplasia and tibiotalar dislocation.
Short Toes HP:0001831 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short toe (HP:0001831). HP:0001831 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"The feet showed a bilateral clubfoot deformity with small broad feet and short toes that appeared constricted at their bases"
The founder had short toes with constricted bases and preserved nails.
Short Femoral Necks HP:0100864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short femoral neck (HP:0100864). HP:0100864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"A radiograph of the pelvis (fig 2G) showed short femoral necks and deformed femoral heads with irregular joint spaces"
Pelvic radiographs showed short femoral necks and deformed femoral heads.
Absent Proximal Thumb Phalanges Absent proximal phalanx of thumb HP:0009637 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent proximal phalanx of thumb (HP:0009637). HP:0009637 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"Both thumbs consisted only of a distal phalanx and the proximal phalanges were missing (fig 2B)."
Both thumbs in the founder lacked their proximal phalanges.
Absent Proximal Index Phalanges Aplasia of the proximal phalanx of the 2nd finger HP:0009596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia of the proximal phalanx of the 2nd finger (HP:0009596). HP:0009596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"Hand radio- graphs showed severely hypoplastic phalangeal bones I–V (fig 2C1, right hand; fig 2C2, left hand); the proximal phalanges of the index fingers were missing."
Radiographs of both hands in the founder showed absent proximal index-finger phalanges.
Musculoskeletal 2
Lumbar Hyperlordosis HP:0002938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lumbar hyperlordosis (HP:0002938). HP:0002938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37524292 SUPPORT Human Clinical
"bilateral simian creases, lumbar hyperlordosis, as well as lower limb length inequality"
Documents lumbar hyperlordosis among the newly reported features.
Delayed Bone Age Delayed skeletal maturation HP:0002750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed skeletal maturation (HP:0002750). HP:0002750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"At the age of 16, the epiphysial plate of the ulna and the radius were not closed indicating retardation of bone age."
Unclosed ulnar and radial growth plates at age 16 were interpreted as delayed bone age.
Growth 2
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)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"She presented with disproportionate short stature (height: 127 cm) due to severe acromesomelic limb shortening"
The measured height and limb distribution are reported for the index patient.
Lower Limb Length Asymmetry Lower limb asymmetry HP:0100559 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb asymmetry (HP:0100559). HP:0100559 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37524292 SUPPORT Human Clinical
"the affected individuals showed additional features including bilateral simian creases, lumbar hyperlordosis, as well as lower limb length inequality and dislocated hips in one of them, which were never reported previously for AMD Grebe type patients"
Lower-limb length inequality was reported in one of the Moroccan siblings; the kindred does not establish population frequency.
🧬

Genetic Associations

1
Biallelic BMPR1B Loss-of-Function Variants (Causative)
Gene: BMPR1B hgnc:1077 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BMPR1B (hgnc:1077). hgnc:1077 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:15805157 SUPPORT Human Clinical
"Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function"
The founding report establishes a homozygous truncating BMPR1B allele as causative.
PMID:24129431 SUPPORT Human Clinical
"Here, we present two consanguineous families with missense (c.157T>C, p.(C53R)) or nonsense (c.657G>A, p.(W219*)) mutations in BMPR1B."
Extends the allelic spectrum to a missense and a second nonsense allele.
PMID:37524292 SUPPORT Human Clinical
"The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein."
Adds a further nonsense allele and states the predicted loss-of-function route.
+ 1 more reference
💊

Medical Actions

2
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
Offer genetic counseling based on the molecularly established autosomal recessive severe disorder and family segregation. Heterozygous relatives may have mild brachydactyly or no apparent hand findings; variants causing dominant brachydactyly represent a different allele-specific risk.
Show evidence (2 references)
PMID:37524292 SUPPORT Human Clinical
"these findings expand the phenotypic and mutational spectrum of AMD, and may improve the diagnosis of AMD and enable appropriate genetic counselling to be offered to patients"
States genetic counselling as the management consequence of a molecular diagnosis in this disorder.
PMID:14523231 SUPPORT Human Clinical
"These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner."
Dominant-negative BMPR1B alleles cause a dominant phenotype, which is why carrier counselling here depends on the allele's functional class.
Hormone Replacement for Ovarian Endocrine Dysfunction
Action: Hormone Replacement TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hormone Replacement Therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. NCIT:C15599
The founding adolescent with primary amenorrhea, hypergonadotropic hypogonadism and low estradiol received hormonal substitution. The report does not specify the hormones, regimen or clinical response; it supplies evidence of treatment use rather than a comparative efficacy estimate.
Mechanism Target:
BYPASSES Ovarian Endocrine Dysfunction — Hormonal substitution was used to compensate for the endocrine deficit in the founder; it was not shown to restore ovarian development or fertility.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"The patient receives hormonal substitution therapy. The diagnostics of LH, FSH, and oestradiol in the patient’s mother and two sisters revealed standard values according to their age."
The full founding report documents hormone substitution in the affected adolescent. Drug, dose, duration and response were not reported.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"The patient receives hormonal substitution therapy. The diagnostics of LH, FSH, and oestradiol in the patient’s mother and two sisters revealed standard values according to their age."
The full founding report documents hormone substitution in the affected adolescent. Drug, dose, duration and response were not reported.
🔬

Diagnosis

3
Molecular Evaluation of BMPR1B and Overlapping Dysplasia Genes
Interpret biallelic BMPR1B variants with the severe acromesomelic phenotype and familial segregation. The founding work excluded coding GDF5 variants before finding the BMPR1B deletion; that historical sequence does not require every present-day test to follow the same order. Distinguish severe recessive alleles from dominant brachydactyly variants and milder Du Pan-associated alleles.
Show evidence (2 references)
PMID:15805157 SUPPORT Human Clinical
"Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function"
The founding report establishes a homozygous truncating BMPR1B allele as causative.
PMID:24129431 SUPPORT Human Clinical
"Here, we present two consanguineous families with missense (c.157T>C, p.(C53R)) or nonsense (c.657G>A, p.(W219*)) mutations in BMPR1B."
Extends the allelic spectrum to a missense and a second nonsense allele.
Clinical and Skeletal Radiographic Assessment
Assess the distribution of limb shortening, phalangeal and metacarpal defects, carpal and tarsal fusion, fibulae and joint alignment. The detailed founding radiographs document absent proximal index/thumb phalanges, short ulnae, tibiotalar dislocations and short femoral necks; these findings vary between families.
Show evidence (1 reference)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"Radiographs of the lower leg (fig 2F) displayed deformed tibiae with wide proximal metaphyses and aplasia of the fibulae resulting in bilateral dislocation of the tibiotalar joints."
Direct radiographic description from the founding patient.
Pubertal, Endocrine and Pelvic Assessment
The founder was evaluated for primary amenorrhea by gonadotropins, estradiol and pelvic ultrasound. Interpret ovarian nonvisualization in its age and imaging context. A normal uterus in the two-year-old C53R patient, whose ovaries could not be assessed, is not evidence of normal adult reproductive function.
Show evidence (2 references)
url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf SUPPORT Human Clinical
"Upon ultrasound examination, the ovaries were not present and the uterus was shown to be hypoplastic."
Pelvic ultrasound contributed to assessment of the founding reproductive phenotype.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/ SUPPORT Human Clinical
"Ultrasound examination of the abdomen showed a normal uterus; the ovaries could not be evaluated because of bowel gas superposition."
The younger patient’s ovarian status remained unresolved.
📊

