Craniometadiaphyseal Osteosclerosis with Hip Dysplasia

Mendelian MONDO:0957832 Pathograph 10 Show in embeddings browser Sclerosing Bone Dysplasias

Craniometadiaphyseal osteosclerosis with hip dysplasia is an autosomal recessive sclerosing skeletal dysplasia caused by homozygous C-terminally truncating variants in AXIN1, the scaffold of the beta-catenin destruction complex. The founding report described seven individuals from four families with macrocephaly, cranial hyperostosis and sclerosis of the vertebral endplates; hip dysplasia, heart malformations, variable developmental delay and hematological anomalies, including anemia and pancytopenia, were also frequent. The truncating alleles remove the C-terminal DIX domain through which AXIN1 polymerizes. In primary and genome-edited cells carrying them, AXIN1 protein levels were reduced, DIX-mediated polymerization was impaired and basal canonical Wnt/beta-catenin signalling was increased, yet the truncated proteins kept part of their Wnt-inhibitory activity when overexpressed, so the alleles are hypomorphic rather than null. A tankyrase inhibitor attenuated the Wnt overactivity in these cell systems. Patient bone biopsy showed increased osteoblast and reduced osteoclast function at the growth-plate resorption zone, and the authors proposed that AXIN1 coordinates osteoblast and osteoclast activity; in mice, deleting Axin1 in osteoblast precursors reduced osteoclast formation through increased osteoprotegerin. How the extraskeletal features arise is unknown.

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1
Inheritance
5
Pathophys.
1
Histopath.
8
Phenotypes
1
Hypotheses
2
Gaps
10
Pathograph
1
Genes
9
Differentials
2
Models
7
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
All affected individuals in the founding report were homozygous for one of three C-terminally truncating AXIN1 variants, across four families.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families"
Homozygous causal variants in affected individuals from four independent families support autosomal recessive inheritance.
◈

Mechanistic Hypotheses

1
Hypomorphic AXIN1 shifts osteoblast-osteoclast coupling toward bone accrual
axin1_osteoblast_osteoclast_coupling EMERGING
Evidence balance 2 support
Reduced AXIN1 function raises canonical Wnt signalling in the skeleton, and this is proposed to act on osteoblasts and, through osteoblast-derived signals such as OPG, on osteoclast formation, so that net bone accrual produces the cranial and vertebral osteosclerosis. The human evidence is the cellular Wnt overactivity, the bone-biopsy finding of increased osteoblast and reduced osteoclast function (known here through OMIM's summary), and the authors' interpretation. The mechanistic link from osteoblast-lineage Axin1 loss to reduced osteoclastogenesis via OPG comes from a complete conditional knockout in mouse osteoblast precursors, a stronger loss of function than the human hypomorphic alleles.
Pathograph links
Enhanced Basal Canonical Wnt/Beta-Catenin Signaling -> Imbalanced Osteoblast-Osteoclast Coupling INDIRECT UNKNOWN INTERMEDIATES Excess Wnt signalling in the skeleton is proposed to shift the balance between bone formation and resorption; the intermediate steps have not been shown in patients.
Imbalanced Osteoblast-Osteoclast Coupling -> Cranial Hyperostosis INDIRECT UNKNOWN INTERMEDIATES
Imbalanced Osteoblast-Osteoclast Coupling -> Sclerotic Vertebral Endplates INDIRECT UNKNOWN INTERMEDIATES
Show evidence (2 references)
PMID:37582359 SUPPORT Human Clinical
"Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts"
The authors' statement of the hypothesis.
PMID:32821442 SUPPORT Model Organism
"Thus, the loss of Axin1 in osteoblast precursor cells caused increased OPG and the decrease in osteoclast formation"
Mouse evidence for the osteoclast arm.
?

