Acromesomelic Dysplasia Demirhan Type

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal Recessive HP:0000007

Biallelic BMPR1B loss of function is required. Heterozygous parents show mild brachydactyly at most, and are often entirely unaffected. This carrier picture is itself evidence that the alleles are loss-of-function rather than dominant-negative, since dominant-negative BMPR1B alleles cause brachydactyly type A2 in the heterozygous state.

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.

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Mechanistic Hypotheses

2

Receptor-Side Equivalence Model

receptor_side_ligand_loss_equivalence CANONICAL

Evidence balance 2 support

Disabling BMPR1B is mechanistically equivalent to disabling GDF5 for the limb skeleton, because the two act as one ligand-receptor pair, and that is why the BMPR1B limb phenotype is Grebe-like. Severity within BMPR1B follows residual receptor function in the same way it follows residual ligand function within GDF5.

Show evidence (2 references)

PMID:26105076 SUPPORT Human Clinical

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

States the equivalence and the dose-dependence it implies.

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."

Shows the receptor lesion acting at the same ligand-receptor step as a GDF5 lesion.

Granulosa-Cell BMPR1B Model of the Genital Phenotype

granulosa_bmpr1b_model EMERGING

Evidence balance 2 support

The genital involvement is proposed to be a direct consequence of losing BMPR1B in the ovary rather than a coincidence of consanguinity. Granulosa cells read GDF5 and BMP4 specifically through BMPR1B, and the ovine Booroola FecB receptor variant alters follicle maturation, so a receptor null is expected to disturb folliculogenesis. Two things keep this short of established. The supporting data are ovine and describe a variant that changes rather than abolishes receptor function, and the human observation rests on the single index patient while later BMPR1B families were reported without genital anomalies. An alternative reading is that the genital findings are a feature of that individual or of a second locus in a multiconsanguineous pedigree.

The two groups here are not competing accounts of one thing. The first covers the limb phenotype and is well supported; the second covers the genital phenotype and is not. They are kept separate so the confidence attached to the limb mechanism does not silently transfer to the ovarian one.

Pathograph links

Failure of GDF5-Driven BMPR1B Activation -> Impaired BMPR1B Signaling in Ovarian Granulosa Cells DIRECT BMPR1B is the receptor through which granulosa cells read GDF5 and BMP4, so removing it withdraws the same signal from the ovary that it withdraws from cartilage. This is the proposed explanation for the genital involvement that distinguishes this entity from the GDF5 disorders.

Impaired BMPR1B Signaling in Ovarian Granulosa Cells -> Ovarian Dysfunction and Uterine Hypoplasia INDIRECT UNKNOWN INTERMEDIATES Disturbed follicle development is proposed to produce the ovarian dysfunction and hypergonadotrophic hypogonadism reported in the index patient. The intermediate steps between granulosa-cell signalling and uterine hypoplasia are not established.

Show evidence (2 references)

PMID:12773124 SUPPORT Model Organism

"these data strongly suggest that the Q249R mutation is associated with a specific alteration of BMPR1B signaling in hyperprolific Booroola ewes"

Establishes that a BMPR1B variant alters ovarian signalling in vivo.

PMID:15805157 SUPPORT Human Clinical

"However, the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype."

The human basis for the model is one patient contrasted against the GDF5 disorders, which is what makes this emerging rather than canonical.

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Discussions and Knowledge Gaps

2

What supportive, orthopaedic and rehabilitative management actually benefits the Demirhan type?

KNOWLEDGE GAP OPEN no_disease_specific_management_literature

Attached to

treatments#

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

Is the genital phenotype a consequence of BMPR1B loss, and if so why does ligand-side loss not produce it?

KNOWLEDGE GAP OPEN bmpr1b_genital_phenotype_mechanism

Attached to

pathophysiology#Failure of GDF5-Driven BMPR1B Activation pathophysiology#Impaired BMPR1B Signaling in Ovarian Granulosa Cells phenotypes#Uterine Hypoplasia

BMPR1B binds ligands beyond GDF5, so a receptor null withdraws more BMP input than a GDF5 null does; that asymmetry is the natural explanation for an extra phenotype on the receptor side, and it has never been tested. The granulosa-cell model records what is known, but its functional support is ovine and its human support is one patient. Reporting how many molecularly confirmed BMPR1B probands have had a gynaecological assessment at all, rather than how many were noted to have anomalies, would settle whether the feature is rare or merely rarely looked for.

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Pathophysiology

6

Biallelic BMPR1B Loss of Function

Pathogenic variants on both BMPR1B alleles remove or disable the type I BMP receptor. Nonsense alleles are expected to be degraded by nonsense-mediated decay; the characterised missense allele yields a receptor that reaches the membrane only partially.