Prevalence

1
🔀

Differential Diagnoses

3

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

Acromesomelic Dysplasia, Grebe Type MONDO:0008703
Overlapping Features GDF5-related Grebe dysplasia has closely overlapping skeletal findings. Molecular cause establishes the distinction; the genital findings in the BMPR1B founder are a clinical clue rather than a sensitive or universally specific discriminator.
Distinguishing Features
  • Biallelic BMPR1B rather than GDF5 variants distinguish the molecular diagnoses.
  • Genital abnormalities occurred in the BMPR1B founder, but their absence does not exclude this diagnosis and case reports do not establish universal absence in every GDF5 disorder.
Show evidence (1 reference)
PMID:15805157 SUPPORT Human Clinical
"the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype"
States the distinguishing features directly.
Du Pan Syndrome MONDO:0009231
Overlapping Features Du Pan dysplasia is a milder acromesomelic phenotype associated with GDF5 or BMPR1B. BMPR1B p.Arg31Cys retained more reporter activity than p.Cys53Arg, supporting an allele-dependent severity hypothesis.
Distinguishing Features
  • The p.Arg31Cys adult had a height of 148 cm and absent fibulae, with preserved radius, ulna and femur; normal stature and preservation of every long bone are not required.
  • Residual signaling has been measured for selected alleles, but a precise functional cutoff separating Du Pan from Grebe dysplasia has not been established.
Show evidence (2 references)
PMID:26105076 SUPPORT In Vitro
"leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia"
Shows the allele-dependent split between the two BMPR1B diagnoses.
PMID:26105076 SUPPORT Human Clinical
"The proposita had disproportionate short stature with a height of 148 cm ( − 2.7 SD) and mild acromesomelic limb shortening."
Measured stature in the adult BMPR1B p.Arg31Cys Du Pan case refutes an absolute normal-stature distinction.
Brachydactyly Type A2
Overlapping Features The dominant BMPR1B disorder. It is caused by dominant-negative missense alleles rather than loss of function, and is the reason a heterozygous BMPR1B variant cannot be read as carrier status without knowing its functional class.
Distinguishing Features
  • Brachydactyly type A2 is autosomal dominant and arises from dominant-negative BMPR1B missense alleles.
  • The Demirhan-type alleles are recessive loss-of-function changes whose heterozygous carriers show at most mild brachydactyly.
Show evidence (3 references)
PMID:24129431 SUPPORT Human Clinical
"In contrast, dominant-negative BMPR1B mutations described previously are associated with autosomal-dominant brachydactyly-type A2."
States the mechanistic and inheritance contrast with the dominant BMPR1B disorder.
PMID:14523231 SUPPORT In Vitro
"An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism."
Even within dominant BMPR1B disease the alleles work differently, so a heterozygous BMPR1B variant cannot be read as carrier status for this recessive disorder without knowing its functional class.
PMID:15805157 SUPPORT Human Clinical
"is thus different from the heterozygous missense mutations in BMPR1B recently shown to cause brachydactyly type A2 through a dominant negative effect"
The founding report draws the same contrast for its truncating allele.
🧫

Experimental Models

2
C53R BMPR1B reporter and localization in NIH/3T3 cells CELL_LINE
Wild-type, C53R and ligand-binding-domain-deletion receptor constructs were compared with empty-vector controls. Reporter samples were triplicate and representative of three independent experiments.
Organism
Mus musculus NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Cell source
Mouse NIH/3T3 fibroblasts
Culture
Transient expression of mouse receptor constructs with a BMP-responsive firefly reporter, Renilla control and human GDF5; HA-tagged constructs for immunofluorescence.
Publication
PMID:24129431
Pathograph links
Reduced BMPR1B-Mediated BMP Signaling measures fidelity: moderate The reporter resolves the C53R signaling defect and microscopy confirms retained surface localization.
Limitations: Overexpression in mouse fibroblasts does not establish ligand affinity, endogenous patient receptor abundance, patient phospho-SMAD levels or developmental outcomes. Folding disruption was separately predicted using a short in-vacuo molecular model.
Readouts
GDF5-responsive luciferase
Direction: DECREASED
Interpretation: C53R failed to induce wild-type GDF5-responsive reporter output.
Show evidence (1 reference)
PMID:24129431 SUPPORT In Vitro
"In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay."
GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
Surface HA immunofluorescence
Direction: DECREASED
Interpretation: Extracellular C53R signal was weaker, but surface localization persisted and the difference was absent after permeabilization; reduced delivery efficiency remains proposed.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/ SUPPORT In Vitro
"is processed and can translocate to the cell surface in our overexpression studies, the efficiency of these processes might be reduced."
The C53R construct retained surface localization; reduced processing or delivery was suggested from weaker extracellular staining, not directly measured.
Show evidence (2 references)
PMID:24129431 SUPPORT In Vitro
"In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay."
GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
+ 1 more reference
Show evidence (2 references)
PMID:24129431 SUPPORT In Vitro
"In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay."
GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/ SUPPORT In Vitro
"is processed and can translocate to the cell surface in our overexpression studies, the efficiency of these processes might be reduced."
The C53R construct retained surface localization; reduced processing or delivery was suggested from weaker extracellular staining, not directly measured.
C53R chick limb-bud micromass comparator assay PRIMARY_CELL_CULTURE
C53R, wild-type and artificial ligand-binding-domain-deletion constructs resembled empty-virus controls. The BDA2-associated I200K positive comparator strongly inhibited chondrogenesis. Four replicate cultures were shown from one of three independent experiments.
Organism
Gallus gallus NCBITaxon:9031 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Gallus gallus (NCBITaxon:9031). NCBITaxon:9031 is an organism from the NCBI Taxonomy.
Cell source
Hamburger-Hamilton stage 23–24 chicken limb-bud cells
Culture
RCAS-mediated receptor overexpression; Alcian blue cartilage-matrix staining at seven days.
Publication
PMID:24129431
Pathograph links
Impaired Digital Chondrocyte Differentiation perturbs fidelity: low This comparator assay tests whether C53R interferes with endogenous chondrogenesis in a dominant-negative manner.
Limitations: Endogenous receptors remain present. Unchanged matrix under C53R overexpression does not show failed patient differentiation, rescue of a null background or absence of a recessive loss-of-function effect.
Readouts
Alcian blue cartilage matrix
Direction: UNCHANGED
Interpretation: C53R showed no significant difference from wild-type, domain-deletion and empty-virus conditions.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/ SUPPORT In Vitro
"When comparing the degree of chondrogenic differentiation of micromass cultures expressing ... with control cultures, no significant differences were observed."
C53R, wild-type and ligand-binding-domain-deletion overexpression gave similar cartilage matrix to empty-virus controls; the experiment did not demonstrate failed differentiation.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/ SUPPORT In Vitro
"When comparing the degree of chondrogenic differentiation of micromass cultures expressing ... with control cultures, no significant differences were observed."
C53R, wild-type and ligand-binding-domain-deletion overexpression gave similar cartilage matrix to empty-virus controls; the experiment did not demonstrate failed differentiation.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/ SUPPORT In Vitro
"When comparing the degree of chondrogenic differentiation of micromass cultures expressing ... with control cultures, no significant differences were observed."
C53R, wild-type and ligand-binding-domain-deletion overexpression gave similar cartilage matrix to empty-virus controls; the experiment did not demonstrate failed differentiation.
🐁