Discussions and Knowledge Gaps

2
How does hypomorphic AXIN1 produce hip dysplasia, heart malformations, developmental delay and the hematological anomalies?
KNOWLEDGE GAP OPEN cmdoh_extraskeletal_mechanism_gap
Attached to
phenotypes#Hip Dysplasia phenotypes#Heart Malformations phenotypes#Developmental Delay phenotypes#Anemia phenotypes#Pancytopenia phenotypes#Macrocephaly
The founding report establishes excess canonical Wnt signalling in patient and edited cells, but the quotable sources do not connect it to any of the extraskeletal features, nor say whether macrocephaly reflects skull thickening alone. These phenotypes are therefore left without an upstream mechanism node. In particular, whether the anemia and pancytopenia reflect encroachment of sclerotic bone on the marrow space or a direct effect of AXIN1 loss on hematopoiesis has not been examined.
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies."
The extraskeletal features whose mechanism is open.
Would a tankyrase inhibitor reduce bone accrual in vivo in a model carrying a patient-equivalent Axin1 C-terminal truncation, at a dose that does not impair normal bone formation?
HUMAN MODEL MISMATCH OPEN cmdoh_tankyrase_inhibitor_translation
Attached to
pathophysiology#Enhanced Basal Canonical Wnt/Beta-Catenin Signaling experimental_models#AXIN1-truncation primary and genome-edited cells
Tankyrase inhibition attenuated the Wnt overactivity only in cultured cells, and the authors proposed it as a way to counter hypomorphic AXIN1. No animal model carrying a patient-equivalent allele exists; the only skeletal Axin1 model is a complete conditional deletion in osteoblast precursors, whose phenotype (delayed postnatal bone growth) differs from the human osteosclerosis. Stabilizing AXIN1 in normal bone is not neutral: mice lacking the ubiquitin ligase RNF146, which normally keeps AXIN1 levels low, in the osteoblast lineage accumulate AXIN1 and become severely osteopenic.
Show evidence (3 references)
PMID:37582359 SUPPORT In Vitro
"tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants"
The authors' therapeutic proposal, based on cell data.
PMID:28581440 SUPPORT Model Organism
"Loss of RNF146 stabilized its substrate AXIN1, leading to impairment of WNT3a-induced β-catenin activation and reduced Fgf18 expression in osteoblasts."
AXIN1 stabilization blunts Wnt signalling in osteoblasts.
PMID:28581440 SUPPORT Model Organism
"mice with loss of RNF146 within the osteoblast lineage had increased fat stores and were glucose intolerant with severe osteopenia because of defective osteoblastogenesis"
Excess AXIN1 in normal osteoblasts causes bone loss, a safety consideration.
⚙