BMPR1B hgnc:1077

Nonsense-mediated decay of BMPR1B transcripts GO:0000184 ↑ INCREASED Receptor delivery to the plasma membrane GO:0072659 ↓ DECREASED

Downstream

Failure of GDF5-Driven BMPR1B Activation Absent or mislocalised receptor directly prevents GDF5 from activating BMP signalling.

Show evidence (2 references)

PMID:24129431 SUPPORT In Vitro

"Functional analysis of the missense mutation C53R revealed that the mutated receptor was partially located at the cell membrane."

Shows the receptor-level defect produced by the characterised missense allele.

PMID:24129431 SUPPORT In Vitro

"The nonsense mutation (c.657G>A, p.(W219*)) introduces a premature stop codon, which is predicted to be subject to nonsense-mediated mRNA decay, causing reduced protein translation of the mutant allele."

Establishes transcript decay as the route by which nonsense alleles remove the receptor.

Failure of GDF5-Driven BMPR1B Activation

This is the same central node as in the GDF5-related acromesomelic dysplasias, reached from the receptor side rather than the ligand side. It is why a BMPR1B disorder is clinically a Grebe dysplasia, and why the severity of BMPR1B disease tracks residual receptor function in exactly the way GDF5 disease tracks residual ligand function.

Granulosa-Cell BMPR1B Model of the Genital Phenotype

Chondrocyte CL:0000138

BMP signaling pathway GO:0030509 ⇓ LOSS OF FUNCTION Cell surface receptor protein serine/threonine kinase signaling pathway GO:0007178 ⇓ LOSS OF FUNCTION SMAD protein signal transduction GO:0060395 ↓ DECREASED Protein phosphorylation GO:0006468 ↓ DECREASED

BMP receptor activity GO:0098821 ⇓ LOSS OF FUNCTION Protein serine/threonine kinase activity GO:0004674 ⇓ LOSS OF FUNCTION

Downstream

Impaired BMPR1B Signaling in Ovarian Granulosa Cells BMPR1B is the receptor through which granulosa cells read GDF5 and BMP4, so removing it withdraws the same signal from the ovary that it withdraws from cartilage. This is the proposed explanation for the genital involvement that distinguishes this entity from the GDF5 disorders.

Failed Chondrogenic Differentiation in the Distal Limb Loss of receptor signalling directly removes the BMP input to chondrogenic differentiation.

Show evidence (3 references)

PMID:15805157 SUPPORT Human Clinical

"The patient's skeletal phenotype shows an overlap with the clinical spectrum of the acromesomelic chondrodysplasias of the Grebe, Hunter-Thompson, and DuPan types caused by homozygous mutations in the gene coding for growth differentiation factor 5 (GDF5) which is a high-affinity ligand to BMPR1B."

The founding report attributes the phenotypic overlap to the shared ligand-receptor pair, which is the claim this node makes.

PMID:26105076 SUPPORT Human Clinical

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

States the dose-dependent relationship this node sits at the severe end of.

PMID:17381068 SUPPORT In Vitro

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

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

Impaired BMPR1B Signaling in Ovarian Granulosa Cells

Granulosa cells depend on BMPR1B to transduce GDF5 and BMP4, and altering that receptor changes how follicles mature. The proposal is that biallelic BMPR1B loss withdraws the same signal from the ovary that it withdraws from cartilage, producing the uterine hypoplasia, ovarian dysfunction and hypergonadotrophic hypogonadism reported in the index patient. The supporting functional data are ovine, from the Booroola FecB receptor variant, and that variant alters follicle maturation rather than abolishing it; no human BMPR1B ovarian tissue has been studied. This node is therefore curated under a non-canonical hypothesis group, and the genital phenotype it explains is itself curated as occasional.

Granulosa-Cell BMPR1B Model of the Genital Phenotype

Granulosa cell CL:0000501

BMP signaling pathway GO:0030509 ↓ DECREASED Ovarian follicle development GO:0001541 ⚠ ABNORMAL

Downstream

Ovarian Dysfunction and Uterine Hypoplasia Disturbed follicle development is proposed to produce the ovarian dysfunction and hypergonadotrophic hypogonadism reported in the index patient. The intermediate steps between granulosa-cell signalling and uterine hypoplasia are not established.

Show evidence (2 references)

PMID:12773124 SUPPORT Model Organism

"The presence of the Booroola mutation was associated with a 3- to 4-fold (P<0.001) decreased responsiveness of GCs from FecB(B) compared with FecB(+) small follicles to the action of BMPR1B ligands."

Quantifies the loss of granulosa-cell responsiveness produced by a BMPR1B variant, the functional basis for expecting ovarian involvement.