Animal Models

2
Bmpr1b-null mouse appendicular development
Targeted disruption by homologous recombination yields viable mice with mainly appendicular skeletal abnormalities. Initial digital rays form, followed by reduced phalangeal precursor proliferation and differentiation.
Species
Mus musculus
Genotype
Targeted homozygous Bmpr1b disruption
Genes
BMPR1B hgnc:1077 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns BMPR1B (hgnc:1077). hgnc:1077 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:10631182
Pathograph links
Reduced Digital Prechondrogenic Cell Proliferation partially recapitulates fidelity: moderate Null mice reproduce reduced precursor proliferation in the phalangeal region.
Limitations: A receptor-null mouse is not a patient allele model; the retrieved primary abstract does not establish the entire human acromesomelic anatomy.
Readouts
Prechondrogenic proliferation
Direction: DECREASED
Interpretation: Molecular-marker analysis found reduced phalangeal precursor proliferation after initial digital rays formed.
Show evidence (1 reference)
PMID:10631182 SUPPORT Model Organism
"Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced."
Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
Show evidence (1 reference)
PMID:10631182 SUPPORT Model Organism
"Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced."
Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
Impaired Digital Chondrocyte Differentiation partially recapitulates fidelity: moderate Null mice exhibit reduced phalangeal chondrocyte differentiation.
Limitations: The modeled developmental defect is not directly measured in human patient cartilage.
Readouts
Phalangeal chondrocyte differentiation
Direction: DECREASED
Interpretation: Differentiation was markedly reduced in the phalangeal region.
Show evidence (1 reference)
PMID:10631182 SUPPORT Model Organism
"Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced."
Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
Show evidence (1 reference)
PMID:10631182 SUPPORT Model Organism
"Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced."
Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
Show evidence (1 reference)
PMID:10631182 SUPPORT Model Organism
"Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced."
Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
Bmpr1b-null female reproductive model
Null females have severely impaired fertility, defective cumulus expansion and deficient uterine gland development. Over 30 matings across 60 weeks yielded two litters, so the phenotype is not absolute sterility. Developing follicles, corpora lutea and gonadotropin-responsive ovulation were preserved.
Species
Mus musculus
Genotype
Homozygous Bmpr1b-null
Background
Hybrid 129Sv × C57BL/6
Genes
BMPR1B hgnc:1077 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns BMPR1B (hgnc:1077). hgnc:1077 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:11416163
Pathograph links
Ovarian Endocrine Dysfunction partially recapitulates fidelity: low The model supports a reproductive requirement for BMPR1B but differs substantially from the founding human ovarian phenotype.
Limitations: Follicles and ovulation remain present. Cyp19 mRNA showed a nonsignificant downward trend, and estradiol was not directly compared. Primary granulosa-cell versus oocyte effects are unresolved; these experiments do not establish human ovarian agenesis or a fertility treatment.
Readouts
Ovarian follicle histology
Direction: UNCHANGED
Interpretation: Developing follicles and corpora lutea were retained despite impaired cumulus expansion and fertility.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice"
Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
Cumulus cell expansion
Direction: DECREASED
Interpretation: Cumulus expansion was defective despite retained follicles and ovulatory responses; the human endocrine mechanism remains unresolved.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"were aggregated and retained fewer cumulus cells ... These data suggest that a primary cause of infertility ... is a failure in cumulus cell expansion."
The null-mouse cumulus complexes retained fewer cells and failed to expand normally. This reproductive defect differs from the founding human endocrine presentation.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice"
Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
+ 1 more reference
Impaired Uterine Development partially recapitulates fidelity: moderate Thin uterine linings and impaired endometrial gland development supply partial correspondence to human uterine hypoplasia.
Limitations: The experiment does not separate direct uterine receptor effects from secondary endocrine effects.
Readouts
Endometrial gland development
Direction: DECREASED
Interpretation: Glands were absent or underdeveloped in eight of nine mutants.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants"
Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants"
Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
The full PMC35456 paper was used to qualify its stronger abstract language about aromatase and estrogen biosynthesis. Oocyte fertilization after cumulus removal in vitro is an experimental result, not a clinical treatment recommendation.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice"
Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants"
Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456 SUPPORT Model Organism
"were aggregated and retained fewer cumulus cells ... These data suggest that a primary cause of infertility ... is a failure in cumulus cell expansion."
The null-mouse cumulus complexes retained fewer cells and failed to expand normally. This reproductive defect differs from the founding human endocrine presentation.
{ }