Pathophysiology

5
Biallelic C-Terminal AXIN1 Truncation
Mechanism confidence: Established
Homozygous truncating variants in AXIN1 that remove the C-terminal DIX domain. Three such variants were found in four families.
AXIN1 hgnc:903 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AXIN1 (hgnc:903). hgnc:903 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context AXIN1 hgnc:903 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns AXIN1 (hgnc:903). hgnc:903 is a gene from the HUGO Gene Nomenclature Committee. allele_type: truncating variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
C-terminally truncating variants that delete the DIX domain. They are hypomorphic: the truncated proteins are less abundant and do not polymerize, but retain part of their Wnt-inhibitory function when overexpressed.
Downstream
Reduced AXIN1 Protein Abundance
Impaired DIX-Domain-Mediated AXIN1 Polymerization
Show evidence (2 references)
PMID:37582359 SUPPORT Human Clinical
"We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families"
Identifies the causal lesion class.
PMID:37582359 SUPPORT In Vitro
"partially retained Wnt-inhibitory function upon overexpression"
Residual inhibitory activity of the truncated proteins, the basis for classifying the alleles as partial loss of function.
Reduced AXIN1 Protein Abundance
Mechanism confidence: Provisional
The truncated AXIN1 proteins are present at lower levels than wild-type AXIN1 in primary and genome-edited cells. PROVISIONAL because the measurements are in cultured cells, not in bone.
Downstream
Enhanced Basal Canonical Wnt/Beta-Catenin Signaling Less AXIN1 scaffold is expected to mean less efficient destruction-complex activity and less beta-catenin degradation in the absence of Wnt ligand.
Show evidence (1 reference)
PMID:37582359 SUPPORT In Vitro
"All three AXIN1-truncating variants resulted in reduced protein levels"
Direct measurement of reduced AXIN1 protein.
Impaired DIX-Domain-Mediated AXIN1 Polymerization
Mechanism confidence: Provisional
AXIN1 polymerizes through its C-terminal DIX domain; the truncated proteins lacking it do not. PROVISIONAL because this was shown in cultured cells.
AXIN1 polymerization GO:0051258 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased AXIN1 polymerization, annotated with protein polymerization (GO:0051258). GO:0051258 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
Show evidence (1 reference)
PMID:37582359 SUPPORT In Vitro
"impaired AXIN1 polymerization mediated by its C-terminal DIX domain"
Direct observation of impaired polymerization.
Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
Mechanism confidence: Provisional
Primary cells from affected individuals and genome-edited cells carrying the truncating variants show increased canonical Wnt pathway activity in the absence of added ligand, attenuated by a tankyrase inhibitor. The modifier is INCREASED rather than GAIN_OF_FUNCTION: the truncated AXIN1 still restrains the pathway in part, so the claim is quantitative. PROVISIONAL because it has not been measured in bone cells of patients.
Hypomorphic AXIN1 shifts osteoblast-osteoclast coupling toward bone accrual
beta-catenin destruction complex GO:0030877 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves beta-catenin destruction complex (GO:0030877). GO:0030877 is a protein complex from the Gene Ontology.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
AXIN1-truncation primary and genome-edited cells OTHER Endogenous truncating alleles reproduce the increased basal Wnt activity that the pathophysiology node describes.
Downstream
Imbalanced Osteoblast-Osteoclast Coupling Excess Wnt signalling in the skeleton is proposed to shift the balance between bone formation and resorption; the intermediate steps have not been shown in patients. Hypomorphic AXIN1 shifts osteoblast-osteoclast coupling toward bone accrual
Show evidence (2 references)
PMID:37582359 SUPPORT In Vitro
"analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity"
Measured increase in basal canonical Wnt signalling.
PMID:37582359 SUPPORT In Vitro
"Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems."
Pharmacological attenuation of the overactivity in the same systems.
Imbalanced Osteoblast-Osteoclast Coupling
Mechanism confidence: Provisional
Sclerosing skeletal dysplasias arise from an imbalance between bone formation and resorption. In this disorder, bone biopsy (as summarized by OMIM) showed increased osteoblast and reduced osteoclast function at the growth-plate resorption zone, and the authors proposed that AXIN1 coordinates osteoblast and osteoclast activity. Mouse data support the osteoclast arm: deleting Axin1 in osteoblast precursors increased osteoblast osteoprotegerin (OPG) and the OPG-to-RANKL ratio and reduced osteoclast formation. PROVISIONAL because the human evidence is a biopsy finding known here only through a database summary, and the mouse model is a complete conditional deletion rather than the human hypomorphic allele.
Hypomorphic AXIN1 shifts osteoblast-osteoclast coupling toward bone accrual
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology. osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology.
bone formation GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bone formation, annotated with ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ↑ INCREASED osteoclast differentiation GO:0030316 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased osteoclast differentiation (GO:0030316). GO:0030316 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Axin1 osteoblast-precursor conditional knockout mouse (Osx-Cre) Mouse partially recapitulates Reproduces the osteoclast arm of the proposed coupling defect.
Downstream
Cranial Hyperostosis Hypomorphic AXIN1 shifts osteoblast-osteoclast coupling toward bone accrual
Sclerotic Vertebral Endplates Hypomorphic AXIN1 shifts osteoblast-osteoclast coupling toward bone accrual
Show evidence (4 references)
PMID:37582359 SUPPORT BACKGROUND Human Clinical
"Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption."
General premise for the node, stated as background in the founding report.
url:https://www.ncbi.nlm.nih.gov/medgen/1844026/ SUPPORT REVIEW SYNTHESIS Other
"Bone biopsy shows evidence of increased osteoblast and reduced osteoclast function at the growth plate resorption zone, resulting in coarse trabeculae (Terhal et al., 2023)."
OMIM's summary of the patient bone biopsy in the founding paper: both arms of the coupling are shifted toward bone accrual in human tissue.
PMID:32821442 SUPPORT Model Organism
"OPG expression and the ratio of Opg to Rankl were significantly increased in osteoblasts of Axin1Osx KO mice."
Osteoblast-lineage Axin1 loss changes the osteoblast signal to osteoclasts.
+ 1 more reference
✶