PMID:12773124 SUPPORT Model Organism

"is associated with a more precocious differentiation of ovarian granulosa cells (GCs)"

The ovine phenotype is altered follicle maturation, not the ovarian failure seen in the human index patient, which is why this is partial support for a hypothesis rather than an established mechanism.

Ovarian Dysfunction and Uterine Hypoplasia

Ovarian dysfunction with hypergonadotrophic hypogonadism and uterine hypoplasia, the extraskeletal feature that named this entity. It was reported in the index patient and is not present in every subsequently reported BMPR1B family, which is why OMIM titles the disorder as being with or without genital anomalies.

Female gonad development GO:0008585 ⚠ ABNORMAL Ovarian follicle development GO:0001541 ⚠ ABNORMAL

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 the phenotype in the index patient.

Failed Chondrogenic Differentiation in the Distal Limb

Without BMPR1B signalling, the mesenchymal condensations of the distal limb fail to differentiate and segment normally, producing missing and fused skeletal elements rather than uniformly small ones.

Chondrocyte CL:0000138

Chondrocyte differentiation GO:0002062 ↓ DECREASED Cartilage condensation GO:0001502 ⚠ ABNORMAL

Downstream

Acromesomelic Appendicular Malformation Failed differentiation and segmentation of distal-limb condensations directly produces the observed skeletal malformation.

Show evidence (1 reference)

PMID:24129431 SUPPORT In Vitro

"overexpression of the C53R mutation in an in vitro chondrogenesis assay showed no effect on cell differentiation, indicating a loss of function"

Directly measures the failure of chondrogenic differentiation.

Acromesomelic Appendicular Malformation

Disproportionate shortening of the appendicular skeleton that predominantly affects the middle and distal segments, with fibular aplasia, severe brachydactyly, and carpal and tarsal fusion, repeated across both hands and feet.

Chondrocyte CL:0000138

Limb development GO:0060173 ⚠ ABNORMAL Bone morphogenesis GO:0060349 ⚠ ABNORMAL Endochondral ossification GO:0001958 ⚠ ABNORMAL Limb morphogenesis GO:0035108 ⚠ ABNORMAL

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.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Endocrine 1

Hypergonadotrophic Hypogonadism OCCASIONAL Hypergonadotropic hypogonadism HP:0000815

Show evidence (2 references)

PMID:15805157 SUPPORT Human Clinical

"ovarian dysfunction resulting in hypergonadotrophic hypogonadism"

Documents the endocrine phenotype in the index patient.

PMID:26926249 SUPPORT Human Clinical

"In later case, it shows association with cardiac, respiratory, neurological and genital abnormalities."

A review of the acromesomelic dysplasias records genital abnormality among the extraskeletal associations of the syndromic forms. Support is partial because the sentence concerns syndromic acromesomelic dysplasia in general rather than this entity specifically.

Limbs 4

Fibular Aplasia HP:0002990

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

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.

Carpal and Tarsal Fusion Carpal synostosis HP:0009702

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

Show evidence (1 reference)

PMID:15805157 SUPPORT Human Clinical

"and fusion of carpal/tarsal bones"

Documents tarsal fusion in the founding case.

Musculoskeletal 1

Lumbar Hyperlordosis OCCASIONAL HP:0002938

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.

Growth 1

Short Stature HP:0004322

Show evidence (1 reference)

PMID:37524292 SUPPORT Human Clinical

"Acromesomelic dysplasia Grebe type (AMD Grebe type) is an autosomal recessive trait characterized by short stature, shortened limbs and malformations of the hands and feet."

States short stature as part of the phenotype the BMPR1B families present with.

Other 4

Ulnar Deviation of the Hands HP:0009487

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.

Uterine Hypoplasia OCCASIONAL Hypoplasia of the uterus HP:0000013

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.

Hip Dislocation OCCASIONAL HP:0002827

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"

Reports hip dislocation as a newly described feature, which is why it is curated as occasional.

Single Transverse Palmar Crease OCCASIONAL HP:0000954

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.

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Genetic Associations

1

Biallelic BMPR1B Loss-of-Function Variants (Causative)

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

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.

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Medical Actions

1

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counselling for an autosomal recessive disorder in what are typically consanguineous families. Heterozygous BMPR1B variants are not automatically benign: dominant-negative alleles in the same gene cause brachydactyly type A2, so a carrier's risk depends on the functional class of the family's allele rather than on carrier status alone.

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.

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Diagnosis

1

Molecular Confirmation of Biallelic BMPR1B Variants

Sequencing BMPR1B establishes the diagnosis in a patient with a Grebe-like limb phenotype and no GDF5 variant. Genital anomalies, when present, raise the prior probability of a BMPR1B rather than a GDF5 aetiology, but their absence does not exclude it.

Show evidence (1 reference)

PMID:15805157 SUPPORT Human Clinical

"However, the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype."