Source YAML

click to show 
name: Acromesomelic Dysplasia Demirhan Type
synonyms:
- Acromesomelic dysplasia 3
- Grebe dysplasia, BMPR1B-related
- Acromesomelic chondrodysplasia with genital anomalies
- AMDD
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
description: An autosomal recessive acromesomelic skeletal dysplasia caused by biallelic BMPR1B variants, corresponding to Grebe dysplasia, BMPR1B-related in the 2023 skeletal nosology. Severe shortening and malformation of the middle and distal limbs include brachydactyly, fibular aplasia and carpal fusion. Tarsal fusion and genital abnormalities were documented in the founding patient but are not established as universal findings. That adolescent had primary amenorrhea, hypergonadotropic hypogonadism and a hypoplastic uterus; later young or male patients do not establish adult female penetrance. Truncating alleles are predicted to reduce receptor function, whereas the C53R missense allele has directly demonstrated defective GDF5-responsive signaling. The phenotype overlaps GDF5-related dysplasia without establishing complete equivalence of ligand and receptor loss.
disease_term:
  preferred_term: acromesomelic dysplasia, Demirhan type
  term:
    id: MONDO:0012274
    label: acromesomelic dysplasia 3
parents:
- Skeletal Dysplasia
classifications:
  isds_skeletal_category:
  - classification_value: acromesomelic_dysplasias
    notes: The 2023 Nosology of Genetic Skeletal Disorders places Grebe dysplasia, BMPR1B-related (NOS 16-0040; MIM 609441) in group 16, Acromesomelic dysplasias. Table 1 distinguishes the BMPR1B-related Du Pan entry (NOS 16-0060).
    evidence:
    - reference: url:https://files.sciconf.cn/upload/file/20240621/20240621121527_55450.pdf
      reference_title: https://files.sciconf.cn/upload/file/20240621/20240621121527_55450.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Group 16 Acromesomelic dysplasias ... NOS 16‐0040 Grebe dysplasia, BMPR1B ‐related AR BMPR1B 609441
      explanation: The actual 2023 nosology table supplies the group and gene-specific row; the intervening rows are omitted.
prevalence:
- population: Reported BMPR1B-related Grebe dysplasia families
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: Published reports describe rare families, often consanguineous. No population denominator or numerical prevalence estimate is established by these reports.
  evidence:
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is caused by variants in the growth differentiation factor 5 (GDF5) or, in rare cases, its receptor, the bone morphogenetic protein receptor-1B (BMPR1B).
    explanation: Characterises BMPR1B-related disease as the rare subset of an already rare disorder.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: Severe disease segregates with homozygous BMPR1B variants in the reported families. Heterozygous relatives range from apparently unaffected to mild brachydactyly. This differs from the severe recessive phenotype and does not imply that every BMPR1B missense variant is a recessive allele.
  evidence:
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A loss-of-function effect of both mutations causing recessive ACD-type Grebe is further supported by the mild brachydactyly or even non-penetrance of these mutations observed in the heterozygous parents.
    explanation: The carrier phenotype in two consanguineous families supports recessive loss-of-function inheritance.
genetic:
- name: Biallelic BMPR1B Loss-of-Function Variants
  gene_term:
    preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: Severe Grebe-like disease has been reported with the founding 8-bp deletion (historically del359-366; subsequently described as c.361_368delGGACCTAT), p.Trp219*, p.Arg401* and p.Cys53Arg. Transcript decay or truncated protein production is predicted for truncating alleles; patient RNA/protein studies were not reported. C53R reaches the cell surface but fails to produce the wild-type GDF5-responsive reporter signal. A separate p.Met397Arg kindred was described clinically as Hunter-Thompson type, illustrating the wider BMPR1B acromesomelic spectrum.
  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: Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function
    explanation: The founding report establishes a homozygous truncating BMPR1B allele as causative.
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we present two consanguineous families with missense (c.157T>C, p.(C53R)) or nonsense (c.657G>A, p.(W219*)) mutations in BMPR1B.
    explanation: Extends the allelic spectrum to a missense and a second nonsense allele.
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein.
    explanation: Adds a further nonsense allele and states the predicted loss-of-function route.
  - reference: PMID:29322508
    reference_title: A novel homozygous variant in BMPR1B underlies acromesomelic dysplasia Hunter-Thompson type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sequence analysis of the gene revealed a novel homozygous missense variant (c.1190T > G, p.Met397Arg) that segregates with the disease phenotype within the family
    explanation: The authors classified this additional BMPR1B family as Hunter-Thompson type; the variant effect was predicted rather than functionally measured.
pathophysiology:
- name: Biallelic BMPR1B Variants
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  description: Homozygous truncating or functionally disruptive missense BMPR1B alleles initiate severe acromesomelic disease. The molecular route depends on the allele.
  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: Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function
    explanation: The founding report establishes a homozygous truncating BMPR1B allele as causative.
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we present two consanguineous families with missense (c.157T>C, p.(C53R)) or nonsense (c.657G>A, p.(W219*)) mutations in BMPR1B.
    explanation: Extends the allelic spectrum to a missense and a second nonsense allele.
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein.
    explanation: Adds a further nonsense allele and states the predicted loss-of-function route.
  downstream:
  - target: Predicted Loss of Functional BMPR1B Protein
    causal_link_type: DIRECT
    description: Truncating alleles are predicted to yield transcript degradation or a nonfunctional truncated receptor; neither route was directly measured in patient cells.
    evidence:
    - reference: PMID:37524292
      reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein.
      explanation: Adds a further nonsense allele and states the predicted loss-of-function route.
  - target: Reduced BMPR1B-Mediated BMP Signaling
    causal_link_type: DIRECT
    description: The C53R missense allele produces defective GDF5-responsive reporter signaling despite detectable membrane localization.
    evidence:
    - reference: PMID:24129431
      reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay.
      explanation: GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
  - target: Ovarian Endocrine Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A contribution of BMPR1B loss to the founding ovarian phenotype is plausible from the human case and null-mouse reproductive defects, but the human intermediate steps and tissue of action remain unresolved.
    evidence:
    - reference: PMID:15805157
      reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism.
      explanation: The founding patient had both ovarian endocrine dysfunction and uterine hypoplasia; this case does not establish the intervening molecular mechanism.
    hypothesis_groups:
    - bmpr1b_reproductive_role
  - target: Impaired Uterine Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The founding uterine phenotype may reflect direct uterine receptor loss, secondary endocrine effects, or both. Null-mouse uterine histology supplies partial biological support.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
      reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants
      explanation: Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
    hypothesis_groups:
    - bmpr1b_reproductive_role
- name: Predicted Loss of Functional BMPR1B Protein
  role: intermediate
  biological_scale: MOLECULAR
  genes:
  - preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  description: Frameshift and nonsense alleles are expected to reduce functional BMPR1B through premature truncation and/or nonsense-mediated RNA decay. The source studies predict these alternatives without demonstrating transcript decay or receptor abundance in patient tissue.
  evidence:
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein.
    explanation: Adds a further nonsense allele and states the predicted loss-of-function route.
  - 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: Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function
    explanation: The founding report establishes a homozygous truncating BMPR1B allele as causative.
  downstream:
  - target: Reduced BMPR1B-Mediated BMP Signaling
    causal_link_type: DIRECT
    description: Predicted loss of a functional type I receptor reduces signaling capacity; the exact contribution of RNA decay versus truncated protein remains untested.
    evidence:
    - reference: PMID:37524292
      reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein.
      explanation: Adds a further nonsense allele and states the predicted loss-of-function route.
- name: Reduced BMPR1B-Mediated BMP Signaling
  role: central_effector
  biological_scale: MOLECULAR
  description: BMPR1B transduces BMP-family signals important in appendicular development. In the C53R expression model, GDF5 fails to induce a wild-type BMP-responsive luciferase signal. The receptor remains detectable at the membrane; impaired folding and ligand recognition are proposed explanations rather than directly assayed binding defects. Neither complete absence of receptor trafficking nor patient SMAD phosphorylation failure was established.
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay.
    explanation: GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: is processed and can translocate to the cell surface in our overexpression studies, the efficiency of these processes might be reduced.
    explanation: The C53R construct retained surface localization; reduced processing or delivery was suggested from weaker extracellular staining, not directly measured.
  downstream:
  - target: Reduced Digital Prechondrogenic Cell Proliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Bmpr1b-null mice show reduced proliferation in the phalangeal region after normal initial digital-ray formation. This provides model-based support for a developmental consequence of impaired receptor signaling.
    evidence:
    - reference: PMID:10631182
      reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
      explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
  - target: Impaired Digital Chondrocyte Differentiation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Loss of Bmpr1b reduces phalangeal chondrocyte differentiation in mice; the human developmental mechanism is inferred from this perturbation model.
    evidence:
    - reference: PMID:10631182
      reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
      explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
- name: Reduced Digital Prechondrogenic Cell Proliferation
  role: intermediate
  biological_scale: CELLULAR
  description: In the Bmpr1b-null mouse, prechondrogenic cell proliferation in the phalangeal region is markedly reduced despite initially normal digital rays. The model supports deficient expansion of committed skeletal precursors, not failed initiation of all limb condensations.
  evidence:
  - reference: PMID:10631182
    reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
    explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
  downstream:
  - target: Acromesomelic Appendicular Malformation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced expansion of digital precursors is a model-supported contributor to distal skeletal underdevelopment; it does not by itself explain every human fusion or fibular defect.
    evidence:
    - reference: PMID:10631182
      reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
      explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
- name: Impaired Digital Chondrocyte Differentiation
  role: intermediate
  biological_scale: CELLULAR
  description: Reduced chondrocyte differentiation in the phalangeal region is demonstrated in Bmpr1b-null mice. The C53R chick micromass experiment instead showed unchanged matrix under overexpression and tested for dominant-negative interference; it is not a demonstration of this developmental defect.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:10631182
    reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
    explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: When comparing the degree of chondrogenic differentiation of micromass cultures expressing ... with control cultures, no significant differences were observed.
    explanation: C53R, wild-type and ligand-binding-domain-deletion overexpression gave similar cartilage matrix to empty-virus controls; the experiment did not demonstrate failed differentiation.
  downstream:
  - target: Acromesomelic Appendicular Malformation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Deficient digital chondrocyte differentiation offers a partial developmental explanation for the human distal-limb malformations. Precise routes to individual skeletal abnormalities remain unresolved.
    evidence:
    - reference: PMID:10631182
      reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
      explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
- name: Acromesomelic Appendicular Malformation
  role: consequence
  biological_scale: TISSUE
  conforms_to: limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation
  description: Middle and distal appendicular segments are disproportionately short and malformed. Severe brachydactyly, absent or shortened phalanges, fibular aplasia and carpal fusion occur in reported BMPR1B-related Grebe families. Tarsal fusion was present in the founder but absent from the three new patients tabulated in the C53R/W219* report.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: limb development
    term:
      id: GO:0060173
      label: limb development
    modifier: ABNORMAL
  - preferred_term: bone morphogenesis
    term:
      id: GO:0060349
      label: bone morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Acromesomelic chondrodysplasias (ACDs) are characterized by disproportionate shortening of the appendicular skeleton, predominantly affecting the middle (forearms and forelegs) and distal segments (hands and feet).
    explanation: Defines the appendicular pattern that this node represents.
  - 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: showed a severe form of limb malformation consisting of aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones
    explanation: Itemises the malformation in the index patient.
  downstream:
  - target: Fibular Aplasia
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    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: a severe form of limb malformation consisting of aplasia of the fibula
      explanation: Documents fibular aplasia in the founding case.
  - target: Severe Brachydactyly
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    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: aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands
      explanation: Documents severe brachydactyly in the founding case.
  - target: Ulnar Deviation of the Hands
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    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: severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones
      explanation: Documents ulnar deviation in the founding case.
  - target: Carpal Synostosis
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    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: ulnar deviation of the hands, and fusion of carpal/tarsal bones
      explanation: Documents carpal and tarsal fusion in the founding case.
  - target: Tarsal Synostosis
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    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: and fusion of carpal/tarsal bones
      explanation: Documents tarsal fusion in the founding case.
  - target: Short Stature
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'She presented with disproportionate short stature (height: 127 cm) due to severe acromesomelic limb shortening'
      explanation: The measured height and limb distribution are reported for the index patient.
  - target: Radial Deviation of Fingers
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Her hands (fig 2B) showed severe brachydactyly and radially deviated fingers. All fingernails were present.
      explanation: The founder’s clinical body describes radial deviation of the fingers, separately from ulnar hand deviation in the abstract.
  - target: Short First Metacarpals
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The metacarpals II–V were of normal length, but metacarpals I were rudimentary.
      explanation: The founder had rudimentary first metacarpals while metacarpals II–V were normal in length.
  - target: Short Ulna
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The ulna was short and the radius appeared broad with an expanded distal epiphysis.
      explanation: The founder’s ulna was short, with a broad radius and expanded distal radial epiphysis.
  - target: Clubfoot
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The feet showed a bilateral clubfoot deformity with small broad feet and short toes that appeared constricted at their bases
      explanation: Bilateral clubfoot deformity was reported in the founder with fibular aplasia and tibiotalar dislocation.
  - target: Short Toes
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The feet showed a bilateral clubfoot deformity with small broad feet and short toes that appeared constricted at their bases
      explanation: The founder had short toes with constricted bases and preserved nails.
  - target: Short Femoral Necks
    causal_link_type: DIRECT
    description: This finding is an observed component of the appendicular malformation pattern; the gene-to-specific-anatomy intermediate steps are not separately established.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A radiograph of the pelvis (fig 2G) showed short femoral necks and deformed femoral heads with irregular joint spaces
      explanation: Pelvic radiographs showed short femoral necks and deformed femoral heads.
  - target: Absent Proximal Thumb Phalanges
    causal_link_type: DIRECT
    description: This absent skeletal element is part of the founding appendicular malformation pattern.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both thumbs consisted only of a distal phalanx and the proximal phalanges were missing (fig 2B).
      explanation: Both thumbs in the founder lacked their proximal phalanges.
  - target: Absent Proximal Index Phalanges
    causal_link_type: DIRECT
    description: This absent skeletal element is part of the founding appendicular malformation pattern.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hand radio- graphs showed severely hypoplastic phalangeal bones I–V (fig 2C1, right hand; fig 2C2, left hand); the proximal phalanges of the index fingers were missing.
      explanation: Radiographs of both hands in the founder showed absent proximal index-finger phalanges.
- name: Ovarian Endocrine Dysfunction
  role: consequence
  biological_scale: TISSUE
  description: The founding adolescent had primary amenorrhea, high gonadotropins and low estradiol, with ovaries not visualized on ultrasound. These establish her endocrine phenotype but not histological ovarian agenesis or a granulosa-cell-specific mechanism. Bmpr1b-null mice have impaired cumulus expansion and fertility despite preserved developing follicles, a partial and biologically distinct reproductive phenotype.
  evidence:
  - reference: PMID:15805157
    reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism.
    explanation: The founding patient had both ovarian endocrine dysfunction and uterine hypoplasia; this case does not establish the intervening molecular mechanism.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
    reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice
    explanation: Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
  downstream:
  - target: Hypergonadotrophic Hypogonadism
    causal_link_type: DIRECT
    description: The founding clinical and endocrine assessment documents this manifestation of ovarian dysfunction.
    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: ovarian dysfunction resulting in hypergonadotrophic hypogonadism
      explanation: Documents the endocrine phenotype in the index patient.
  - target: Primary Amenorrhea
    causal_link_type: DIRECT
    description: The founding clinical and endocrine assessment documents this manifestation of ovarian dysfunction.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In addition to the skeletal phenotype, the patient presented with genital anomalies and primary amenorrhea.
      explanation: Primary amenorrhea was present at age 16 in the founder.
- name: Impaired Uterine Development
  role: consequence
  biological_scale: TISSUE
  description: Uterine hypoplasia was observed in the founding adolescent. Null-mouse thin uterine linings and underdeveloped glands support a role for BMPR1B in reproductive tissues, while direct uterine versus secondary endocrine causation remains unresolved.
  evidence:
  - reference: PMID:15805157
    reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism.
    explanation: The founding patient had both ovarian endocrine dysfunction and uterine hypoplasia; this case does not establish the intervening molecular mechanism.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
    reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants
    explanation: Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
  downstream:
  - target: Uterine Hypoplasia
    causal_link_type: DIRECT
    description: The uterine developmental endpoint was documented by ultrasound in the founder.
    evidence:
    - reference: PMID:15805157
      reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism.
      explanation: Documents uterine hypoplasia in the index patient.
mechanistic_hypotheses:
- hypothesis_group_id: bmpr1b_reproductive_role
  hypothesis_label: BMPR1B contribution to the reproductive phenotype
  status: EMERGING
  description: Loss of BMPR1B may contribute to the ovarian endocrine and uterine abnormalities documented in the founder. Null mice show impaired cumulus expansion, fertility and uterine gland formation but retain follicles and ovulation. These findings support reproductive involvement without reproducing human ovarian nonvisualization or proving a granulosa-cell-specific human pathway. A second genetic contributor in the consanguineous family remains an alternative.
  evidence:
  - reference: PMID:15805157
    reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism.
    explanation: The founding patient had both ovarian endocrine dysfunction and uterine hypoplasia; this case does not establish the intervening molecular mechanism.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
    reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants
    explanation: Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
    reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice
    explanation: Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
  notes: Later reports include males and a two-year-old girl whose uterus was normal but ovaries were not assessable. These observations cannot estimate adult female penetrance. The sheep Q249R hyperprolific allele is not a model of complete receptor loss. In the null-mouse full text, aromatase mRNA reduction was not statistically significant and estradiol was not directly compared.
phenotypes:
- category: Skeletal
  name: Fibular Aplasia
  description: Complete absence of the fibula in the index patient.
  phenotype_term:
    preferred_term: Fibular aplasia
    term:
      id: HP:0002990
      label: Fibular aplasia
  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: a severe form of limb malformation consisting of aplasia of the fibula
    explanation: Documents fibular aplasia in the founding case.