Histopathology

1
Increased osteoblast and reduced osteoclast function at the growth-plate resorption zone
Patient bone biopsy in the founding report, as summarized by OMIM, showed increased osteoblast and reduced osteoclast function at the growth-plate resorption zone with coarse trabeculae. The per-patient histology is in the full paper, which is not quotable here.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/medgen/1844026/ SUPPORT REVIEW SYNTHESIS Other
"Bone biopsy shows evidence of increased osteoblast and reduced osteoclast function at the growth plate resorption zone, resulting in coarse trabeculae (Terhal et al., 2023)."
OMIM's summary of the biopsy finding in the founding paper.
⬡

Pathograph

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

Phenotypes

8
Blood 2
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37582359 SUPPORT Human Clinical
"Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies."
The founding report lists hematological anomalies among the frequent features without naming them in its abstract.
url:https://www.ncbi.nlm.nih.gov/medgen/1844026/ SUPPORT REVIEW SYNTHESIS Other
"hematologic anomalies including anemia and pancytopenia"
The OMIM definition reproduced in MedGen, which summarizes the full founding paper, names anemia as one of the hematological anomalies.
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/medgen/1844026/ SUPPORT REVIEW SYNTHESIS Other
"hematologic anomalies including anemia and pancytopenia"
The OMIM definition reproduced in MedGen names pancytopenia among the hematological anomalies of the founding cohort.
Cardiovascular 1
Heart Malformations Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
The quotable abstract says "heart malformations" without naming a lesion, so the term carrying "Congenital heart defect" as an exact synonym is bound rather than a specific defect.
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies."
Heart malformations are a frequent extraskeletal feature.
Head and Neck 2
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis"
Macrocephaly is one of the three cardinal features of the cohort.
Cranial Hyperostosis HP:0004437 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cranial hyperostosis (HP:0004437). HP:0004437 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis"
Cranial hyperostosis is one of the three cardinal features.
Musculoskeletal 2
Sclerotic Vertebral Endplates HP:0004576 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sclerotic vertebral endplates (HP:0004576). HP:0004576 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis"
Vertebral endplate sclerosis is one of the three cardinal features.
Hip Dysplasia HP:0001385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip dysplasia (HP:0001385). HP:0001385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies."
Hip dysplasia is a frequent feature and gives the disorder its name.
Nervous System 1
Developmental Delay Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies."
Variable developmental delay is a frequent feature.
🧬

Genetic Associations

1
AXIN1 (CAUSATIVE)
Gene: AXIN1 hgnc:903 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AXIN1 (hgnc:903). hgnc:903 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (2 references)
PMID:37582359 SUPPORT Human Clinical
"We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families"
Gene discovery in four families.
PMID:37582359 SUPPORT In Vitro
"All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression."
Functional characterization showing the alleles are hypomorphic.
🔬

Diagnosis

2
Skeletal radiography
The defining features are radiographic: cranial hyperostosis with macrocephaly, sclerosis of the vertebral endplates, and hip dysplasia on pelvic imaging.
skeletal survey NCIT:C38092 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37582359 SUPPORT INDIRECT Human Clinical
"seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis"
Two of the three cardinal features are radiographic findings. INDIRECT because the source reports the features, not a diagnostic protocol.
AXIN1 molecular genetic testing
Confirmation is by finding biallelic C-terminally truncating AXIN1 variants. No diagnostic criteria or testing guideline for this disorder has been published.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37582359 SUPPORT INDIRECT Human Clinical
"We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families"
Defines the molecular finding that establishes the diagnosis. INDIRECT because the source is a gene-discovery report rather than a testing recommendation.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Seven affected individuals from four families in the founding report.
Show evidence (1 reference)
PMID:37582359 SUPPORT Human Clinical
"We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families"
Literature case count from the founding cohort.
🔀