Identifies the clinical feature that distinguishes this disorder from the GDF5 disorders.

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Prevalence

1

Consanguineous kindreds worldwide

Cases In Literature Ultra Rare

No population-based estimate exists. The entity was founded on a single patient in 2005 and the reported case base since then is a handful of consanguineous families, described in the literature as rare cases of acromesomelic chondrodysplasia.

Show evidence (1 reference)

PMID:37524292 SUPPORT Human Clinical

"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)."

Characterises BMPR1B-related disease as the rare subset of an already rare disorder.

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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 The GDF5-related disorder with a closely overlapping limb phenotype; the two are separated by the causal gene and by the genital involvement.

Distinguishing Features

Genital anomalies with hypergonadotrophic hypogonadism occur in the BMPR1B disorder and not in GDF5-related Grebe dysplasia.
Biallelic BMPR1B rather than biallelic GDF5 variants establish the diagnosis.

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 The mild end of the same receptor's allelic series; hypomorphic BMPR1B variants cause du Pan syndrome rather than this disorder.

Distinguishing Features

Stature and the long bones are preserved in du Pan syndrome.
The BMPR1B allele determines which diagnosis results, with hypomorphic missense alleles giving du Pan syndrome and severe loss-of-function alleles giving the Grebe-like phenotype.

Show evidence (1 reference)

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.

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.