- category: Skeletal
  name: Severe Brachydactyly
  description: Severe shortening of the digits, part of the Grebe-like limb picture.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
    severity: SEVERE
  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: aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands
    explanation: Documents severe brachydactyly in the founding case.
- category: Skeletal
  name: Ulnar Deviation of the Hands
  description: The founding abstract describes ulnar deviation of the hands. Its clinical body separately describes radial deviation of the fingers; these anatomical descriptions are retained without inferring that either direction was fixed.
  phenotype_term:
    preferred_term: Ulnar deviation of the hand
    term:
      id: HP:0009487
      label: Ulnar deviation of the hand
  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: severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones
    explanation: Documents ulnar deviation in the founding case.
- category: Skeletal
  name: Carpal Synostosis
  description: Multiple carpal bones were fused in the founding patient; carpal fusion also appears in the later Grebe-type families.
  phenotype_term:
    preferred_term: Carpal synostosis
    term:
      id: HP:0009702
      label: Carpal synostosis
  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: ulnar deviation of the hands, and fusion of carpal/tarsal bones
    explanation: Documents carpal and tarsal fusion in the founding case.
- category: Skeletal
  name: Tarsal Synostosis
  description: Partial tarsal fusion in the founder. Table 1 of the later C53R/W219* report records no tarsal synostosis in its three new patients, so this is not treated as universal.
  phenotype_term:
    preferred_term: Tarsal synostosis
    term:
      id: HP:0008368
      label: Tarsal synostosis
  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: and fusion of carpal/tarsal bones
    explanation: Documents tarsal fusion in the founding case.
- category: Reproductive
  name: Uterine Hypoplasia
  description: A hypoplastic uterus was demonstrated by ultrasound in the founding adolescent. The younger C53R girl had a normal uterus, but this does not establish adult ovarian function or the frequency of genital involvement.
  phenotype_term:
    preferred_term: Hypoplasia of the uterus
    term:
      id: HP:0000013
      label: Hypoplasia of the uterus
  evidence:
  - reference: PMID:15805157
    reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism.
    explanation: Documents uterine hypoplasia in the index patient.
- category: Endocrine
  name: Hypergonadotrophic Hypogonadism
  description: Ovarian dysfunction producing hypergonadotrophic hypogonadism in the index patient.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  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: ovarian dysfunction resulting in hypergonadotrophic hypogonadism
    explanation: Documents the endocrine phenotype in the index patient.
- category: Skeletal
  name: Short Stature
  description: Disproportionate short stature from acromesomelic limb shortening; the founding adolescent measured 127 cm with a normal-length trunk.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'She presented with disproportionate short stature (height: 127 cm) due to severe acromesomelic limb shortening'
    explanation: The measured height and limb distribution are reported for the index patient.
- category: Skeletal
  name: Hip Dislocation
  description: Dislocated hips were reported in one of two affected siblings in a Moroccan family and were described by the authors as not previously reported in this disorder.
  phenotype_term:
    preferred_term: Hip dislocation
    term:
      id: HP:0002827
      label: Hip dislocation
  evidence:
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the affected individuals showed additional features including bilateral simian creases, lumbar hyperlordosis, as well as lower limb length inequality and dislocated hips in one of them, which were never reported previously for AMD Grebe type patients
    explanation: Observed in one affected sibling in the Moroccan report. A case count does not establish a population frequency.
- category: Skeletal
  name: Lumbar Hyperlordosis
  description: Lumbar hyperlordosis reported in a Moroccan sibling pair.
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  evidence:
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: bilateral simian creases, lumbar hyperlordosis, as well as lower limb length inequality
    explanation: Documents lumbar hyperlordosis among the newly reported features.
- category: Skeletal
  name: Single Transverse Palmar Crease
  description: Bilateral single transverse palmar creases reported in a Moroccan sibling pair.
  phenotype_term:
    preferred_term: Single transverse palmar crease
    term:
      id: HP:0000954
      label: Single transverse palmar crease
  evidence:
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the affected individuals showed additional features including bilateral simian creases
    explanation: Documents the palmar crease finding among the newly reported features.
- category: Reproductive
  name: Primary Amenorrhea
  description: Primary amenorrhea was present at age 16 in the founder.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition to the skeletal phenotype, the patient presented with genital anomalies and primary amenorrhea.
    explanation: Primary amenorrhea was present at age 16 in the founder.
- category: Skeletal
  name: Radial Deviation of Fingers
  description: The founder’s clinical body describes radial deviation of the fingers, separately from ulnar hand deviation in the abstract.
  phenotype_term:
    preferred_term: Radial deviation of finger
    term:
      id: HP:0009466
      label: Radial deviation of finger
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her hands (fig 2B) showed severe brachydactyly and radially deviated fingers. All fingernails were present.
    explanation: The founder’s clinical body describes radial deviation of the fingers, separately from ulnar hand deviation in the abstract.
- category: Skeletal
  name: Short First Metacarpals
  description: The founder had rudimentary first metacarpals while metacarpals II–V were normal in length.
  phenotype_term:
    preferred_term: Short 1st metacarpal
    term:
      id: HP:0010034
      label: Short 1st metacarpal
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The metacarpals II–V were of normal length, but metacarpals I were rudimentary.
    explanation: The founder had rudimentary first metacarpals while metacarpals II–V were normal in length.
- category: Skeletal
  name: Short Ulna
  description: The founder’s ulna was short, with a broad radius and expanded distal radial epiphysis.
  phenotype_term:
    preferred_term: Hypoplasia of the ulna
    term:
      id: HP:0003022
      label: Hypoplasia of the ulna
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ulna was short and the radius appeared broad with an expanded distal epiphysis.
    explanation: The founder’s ulna was short, with a broad radius and expanded distal radial epiphysis.
- category: Skeletal
  name: Delayed Bone Age
  description: Unclosed ulnar and radial growth plates at age 16 were interpreted as delayed bone age.
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 16, the epiphysial plate of the ulna and the radius were not closed indicating retardation of bone age.
    explanation: Unclosed ulnar and radial growth plates at age 16 were interpreted as delayed bone age.
- category: Skeletal
  name: Clubfoot
  description: Bilateral clubfoot deformity was reported in the founder with fibular aplasia and tibiotalar dislocation.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The feet showed a bilateral clubfoot deformity with small broad feet and short toes that appeared constricted at their bases
    explanation: Bilateral clubfoot deformity was reported in the founder with fibular aplasia and tibiotalar dislocation.
- category: Skeletal
  name: Short Toes
  description: The founder had short toes with constricted bases and preserved nails.
  phenotype_term:
    preferred_term: Short toe
    term:
      id: HP:0001831
      label: Short toe
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The feet showed a bilateral clubfoot deformity with small broad feet and short toes that appeared constricted at their bases
    explanation: The founder had short toes with constricted bases and preserved nails.
- category: Skeletal
  name: Short Femoral Necks
  description: Pelvic radiographs showed short femoral necks and deformed femoral heads.
  phenotype_term:
    preferred_term: Short femoral neck
    term:
      id: HP:0100864
      label: Short femoral neck
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A radiograph of the pelvis (fig 2G) showed short femoral necks and deformed femoral heads with irregular joint spaces
    explanation: Pelvic radiographs showed short femoral necks and deformed femoral heads.
- name: Absent Proximal Thumb Phalanges
  category: Skeletal
  description: Both thumbs in the founder lacked their proximal phalanges.
  phenotype_term:
    preferred_term: Absent proximal phalanx of thumb
    term:
      id: HP:0009637
      label: Absent proximal phalanx of thumb
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both thumbs consisted only of a distal phalanx and the proximal phalanges were missing (fig 2B).
    explanation: Both thumbs in the founder lacked their proximal phalanges.
- name: Absent Proximal Index Phalanges
  category: Skeletal
  description: Radiographs of both hands in the founder showed absent proximal index-finger phalanges.
  phenotype_term:
    preferred_term: Aplasia of the proximal phalanx of the 2nd finger
    term:
      id: HP:0009596
      label: Aplasia of the proximal phalanx of the 2nd finger
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hand radio- graphs showed severely hypoplastic phalangeal bones I–V (fig 2C1, right hand; fig 2C2, left hand); the proximal phalanges of the index fingers were missing.
    explanation: Radiographs of both hands in the founder showed absent proximal index-finger phalanges.
- name: Lower Limb Length Asymmetry
  category: Skeletal
  description: Lower-limb length inequality was reported in one of the Moroccan siblings; the kindred does not establish population frequency.
  phenotype_term:
    preferred_term: Lower limb asymmetry
    term:
      id: HP:0100559
      label: Lower limb asymmetry
  evidence:
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the affected individuals showed additional features including bilateral simian creases, lumbar hyperlordosis, as well as lower limb length inequality and dislocated hips in one of them, which were never reported previously for AMD Grebe type patients
    explanation: Lower-limb length inequality was reported in one of the Moroccan siblings; the kindred does not establish population frequency.
diagnosis:
- name: Molecular Evaluation of BMPR1B and Overlapping Dysplasia Genes
  description: Interpret biallelic BMPR1B variants with the severe acromesomelic phenotype and familial segregation. The founding work excluded coding GDF5 variants before finding the BMPR1B deletion; that historical sequence does not require every present-day test to follow the same order. Distinguish severe recessive alleles from dominant brachydactyly variants and milder Du Pan-associated alleles.
  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: Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function
    explanation: The founding report establishes a homozygous truncating BMPR1B allele as causative.
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we present two consanguineous families with missense (c.157T>C, p.(C53R)) or nonsense (c.657G>A, p.(W219*)) mutations in BMPR1B.
    explanation: Extends the allelic spectrum to a missense and a second nonsense allele.
- name: Clinical and Skeletal Radiographic Assessment
  description: Assess the distribution of limb shortening, phalangeal and metacarpal defects, carpal and tarsal fusion, fibulae and joint alignment. The detailed founding radiographs document absent proximal index/thumb phalanges, short ulnae, tibiotalar dislocations and short femoral necks; these findings vary between families.