Differential Diagnoses

9

Conditions with similar clinical presentations that must be differentiated from Craniometadiaphyseal Osteosclerosis with Hip Dysplasia:

Craniometadiaphyseal dysplasia, wormian bone type Not Yet Curated MONDO:0010014
Overlapping Features Near-homonymous recessive craniotubular disorder attributed to biallelic WRAP53 variants, with cortical thinning and absent metaphyseal flaring and diaphyseal constriction rather than osteosclerosis.
Show evidence (1 reference)
PMID:34484289 SUPPORT Human Clinical
"Our study showed that craniometadiaphyseal dysplasia was caused by a deficiency of WRAP53 with autosomal recessive inheritance."
Different gene for the similarly named disorder.
Sclerosteosis MONDO:0017838
Overlapping Features Recessive SOST-related sclerosing bone dysplasia with progressive cranial hyperostosis caused by loss of the Wnt antagonist sclerostin, with syndactyly and tall stature. Distinguished by gene testing.
Van Buchem disease MONDO:0009395
Overlapping Features Recessive endosteal hyperostosis from a deletion of a SOST regulatory region, with progressive skull and mandibular thickening and cranial nerve entrapment but without syndactyly; distinguished by gene testing.
Craniometaphyseal dysplasia MONDO:0015465
Overlapping Features Craniotubular dysplasia with cranial hyperostosis and metaphyseal flaring; distinguished by gene testing.
Camurati-Engelmann disease MONDO:0007542
Overlapping Features Autosomal dominant diaphyseal dysplasia with cortical thickening from TGFB1 variants.
Osteopetrosis MONDO:0017198
Overlapping Features Generalized increased bone density from defective osteoclast resorption, which, like this disorder, can be accompanied by hematological anomalies. OMIM lists the recessive and dominant osteopetroses as overlapping syndromes.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/medgen/1844026/ SUPPORT REVIEW SYNTHESIS Other
"For syndromes with overlapping features, see osteopetrosis, autosomal recessive (OPTB1; 259700) and dominant (OPTA1; 607634), and osteopathia with cranial sclerosis (OSCS; 300373)."
OMIM names the osteopetroses as overlapping syndromes.
Osteopathia striata with cranial sclerosis Not Yet Curated MONDO:0010310
Overlapping Features X-linked AMER1-related sclerosing dysplasia with cranial sclerosis and macrocephaly, named by OMIM as an overlapping syndrome; distinguished by inheritance, metaphyseal striations and gene testing.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/medgen/1844026/ SUPPORT REVIEW SYNTHESIS Other
"For syndromes with overlapping features, see osteopetrosis, autosomal recessive (OPTB1; 259700) and dominant (OPTA1; 607634), and osteopathia with cranial sclerosis (OSCS; 300373)."
OMIM names osteopathia striata with cranial sclerosis as an overlapping syndrome.
Craniotubular dysplasia, Ikegawa type Not Yet Curated MONDO:0859226
Overlapping Features Recessive TMEM53-related sclerosing bone dysplasia with skull hyperostosis and increased bone density, driven by excess BMP-SMAD rather than Wnt signalling; distinguished by gene testing.
Show evidence (1 reference)
PMID:41408477 SUPPORT REVIEW SYNTHESIS Human Clinical
"Pathogenic variants in TMEM53 have been identified as the genetic cause of craniotubular dysplasia, Ikegawa type (CTDI), a rare form of sclerosing bone dysplasia characterized by skull hyperostosis, cranial deformities, and increased bone density."
The overlapping cranial hyperostosis phenotype and the different gene.
🧫