{ }

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: >-
  Acromesomelic dysplasia Demirhan type is the receptor-side counterpart of Grebe
  dysplasia: an autosomal recessive acromesomelic chondrodysplasia caused by
  biallelic loss-of-function variants in BMPR1B, the type I bone morphogenetic
  protein receptor that GDF5 binds with high affinity. The limb phenotype is
  Grebe-like, with fibular aplasia, severe brachydactyly, ulnar deviation of the
  hands, and fusion of carpal and tarsal bones. What sets it apart from the
  GDF5-related disorders, and is the reason the 2023 ISDS nosology keeps it as a
  separate group-16 entity, is the additional genital involvement reported in the
  index case: uterine hypoplasia with ovarian dysfunction and hypergonadotrophic
  hypogonadism. Genital anomalies are not obligate, and OMIM accordingly titles
  the entity "with or without genital anomalies". The disorder is mechanistically
  distinct from the dominant BMPR1B brachydactylies: those arise from
  dominant-negative missense alleles, whereas the Demirhan-type alleles are
  straightforward loss of function, which is why heterozygous carriers here show
  at most mild brachydactyly or no phenotype at all.
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: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 16 "Acromesomelic dysplasias"; listed as "Grebe
      dysplasia, BMPR1B-related" (OMIM 609441). The 2019 revision
      (PMID:31633310) placed the same entity in group 16 under the older
      descriptive name.
    evidence:
    - reference: PMID:39441036
      reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        To date, four disease genes and seven distinct ACD subtypes with varying
        severity are recognised according to the 2023 revision of the nosology
        and classification of genetic skeletal disorders
      explanation: >-
        This is the sentence that ties the enumeration below to the 2023 ISDS
        nosology revision. It is quoted separately because the enumeration
        itself names diseases and OMIM numbers without repeating the nosology
        attribution, so on its own it would not support a group assignment.
    - reference: PMID:39441036
      reference_title: "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        whereas pathogenic variants in BMPR1B can cause a Grebe dysplasia-like
        phenotype (OMIM #609441), as well as BMPR1B-related du Pan dysplasia
      explanation: >-
        A 2024 report enumerating the acromesomelic chondrodysplasia types of the
        2023 nosology revision places the OMIM 609441 entity, curated here, in
        that group.
prevalence:
- population: Consanguineous kindreds worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based estimate exists. The entity was founded on a single
    patient in 2005 and the reported case base since then is a handful of
    consanguineous families, described in the literature as rare cases of
    acromesomelic chondrodysplasia.
  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: >-
    Biallelic BMPR1B loss of function is required. Heterozygous parents show mild
    brachydactyly at most, and are often entirely unaffected. This carrier
    picture is itself evidence that the alleles are loss-of-function rather than
    dominant-negative, since dominant-negative BMPR1B alleles cause brachydactyly
    type A2 in the heterozygous state.
  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: >-
    Reported causative alleles are homozygous and include an 8 bp deletion
    (del359-366) in the index patient, the nonsense variants p.Trp219* and
    p.Arg401*, and the missense variant p.Cys53Arg. Nonsense alleles are
    predicted to trigger nonsense-mediated decay; the p.Cys53Arg receptor is
    partially mislocalised and cannot be activated by GDF5.
  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.
pathophysiology:
- name: Biallelic BMPR1B Loss of Function
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Pathogenic variants on both BMPR1B alleles remove or disable the type I BMP
    receptor. Nonsense alleles are expected to be degraded by nonsense-mediated
    decay; the characterised missense allele yields a receptor that reaches the
    membrane only partially.
  genes:
  - preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  biological_processes:
  - preferred_term: Nonsense-mediated decay of BMPR1B transcripts
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  - preferred_term: Receptor delivery to the plasma membrane
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    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: >-
      Functional analysis of the missense mutation C53R revealed that the
      mutated receptor was partially located at the cell membrane.
    explanation: Shows the receptor-level defect produced by the characterised missense allele.
  - reference: PMID:24129431
    reference_title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The nonsense mutation (c.657G>A, p.(W219*)) introduces a premature stop
      codon, which is predicted to be subject to nonsense-mediated mRNA decay,
      causing reduced protein translation of the mutant allele.
    explanation: Establishes transcript decay as the route by which nonsense alleles remove the receptor.
  downstream:
  - target: Failure of GDF5-Driven BMPR1B Activation
    causal_link_type: DIRECT
    description: >-
      Absent or mislocalised receptor directly prevents GDF5 from activating BMP
      signalling.
    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: Reporter assays demonstrate the failure of ligand-driven receptor activation.
- name: Failure of GDF5-Driven BMPR1B Activation
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    This is the same central node as in the GDF5-related acromesomelic
    dysplasias, reached from the receptor side rather than the ligand side. It is
    why a BMPR1B disorder is clinically a Grebe dysplasia, and why the severity
    of BMPR1B disease tracks residual receptor function in exactly the way GDF5
    disease tracks residual ligand function.
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: LOSS_OF_FUNCTION
  - preferred_term: Cell surface receptor protein serine/threonine kinase signaling pathway
    term:
      id: GO:0007178
      label: cell surface receptor protein serine/threonine kinase signaling pathway
    modifier: LOSS_OF_FUNCTION
  - preferred_term: SMAD protein signal transduction
    term:
      id: GO:0060395
      label: SMAD protein signal transduction
    modifier: DECREASED
  - preferred_term: Protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: DECREASED
  molecular_functions:
  - preferred_term: BMP receptor activity
    term:
      id: GO:0098821
      label: BMP receptor activity