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Radiographs of the lower leg (fig 2F) displayed deformed tibiae with wide proximal metaphyses and aplasia of the fibulae resulting in bilateral dislocation of the tibiotalar joints.
    explanation: Direct radiographic description from the founding patient.
- name: Pubertal, Endocrine and Pelvic Assessment
  description: The founder was evaluated for primary amenorrhea by gonadotropins, estradiol and pelvic ultrasound. Interpret ovarian nonvisualization in its age and imaging context. A normal uterus in the two-year-old C53R patient, whose ovaries could not be assessed, is not evidence of normal adult reproductive function.
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Upon ultrasound examination, the ovaries were not present and the uterus was shown to be hypoplastic.
    explanation: Pelvic ultrasound contributed to assessment of the founding reproductive phenotype.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ultrasound examination of the abdomen showed a normal uterus; the ovaries could not be evaluated because of bowel gas superposition.
    explanation: The younger patient’s ovarian status remained unresolved.
treatments:
- name: Genetic Counseling
  description: Offer genetic counseling based on the molecularly established autosomal recessive severe disorder and family segregation. Heterozygous relatives may have mild brachydactyly or no apparent hand findings; variants causing dominant brachydactyly represent a different allele-specific risk.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37524292
    reference_title: 'A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: these findings expand the phenotypic and mutational spectrum of AMD, and may improve the diagnosis of AMD and enable appropriate genetic counselling to be offered to patients
    explanation: States genetic counselling as the management consequence of a molecular diagnosis in this disorder.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner.
    explanation: Dominant-negative BMPR1B alleles cause a dominant phenotype, which is why carrier counselling here depends on the allele's functional class.
- name: Hormone Replacement for Ovarian Endocrine Dysfunction
  description: The founding adolescent with primary amenorrhea, hypergonadotropic hypogonadism and low estradiol received hormonal substitution. The report does not specify the hormones, regimen or clinical response; it supplies evidence of treatment use rather than a comparative efficacy estimate.
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
  target_mechanisms:
  - target: Ovarian Endocrine Dysfunction
    treatment_effect: BYPASSES
    description: Hormonal substitution was used to compensate for the endocrine deficit in the founder; it was not shown to restore ovarian development or fertility.
    evidence:
    - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The patient receives hormonal substitution therapy. The diagnostics of LH, FSH, and oestradiol in the patient’s mother and two sisters revealed standard values according to their age.
      explanation: The full founding report documents hormone substitution in the affected adolescent. Drug, dose, duration and response were not reported.
  evidence:
  - reference: url:https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    reference_title: https://avesis.cu.edu.tr/yayin/034022d6-aced-4a93-8ed2-163cb56fae78/a-homozygous-bmpr1b-mutation-causes-a-new-subtype-of-acromesomelic-chondrodysplasia-with-genital-anomalies/document.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient receives hormonal substitution therapy. The diagnostics of LH, FSH, and oestradiol in the patient’s mother and two sisters revealed standard values according to their age.
    explanation: The full founding report documents hormone substitution in the affected adolescent. Drug, dose, duration and response were not reported.
  notes: The full 2005 Demirhan et al. report is preserved in the university-hosted PDF cache, which adds this treatment detail beyond the PubMed abstract.
differential_diagnoses:
- name: Acromesomelic Dysplasia, Grebe Type
  disease_term:
    preferred_term: acromesomelic dysplasia, Grebe type
    term:
      id: MONDO:0008703
      label: acromesomelic dysplasia 2A
  description: GDF5-related Grebe dysplasia has closely overlapping skeletal findings. Molecular cause establishes the distinction; the genital findings in the BMPR1B founder are a clinical clue rather than a sensitive or universally specific discriminator.
  distinguishing_features:
  - Biallelic BMPR1B rather than GDF5 variants distinguish the molecular diagnoses.
  - Genital abnormalities occurred in the BMPR1B founder, but their absence does not exclude this diagnosis and case reports do not establish universal absence in every GDF5 disorder.
  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: the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype
    explanation: States the distinguishing features directly.
- name: Du Pan Syndrome
  disease_term:
    preferred_term: du Pan syndrome
    term:
      id: MONDO:0009231
      label: acromesomelic dysplasia 2B
  description: Du Pan dysplasia is a milder acromesomelic phenotype associated with GDF5 or BMPR1B. BMPR1B p.Arg31Cys retained more reporter activity than p.Cys53Arg, supporting an allele-dependent severity hypothesis.
  distinguishing_features:
  - The p.Arg31Cys adult had a height of 148 cm and absent fibulae, with preserved radius, ulna and femur; normal stature and preservation of every long bone are not required.
  - Residual signaling has been measured for selected alleles, but a precise functional cutoff separating Du Pan from Grebe dysplasia has not been established.
  evidence:
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia
    explanation: Shows the allele-dependent split between the two BMPR1B diagnoses.
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proposita had disproportionate short stature with a height of 148 cm ( − 2.7 SD) and mild acromesomelic limb shortening.
    explanation: Measured stature in the adult BMPR1B p.Arg31Cys Du Pan case refutes an absolute normal-stature distinction.
- name: Brachydactyly Type A2
  description: The dominant BMPR1B disorder. It is caused by dominant-negative missense alleles rather than loss of function, and is the reason a heterozygous BMPR1B variant cannot be read as carrier status without knowing its functional class.
  distinguishing_features:
  - Brachydactyly type A2 is autosomal dominant and arises from dominant-negative BMPR1B missense alleles.
  - The Demirhan-type alleles are recessive loss-of-function changes whose heterozygous carriers show at most mild brachydactyly.
  evidence:
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast, dominant-negative BMPR1B mutations described previously are associated with autosomal-dominant brachydactyly-type A2.
    explanation: States the mechanistic and inheritance contrast with the dominant BMPR1B disorder.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism.
    explanation: Even within dominant BMPR1B disease the alleles work differently, so a heterozygous BMPR1B variant cannot be read as carrier status for this recessive disorder without knowing its functional class.
  - 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: is thus different from the heterozygous missense mutations in BMPR1B recently shown to cause brachydactyly type A2 through a dominant negative effect
    explanation: The founding report draws the same contrast for its truncating allele.
discussions:
- discussion_id: supportive_management_outcomes
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#
  prompt: What functional outcomes follow orthopedic, rehabilitative and endocrine care in severe BMPR1B-related acromesomelic dysplasia?
  rationale: Genetic counseling is discussed in the Moroccan report and hormone substitution is explicitly documented in the founding full text. The retrieved disease-specific sources do not supply the hormone regimen or response, or comparative outcomes for surgery, prostheses and rehabilitation. These are gaps in evidence, not an absence of all reported care.
- discussion_id: bmpr1b_genital_phenotype_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Ovarian Endocrine Dysfunction
  - pathophysiology#Impaired Uterine Development
  prompt: Which BMPR1B-related reproductive defects recur in adequately assessed adult patients, and which tissues mediate them?
  rationale: The founding human case and Bmpr1b-null mouse reproductive phenotypes support further investigation, but the mice retain follicles and ovulation and do not reproduce confirmed human ovarian agenesis. The mouse full text reports nonsignificant aromatase mRNA differences and no direct estradiol comparison. Direct uterine effects, ovarian endocrine effects, and a possible second genetic contributor in the founder remain unresolved. Males and a prepubertal girl with unassessable ovaries cannot establish adult female penetrance.
- discussion_id: residual_signaling_and_severity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced BMPR1B-Mediated BMP Signaling
  prompt: How well does residual signaling predict the BMPR1B acromesomelic phenotype across alleles?
  rationale: C53R and the milder Du Pan-associated R31C allele differ in reporter activity. This supports a proposed severity-function relationship for selected alleles, not exact equivalence of GDF5 and BMPR1B loss or a validated diagnostic functional threshold.
notes: 'This entry retains the severe Demirhan/Grebe BMPR1B scope (MONDO:0012274, MIM 609441). The university-hosted PDF contains Demirhan et al., A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies (2005; PMID:15805157). The conference-hosted PDF contains Unger et al., Nosology of genetic skeletal disorders: 2023 revision (PMID:36779427), including the complete Table 1. Separate generated PMC URL caches preserve the full C53R/W219* study (PMID:24129431) and null-mouse reproductive study (PMID:11416163). The mild 2024 BMPR1B Du Pan case with polydactyly is allelic context and does not establish polydactyly in this severe Grebe entry.'
experimental_models:
- name: C53R BMPR1B reporter and localization in NIH/3T3 cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: Mouse NIH/3T3 fibroblasts
  culture_system: Transient expression of mouse receptor constructs with a BMP-responsive firefly reporter, Renilla control and human GDF5; HA-tagged constructs for immunofluorescence.
  publication: PMID:24129431
  description: Wild-type, C53R and ligand-binding-domain-deletion receptor constructs were compared with empty-vector controls. Reporter samples were triplicate and representative of three independent experiments.
  modeled_mechanisms:
  - target: Reduced BMPR1B-Mediated BMP Signaling
    relationship: MEASURES
    description: The reporter resolves the C53R signaling defect and microscopy confirms retained surface localization.
    fidelity: MODERATE
    limitations: Overexpression in mouse fibroblasts does not establish ligand affinity, endogenous patient receptor abundance, patient phospho-SMAD levels or developmental outcomes. Folding disruption was separately predicted using a short in-vacuo molecular model.
    readouts:
    - name: GDF5-responsive luciferase
      target: Reduced BMPR1B-Mediated BMP Signaling
      direction: DECREASED
      interpretation: C53R failed to induce wild-type GDF5-responsive reporter output.
      evidence:
      - reference: PMID:24129431
        reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay.
        explanation: GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
    - name: Surface HA immunofluorescence
      target: Reduced BMPR1B-Mediated BMP Signaling
      direction: DECREASED
      interpretation: Extracellular C53R signal was weaker, but surface localization persisted and the difference was absent after permeabilization; reduced delivery efficiency remains proposed.
      evidence:
      - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
        reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: is processed and can translocate to the cell surface in our overexpression studies, the efficiency of these processes might be reduced.