Experimental Models

1
AXIN1-truncation primary and genome-edited cells OTHER
Primary cells from affected individuals and genome-edited cells carrying the AXIN1-truncating variants, used to measure AXIN1 protein level, polymerization and basal canonical Wnt activity, and to test a tankyrase inhibitor.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:37582359
Pathograph links
Enhanced Basal Canonical Wnt/Beta-Catenin Signaling recapitulates fidelity: unknown observes: cellular Endogenous truncating alleles reproduce the increased basal Wnt activity that the pathophysiology node describes.
Limitations: The quotable abstract does not name the primary or edited cell types; whether they are osteoblast-lineage cells, and so whether the readout reflects the skeletal compartment, is not recorded here.
Readouts
Basal canonical Wnt pathway activity
Direction: INCREASED
Interpretation: Ligand-independent pathway activity is raised in mutant cells.
Show evidence (1 reference)
PMID:37582359 SUPPORT In Vitro
"analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity"
The readout measured in the mutant cells.
Wnt activity after tankyrase inhibition
Direction: DECREASED
Interpretation: A tankyrase inhibitor attenuated the Wnt overactivity of the mutant cells; the abstract does not say whether it was normalized.
Show evidence (1 reference)
PMID:37582359 SUPPORT In Vitro
"Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems."
Pharmacological attenuation in the same systems.
Show evidence (1 reference)
PMID:37582359 SUPPORT In Vitro
"analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity"
The model carries the patient alleles and shows the node's defect.
🐁

Animal Models

1
Axin1 osteoblast-precursor conditional knockout mouse (Osx-Cre)
Axin1 deleted in Osterix-expressing osteoblast precursors. Osteoblast OPG and the OPG-to-RANKL ratio increase, osteoclast formation falls, hypertrophic cartilage expands and postnatal bone growth is delayed.
Species
Mouse
Genotype
Osx-Cre;Axin1 flox/flox
Publication
PMID:32821442
Pathograph links
Imbalanced Osteoblast-Osteoclast Coupling partially recapitulates fidelity: low observes: tissue Reproduces the osteoclast arm of the proposed coupling defect.
Limitations: Complete, cell-type-restricted deletion in mouse rather than the germline hypomorphic C-terminal truncation of the human disorder. The reported phenotype is delayed postnatal bone growth with expanded hypertrophic cartilage; osteosclerosis comparable to the human disease is not reported, and osteoblast number was unchanged, so the model does not address increased bone formation.
Readouts
Osteoblast OPG and OPG-to-RANKL ratio
Direction: INCREASED
Interpretation: Osteoblast-lineage signal that restrains osteoclastogenesis.
Show evidence (1 reference)
PMID:32821442 SUPPORT Model Organism
"OPG expression and the ratio of Opg to Rankl were significantly increased in osteoblasts of Axin1Osx KO mice."
Measured in osteoblasts of the knockout.
Show evidence (1 reference)
PMID:32821442 SUPPORT Model Organism
"Thus, the loss of Axin1 in osteoblast precursor cells caused increased OPG and the decrease in osteoclast formation"
The model's conclusion about the osteoclast arm.
{ }

Source YAML

click to show 
name: Craniometadiaphyseal Osteosclerosis with Hip Dysplasia
creation_date: "2026-09-25T13:56:18Z"
category: Mendelian
synonyms:
- CMDOH
description: >-
  Craniometadiaphyseal osteosclerosis with hip dysplasia is an autosomal
  recessive sclerosing skeletal dysplasia caused by homozygous
  C-terminally truncating variants in AXIN1, the scaffold of the
  beta-catenin destruction complex. The founding report described seven
  individuals from four families with macrocephaly, cranial hyperostosis and
  sclerosis of the vertebral endplates; hip dysplasia, heart malformations,
  variable developmental delay and hematological anomalies, including anemia
  and pancytopenia, were also frequent.