    modifier: LOSS_OF_FUNCTION
  - preferred_term: Protein serine/threonine kinase activity
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    modifier: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  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 patient's skeletal phenotype shows an overlap with the clinical
      spectrum of the acromesomelic chondrodysplasias of the Grebe,
      Hunter-Thompson, and DuPan types caused by homozygous mutations in the gene
      coding for growth differentiation factor 5 (GDF5) which is a high-affinity
      ligand to BMPR1B.
    explanation: >-
      The founding report attributes the phenotypic overlap to the shared
      ligand-receptor pair, which is the claim this node makes.
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypic severity gradient of the clinically and radiologically
      related acromesomelic chondrodysplasia spectrum of skeletal disorders may
      be due to the extent of functional impairment of the ligand-receptor pair
      GDF5-BMPR1B.
    explanation: States the dose-dependent relationship this node sits at the severe end of.
  - reference: PMID:17381068
    reference_title: Potential involvement of BMP receptor type IB activation in a synergistic effect of chondrogenic promotion between rhTGFbeta3 and rhGDF5 or rhBMP7 in human mesenchymal stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SMAD1/5/8 phosphorylation in nascent human mesenchymal stem cells (HMSCs)
      was stimulated weakly by rhGDF5 but strongly by rhBMP7.
    explanation: >-
      Establishes SMAD1/5/8 phosphorylation as the transducer engaged by GDF5 in
      a human chondrogenic system, which is the basis for annotating SMAD
      signalling on this node. Support is partial, and deliberately so: GDF5's
      own SMAD stimulation is reported as weak, so SMAD phosphorylation may not
      be the whole of how GDF5 acts here.
  downstream:
  - target: Impaired BMPR1B Signaling in Ovarian Granulosa Cells
    causal_link_type: DIRECT
    hypothesis_groups:
    - granulosa_bmpr1b_model
    description: >-
      BMPR1B is the receptor through which granulosa cells read GDF5 and BMP4,
      so removing it withdraws the same signal from the ovary that it withdraws
      from cartilage. This is the proposed explanation for the genital
      involvement that distinguishes this entity from the GDF5 disorders.
    evidence:
    - reference: PMID:12773124
      reference_title: The Booroola mutation in sheep is associated with an alteration of the bone morphogenetic protein receptor-IB functionality.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the action of ligands of the transforming growth factor-beta
        (TGFbeta)/BMP family that act through (growth and differentiation
        factor-5, BMP-4) or independently of (activin A, TGFbeta-1) BMPR1B were
        studied on primary cultures of GCs
      explanation: >-
        Establishes that granulosa cells respond to GDF5 and BMP4 specifically
        through BMPR1B, which is what makes the ovary a predicted target of
        receptor loss.
  - target: Failed Chondrogenic Differentiation in the Distal Limb
    causal_link_type: DIRECT
    description: >-
      Loss of receptor signalling directly removes the BMP input to chondrogenic
      differentiation.
    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: >-
        overexpression of the C53R mutation in an in vitro chondrogenesis assay
        showed no effect on cell differentiation, indicating a loss of function
      explanation: A chondrogenesis assay shows the mutant receptor cannot drive differentiation.
- name: Impaired BMPR1B Signaling in Ovarian Granulosa Cells
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    Granulosa cells depend on BMPR1B to transduce GDF5 and BMP4, and altering
    that receptor changes how follicles mature. The proposal is that biallelic
    BMPR1B loss withdraws the same signal from the ovary that it withdraws from
    cartilage, producing the uterine hypoplasia, ovarian dysfunction and
    hypergonadotrophic hypogonadism reported in the index patient. The
    supporting functional data are ovine, from the Booroola FecB receptor
    variant, and that variant alters follicle maturation rather than abolishing
    it; no human BMPR1B ovarian tissue has been studied. This node is therefore
    curated under a non-canonical hypothesis group, and the genital phenotype it
    explains is itself curated as occasional.
  cell_types:
  - preferred_term: Granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DECREASED
  - preferred_term: Ovarian follicle development
    term:
      id: GO:0001541
      label: ovarian follicle development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12773124
    reference_title: The Booroola mutation in sheep is associated with an alteration of the bone morphogenetic protein receptor-IB functionality.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The presence of the Booroola mutation was associated with a 3- to 4-fold
      (P<0.001) decreased responsiveness of GCs from FecB(B) compared with
      FecB(+) small follicles to the action of BMPR1B ligands.
    explanation: >-
      Quantifies the loss of granulosa-cell responsiveness produced by a BMPR1B
      variant, the functional basis for expecting ovarian involvement.
  - reference: PMID:12773124
    reference_title: The Booroola mutation in sheep is associated with an alteration of the bone morphogenetic protein receptor-IB functionality.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      is associated with a more precocious differentiation of ovarian granulosa
      cells (GCs)
    explanation: >-
      The ovine phenotype is altered follicle maturation, not the ovarian failure
      seen in the human index patient, which is why this is partial support for
      a hypothesis rather than an established mechanism.
  downstream:
  - target: Ovarian Dysfunction and Uterine Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - granulosa_bmpr1b_model
    description: >-
      Disturbed follicle development is proposed to produce the ovarian
      dysfunction and hypergonadotrophic hypogonadism reported in the index
      patient. The intermediate steps between granulosa-cell signalling and
      uterine hypoplasia are not 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: >-
        In addition, she presented with hypoplasia of the uterus and ovarian
        dysfunction resulting in hypergonadotrophic hypogonadism.
      explanation: >-
        Documents the human endpoint. Support is partial because the report
        establishes co-occurrence with the BMPR1B genotype, not the causal chain.
- name: Ovarian Dysfunction and Uterine Hypoplasia
  role: consequence
  biological_scale: ORGANISM