        explanation: The C53R construct retained surface localization; reduced processing or delivery was suggested from weaker extracellular staining, not directly measured.
    evidence:
    - reference: PMID:24129431
      reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay.
      explanation: GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
      reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: is processed and can translocate to the cell surface in our overexpression studies, the efficiency of these processes might be reduced.
      explanation: The C53R construct retained surface localization; reduced processing or delivery was suggested from weaker extracellular staining, not directly measured.
  evidence:
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay.
    explanation: GDF5-responsive reporter output was defective in transfected NIH/3T3 cells; this does not directly measure ligand binding or SMAD phosphorylation.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: is processed and can translocate to the cell surface in our overexpression studies, the efficiency of these processes might be reduced.
    explanation: The C53R construct retained surface localization; reduced processing or delivery was suggested from weaker extracellular staining, not directly measured.
- name: C53R chick limb-bud micromass comparator assay
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Gallus gallus
    term:
      id: NCBITaxon:9031
      label: Gallus gallus
  cell_source: Hamburger-Hamilton stage 23–24 chicken limb-bud cells
  culture_system: RCAS-mediated receptor overexpression; Alcian blue cartilage-matrix staining at seven days.
  publication: PMID:24129431
  description: C53R, wild-type and artificial ligand-binding-domain-deletion constructs resembled empty-virus controls. The BDA2-associated I200K positive comparator strongly inhibited chondrogenesis. Four replicate cultures were shown from one of three independent experiments.
  modeled_mechanisms:
  - target: Impaired Digital Chondrocyte Differentiation
    relationship: PERTURBS
    description: This comparator assay tests whether C53R interferes with endogenous chondrogenesis in a dominant-negative manner.
    fidelity: LOW
    limitations: Endogenous receptors remain present. Unchanged matrix under C53R overexpression does not show failed patient differentiation, rescue of a null background or absence of a recessive loss-of-function effect.
    readouts:
    - name: Alcian blue cartilage matrix
      target: Impaired Digital Chondrocyte Differentiation
      direction: UNCHANGED
      interpretation: C53R showed no significant difference from wild-type, domain-deletion and empty-virus conditions.
      evidence:
      - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
        reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: When comparing the degree of chondrogenic differentiation of micromass cultures expressing ... with control cultures, no significant differences were observed.
        explanation: C53R, wild-type and ligand-binding-domain-deletion overexpression gave similar cartilage matrix to empty-virus controls; the experiment did not demonstrate failed differentiation.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
      reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: When comparing the degree of chondrogenic differentiation of micromass cultures expressing ... with control cultures, no significant differences were observed.
      explanation: C53R, wild-type and ligand-binding-domain-deletion overexpression gave similar cartilage matrix to empty-virus controls; the experiment did not demonstrate failed differentiation.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023204/
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: When comparing the degree of chondrogenic differentiation of micromass cultures expressing ... with control cultures, no significant differences were observed.
    explanation: C53R, wild-type and ligand-binding-domain-deletion overexpression gave similar cartilage matrix to empty-virus controls; the experiment did not demonstrate failed differentiation.
animal_models:
- name: Bmpr1b-null mouse appendicular development
  species: Mus musculus
  genotype: Targeted homozygous Bmpr1b disruption
  genes:
  - preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  publication: PMID:10631182
  description: Targeted disruption by homologous recombination yields viable mice with mainly appendicular skeletal abnormalities. Initial digital rays form, followed by reduced phalangeal precursor proliferation and differentiation.
  modeled_mechanisms:
  - target: Reduced Digital Prechondrogenic Cell Proliferation
    relationship: PARTIALLY_RECAPITULATES
    description: Null mice reproduce reduced precursor proliferation in the phalangeal region.
    fidelity: MODERATE
    limitations: A receptor-null mouse is not a patient allele model; the retrieved primary abstract does not establish the entire human acromesomelic anatomy.
    readouts:
    - name: Prechondrogenic proliferation
      target: Reduced Digital Prechondrogenic Cell Proliferation
      direction: DECREASED
      interpretation: Molecular-marker analysis found reduced phalangeal precursor proliferation after initial digital rays formed.
      evidence:
      - reference: PMID:10631182
        reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
        explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
    evidence:
    - reference: PMID:10631182
      reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
      explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
  - target: Impaired Digital Chondrocyte Differentiation
    relationship: PARTIALLY_RECAPITULATES
    description: Null mice exhibit reduced phalangeal chondrocyte differentiation.
    fidelity: MODERATE
    limitations: The modeled developmental defect is not directly measured in human patient cartilage.
    readouts:
    - name: Phalangeal chondrocyte differentiation
      target: Impaired Digital Chondrocyte Differentiation
      direction: DECREASED
      interpretation: Differentiation was markedly reduced in the phalangeal region.
      evidence:
      - reference: PMID:10631182
        reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
        explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
    evidence:
    - reference: PMID:10631182
      reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
      explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
  evidence:
  - reference: PMID:10631182
    reference_title: The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Using molecular markers, we show that the initial formation of the digital rays occurs normally in null mutants, but proliferation of prechondrogenic cells and chondrocyte differentiation in the phalangeal region are markedly reduced.
    explanation: Targeted Bmpr1b-null mice establish cellular defects after initial digital-ray formation. Translation to human BMPR1B disease is model-based.
- name: Bmpr1b-null female reproductive model
  species: Mus musculus
  genotype: Homozygous Bmpr1b-null
  background: Hybrid 129Sv × C57BL/6
  genes:
  - preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  publication: PMID:11416163
  description: Null females have severely impaired fertility, defective cumulus expansion and deficient uterine gland development. Over 30 matings across 60 weeks yielded two litters, so the phenotype is not absolute sterility. Developing follicles, corpora lutea and gonadotropin-responsive ovulation were preserved.
  modeled_mechanisms:
  - target: Ovarian Endocrine Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    description: The model supports a reproductive requirement for BMPR1B but differs substantially from the founding human ovarian phenotype.
    fidelity: LOW
    limitations: Follicles and ovulation remain present. Cyp19 mRNA showed a nonsignificant downward trend, and estradiol was not directly compared. Primary granulosa-cell versus oocyte effects are unresolved; these experiments do not establish human ovarian agenesis or a fertility treatment.
    readouts:
    - name: Ovarian follicle histology
      target: Ovarian Endocrine Dysfunction
      direction: UNCHANGED
      interpretation: Developing follicles and corpora lutea were retained despite impaired cumulus expansion and fertility.
      evidence:
      - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
        reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice
        explanation: Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
    - name: Cumulus cell expansion
      target: Ovarian Endocrine Dysfunction
      direction: DECREASED
      interpretation: Cumulus expansion was defective despite retained follicles and ovulatory responses; the human endocrine mechanism remains unresolved.
      evidence:
      - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
        reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: were aggregated and retained fewer cumulus cells ... These data suggest that a primary cause of infertility ... is a failure in cumulus cell expansion.
        explanation: The null-mouse cumulus complexes retained fewer cells and failed to expand normally. This reproductive defect differs from the founding human endocrine presentation.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
      reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice
      explanation: Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
      reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: were aggregated and retained fewer cumulus cells ... These data suggest that a primary cause of infertility ... is a failure in cumulus cell expansion.
      explanation: The null-mouse cumulus complexes retained fewer cells and failed to expand normally. This reproductive defect differs from the founding human endocrine presentation.
  - target: Impaired Uterine Development
    relationship: PARTIALLY_RECAPITULATES
    description: Thin uterine linings and impaired endometrial gland development supply partial correspondence to human uterine hypoplasia.
    fidelity: MODERATE
    limitations: The experiment does not separate direct uterine receptor effects from secondary endocrine effects.
    readouts:
    - name: Endometrial gland development
      target: Impaired Uterine Development
      direction: DECREASED
      interpretation: Glands were absent or underdeveloped in eight of nine mutants.
      evidence:
      - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
        reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants
        explanation: Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
      reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants
      explanation: Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
    reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: No obvious abnormalities or differences in the numbers of developing follicles or corpora lutea were observed in mutant vs. WT adult mice
    explanation: Preserved follicles in null mice limit their correspondence to the human patient whose ovaries were not visualized on ultrasound.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
    reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The uterine linings were thin, and endometrial glands were absent or underdeveloped in 89% (8/9) of the mutants
    explanation: Uterine histology in Bmpr1b-null mice supports a reproductive role but cannot distinguish a direct uterine effect from secondary ovarian effects.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/35456
    reference_title: The type I BMP receptor BmprIB is essential for female reproductive function - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: were aggregated and retained fewer cumulus cells ... These data suggest that a primary cause of infertility ... is a failure in cumulus cell expansion.
    explanation: The null-mouse cumulus complexes retained fewer cells and failed to expand normally. This reproductive defect differs from the founding human endocrine presentation.
  notes: The full PMC35456 paper was used to qualify its stronger abstract language about aromatase and estrogen biosynthesis. Oocyte fertilization after cumulus removal in vitro is an experimental result, not a clinical treatment recommendation.