  description: >-
    Ovarian dysfunction with hypergonadotrophic hypogonadism and uterine
    hypoplasia, the extraskeletal feature that named this entity. It was
    reported in the index patient and is not present in every subsequently
    reported BMPR1B family, which is why OMIM titles the disorder as being with
    or without genital anomalies.
  biological_processes:
  - preferred_term: Female gonad development
    term:
      id: GO:0008585
      label: female gonad development
    modifier: ABNORMAL
  - preferred_term: Ovarian follicle development
    term:
      id: GO:0001541
      label: ovarian follicle development
    modifier: ABNORMAL
  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 the phenotype in the index patient.
- name: Failed Chondrogenic Differentiation in the Distal Limb
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    Without BMPR1B signalling, the mesenchymal condensations of the distal limb
    fail to differentiate and segment normally, producing missing and fused
    skeletal elements rather than uniformly small ones.
  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
  - preferred_term: Cartilage condensation
    term:
      id: GO:0001502
      label: cartilage condensation
    modifier: ABNORMAL
  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: >-
      overexpression of the C53R mutation in an in vitro chondrogenesis assay
      showed no effect on cell differentiation, indicating a loss of function
    explanation: Directly measures the failure of chondrogenic differentiation.
  downstream:
  - target: Acromesomelic Appendicular Malformation
    causal_link_type: DIRECT
    description: >-
      Failed differentiation and segmentation of distal-limb condensations
      directly produces the observed skeletal malformation.
    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: >-
        Homozygous affected individuals show clinical and radiographic findings
        consistent with ACD-type Grebe.
      explanation: Links the functionally characterised alleles to the skeletal outcome in the same families.
- name: Acromesomelic Appendicular Malformation
  role: consequence
  biological_scale: TISSUE
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  description: >-
    Disproportionate shortening of the appendicular skeleton that predominantly
    affects the middle and distal segments, with fibular aplasia, severe
    brachydactyly, and carpal and tarsal fusion, repeated across both hands and
    feet.
  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
  - preferred_term: Endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: ABNORMAL
  - preferred_term: Limb morphogenesis
    term:
      id: GO:0035108
      label: limb 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.
mechanistic_hypotheses:
- hypothesis_group_id: receptor_side_ligand_loss_equivalence
  hypothesis_label: Receptor-Side Equivalence Model
  status: CANONICAL
  description: >-
    Disabling BMPR1B is mechanistically equivalent to disabling GDF5 for the
    limb skeleton, because the two act as one ligand-receptor pair, and that is
    why the BMPR1B limb phenotype is Grebe-like. Severity within BMPR1B follows
    residual receptor function in the same way it follows residual ligand
    function within GDF5.
  evidence:
  - reference: PMID:26105076
    reference_title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypic severity gradient of the clinically and radiologically
      related acromesomelic chondrodysplasia spectrum of skeletal disorders may
      be due to the extent of functional impairment of the ligand-receptor pair
      GDF5-BMPR1B.
    explanation: States the equivalence and the dose-dependence it implies.
  - 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: Shows the receptor lesion acting at the same ligand-receptor step as a GDF5 lesion.
- hypothesis_group_id: granulosa_bmpr1b_model
  hypothesis_label: Granulosa-Cell BMPR1B Model of the Genital Phenotype
  status: EMERGING
  description: >-
    The genital involvement is proposed to be a direct consequence of losing
    BMPR1B in the ovary rather than a coincidence of consanguinity. Granulosa
    cells read GDF5 and BMP4 specifically through BMPR1B, and the ovine Booroola
    FecB receptor variant alters follicle maturation, so a receptor null is
    expected to disturb folliculogenesis. Two things keep this short of
    established. The supporting data are ovine and describe a variant that
    changes rather than abolishes receptor function, and the human observation
    rests on the single index patient while later BMPR1B families were reported
    without genital anomalies. An alternative reading is that the genital
    findings are a feature of that individual or of a second locus in a
    multiconsanguineous pedigree.
  evidence:
  - reference: PMID:12773124
    reference_title: The Booroola mutation in sheep is associated with an alteration of the bone morphogenetic protein receptor-IB functionality.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      these data strongly suggest that the Q249R mutation is associated with a
      specific alteration of BMPR1B signaling in hyperprolific Booroola ewes
    explanation: Establishes that a BMPR1B variant alters ovarian signalling in vivo.
  - reference: PMID:15805157
    reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the phenotype described here differs from GDF5 associated
      chondrodysplasias because of the additional presence of genital anomalies
      and the distinct limb phenotype.
    explanation: >-
      The human basis for the model is one patient contrasted against the GDF5
      disorders, which is what makes this emerging rather than canonical.
  notes: >-
    The two groups here are not competing accounts of one thing. The first
    covers the limb phenotype and is well supported; the second covers the
    genital phenotype and is not. They are kept separate so the confidence
    attached to the limb mechanism does not silently transfer to the ovarian
    one.
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: Fixed ulnar deviation of both hands.
  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 and Tarsal Fusion
  description: Fusion of carpal and tarsal bones.
  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: Fusion of tarsal bones, the hindlimb counterpart of the carpal fusion.
  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
  frequency: OCCASIONAL
  description: >-
    Hypoplasia of the uterus in the index patient. Genital involvement is the
    feature that named this entity but it is not obligate, and OMIM titles the
    disorder as being with or without genital anomalies.
  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
  frequency: OCCASIONAL
  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.
  - reference: PMID:26926249
    reference_title: Genetics of human isolated acromesomelic dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In later case, it shows association with cardiac, respiratory,
      neurological and genital abnormalities.
    explanation: >-
      A review of the acromesomelic dysplasias records genital abnormality among
      the extraskeletal associations of the syndromic forms. Support is partial
      because the sentence concerns syndromic acromesomelic dysplasia in general
      rather than this entity specifically.
- category: Skeletal
  name: Short Stature
  description: >-
    Short stature accompanies the shortened limbs, as in the GDF5-related Grebe
    phenotype.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  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: >-
      Acromesomelic dysplasia Grebe type (AMD Grebe type) is an autosomal
      recessive trait characterized by short stature, shortened limbs and
      malformations of the hands and feet.
    explanation: States short stature as part of the phenotype the BMPR1B families present with.
- category: Skeletal
  name: Hip Dislocation
  frequency: OCCASIONAL
  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: >-
      Reports hip dislocation as a newly described feature, which is why it is
      curated as occasional.
- category: Skeletal
  name: Lumbar Hyperlordosis
  frequency: OCCASIONAL
  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
  frequency: OCCASIONAL
  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.
diagnosis:
- name: Molecular Confirmation of Biallelic BMPR1B Variants
  description: >-
    Sequencing BMPR1B establishes the diagnosis in a patient with a Grebe-like
    limb phenotype and no GDF5 variant. Genital anomalies, when present, raise
    the prior probability of a BMPR1B rather than a GDF5 aetiology, but their
    absence does not exclude it.
  evidence:
  - reference: PMID:15805157
    reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the phenotype described here differs from GDF5 associated
      chondrodysplasias because of the additional presence of genital anomalies
      and the distinct limb phenotype.
    explanation: Identifies the clinical feature that distinguishes this disorder from the GDF5 disorders.
treatments:
- name: Genetic Counseling
  description: >-
    Counselling for an autosomal recessive disorder in what are typically
    consanguineous families. Heterozygous BMPR1B variants are not automatically
    benign: dominant-negative alleles in the same gene cause brachydactyly type
    A2, so a carrier's risk depends on the functional class of the family's
    allele rather than on carrier status alone.
  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.
differential_diagnoses:
- name: Acromesomelic Dysplasia, Grebe Type
  disease_term:
    preferred_term: acromesomelic dysplasia, Grebe type
    term:
      id: MONDO:0008703
      label: acromesomelic dysplasia 2A
  description: >-
    The GDF5-related disorder with a closely overlapping limb phenotype; the two
    are separated by the causal gene and by the genital involvement.
  distinguishing_features:
  - Genital anomalies with hypergonadotrophic hypogonadism occur in the BMPR1B disorder and not in GDF5-related Grebe dysplasia.
  - Biallelic BMPR1B rather than biallelic GDF5 variants establish the diagnosis.
  evidence:
  - reference: PMID:15805157
    reference_title: A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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: >-
    The mild end of the same receptor's allelic series; hypomorphic BMPR1B
    variants cause du Pan syndrome rather than this disorder.
  distinguishing_features:
  - Stature and the long bones are preserved in du Pan syndrome.
  - >-
    The BMPR1B allele determines which diagnosis results, with hypomorphic
    missense alleles giving du Pan syndrome and severe loss-of-function alleles
    giving the Grebe-like phenotype.
  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.
- 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: no_disease_specific_management_literature
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#
  prompt: >-
    What supportive, orthopaedic and rehabilitative management actually benefits
    the Demirhan type?
  rationale: >-
    The treatments section is deliberately limited to genetic counselling, which
    is the one intervention the published literature for this disorder actually
    documents. Reconstructive and orthopaedic surgery, prosthetics, and
    physiotherapy are all plausible for a limb malformation of this severity and
    are presumably used in practice, but a search of the indexed literature
    returned no disease-specific management report for this disorder to cite. Curating
    them from general skeletal-dysplasia practice would be inference, not
    evidence, so the gap is recorded rather than filled. A case series reporting functional outcomes after surgical or
    prosthetic management would close it. Management of the reported ovarian
    dysfunction and hypergonadotrophic hypogonadism is equally undocumented and
    is part of the same gap.
- discussion_id: bmpr1b_genital_phenotype_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the genital phenotype a consequence of BMPR1B loss, and if so why does
    ligand-side loss not produce it?
  rationale: >-
    BMPR1B binds ligands beyond GDF5, so a receptor null withdraws more BMP
    input than a GDF5 null does; that asymmetry is the natural explanation for
    an extra phenotype on the receptor side, and it has never been tested. The
    granulosa-cell model records what is known, but its functional support is
    ovine and its human support is one patient. Reporting how many
    molecularly confirmed BMPR1B probands have had a gynaecological assessment
    at all, rather than how many were noted to have anomalies, would settle
    whether the feature is rare or merely rarely looked for.
  attaches_to:
  - pathophysiology#Failure of GDF5-Driven BMPR1B Activation
  - pathophysiology#Impaired BMPR1B Signaling in Ovarian Granulosa Cells
  - phenotypes#Uterine Hypoplasia
notes: >-
  Curated as part of a review of ISDS 2023 nosology group 16 (acromesomelic
  dysplasias). The entity is named here for Demirhan, following MONDO and OMIM;
  the 2023 nosology calls the same entity "Grebe dysplasia, BMPR1B-related". No
  Orphanet structured record was cited: the pinned Orphadata snapshot in
  data/orphadata/MANIFEST.yaml no longer matches upstream, and re-pinning it
  would rewrite every ORPHA cache file in the repository.

Acromesomelic Dysplasia Demirhan Type

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