  The truncating alleles remove the C-terminal DIX domain through which AXIN1
  polymerizes. In primary and genome-edited cells carrying them, AXIN1
  protein levels were reduced, DIX-mediated polymerization was impaired and
  basal canonical Wnt/beta-catenin signalling was increased, yet the
  truncated proteins kept part of their Wnt-inhibitory activity when
  overexpressed, so the alleles are hypomorphic rather than null. A
  tankyrase inhibitor attenuated the Wnt overactivity in these cell systems.
  Patient bone biopsy showed increased osteoblast and reduced osteoclast
  function at the growth-plate resorption zone, and the authors proposed
  that AXIN1 coordinates osteoblast and osteoclast activity; in mice,
  deleting Axin1 in osteoblast precursors reduced osteoclast formation
  through increased osteoprotegerin. How the extraskeletal features arise is
  unknown.
disease_term:
  preferred_term: craniometadiaphyseal osteosclerosis with hip dysplasia
  term:
    id: MONDO:0957832
    label: craniometadiaphyseal osteosclerosis with hip dysplasia
parents:
- Sclerosing Bone Dysplasias
notes: >-
  OMIM 620558 (the MONDO:0957832 cross-reference); CMDOH is the OMIM
  abbreviation shown in MedGen. The clinical and cellular description rests
  on a single report of seven individuals from four families
  (PMID:37582359). Only its PubMed abstract is quotable here: the reference
  fetcher declines the full text (full_text_declined: publisher_free in the
  cache frontmatter). Specific findings from the full paper are cited only
  where OMIM's definition, reproduced on the MedGen page
  (url:https://www.ncbi.nlm.nih.gov/medgen/1844026/), states them in a
  sentence: anemia and pancytopenia, and the bone-biopsy result. Per-feature
  counts, variant nomenclature and the further features listed in OMIM's
  clinical synopsis (among them hypertelorism, depressed nasal bridge,
  frontal bossing, proptosis, atrial and ventricular septal defects, patent
  ductus arteriosus, flared metaphyses, sandwich-appearance vertebral bodies,
  thickened calvaria and choanal stenosis) are not curated as phenotypes,
  because no quotable sentence states them; no phenotype carries a frequency
  band for the same reason.

  Name collision: craniometadiaphyseal dysplasia, wormian bone type
  (MONDO:0010014, OMIM 269300) is a different recessive disorder with
  cortical thinning and absent metaphyseal modelling rather than
  osteosclerosis, attributed to biallelic WRAP53 variants (PMID:34484289).
  Literature and database records for one should not be attached to the
  other.

  Allelic and context boundaries: rare heterozygous AXIN1 variants have been
  reported in nonsyndromic craniosynostosis (PMID:38905707), and somatic
  AXIN1 mutations occur in hepatocellular carcinoma (PMID:41550750). Neither
  is part of this entry. Neither the founding abstract nor OMIM's
  definition mentions cancer in affected individuals.

  The disorder was described after the 2023 revision of the ISDS Nosology of
  Genetic Skeletal Disorders (PMID:36779427), so no ISDS group is assigned.
  No mechanism module in kb/modules covers Wnt-driven high bone mass, so no
  node declares conforms_to. No treatment is curated: no source reports
  management of affected individuals, and the tankyrase inhibitor result is
  a cell-culture finding (see discussions).

  No GeneReviews chapter exists for this disease (just check-genereviews
  --online, Bookshelf index snapshot 2026-09-10: NO_CHAPTER). The ClinGen
  gene-disease validity download (search.clinicalgenome.org, retrieved
  2026-09-25) has no AXIN1 row, and no Orphanet record for this disorder is
  present in references_cache.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All affected individuals in the founding report were homozygous for one of
    three C-terminally truncating AXIN1 variants, across four families.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified three homozygous, C-terminally truncating AXIN1 variants in
      seven individuals from four families
    explanation: >-
      Homozygous causal variants in affected individuals from four independent
      families support autosomal recessive inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Seven affected individuals from four families in the founding report.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified three homozygous, C-terminally truncating AXIN1 variants in
      seven individuals from four families
    explanation: Literature case count from the founding cohort.
pathophysiology:
- name: Biallelic C-Terminal AXIN1 Truncation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Homozygous truncating variants in AXIN1 that remove the C-terminal DIX
    domain. Three such variants were found in four families.
  gene:
    preferred_term: AXIN1
    term:
      id: hgnc:903
      label: AXIN1
  genetic_context:
    gene:
      preferred_term: AXIN1
      term:
        id: hgnc:903
        label: AXIN1
    allele_type: truncating
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      C-terminally truncating variants that delete the DIX domain. They are
      hypomorphic: the truncated proteins are less abundant and do not
      polymerize, but retain part of their Wnt-inhibitory function when
      overexpressed.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified three homozygous, C-terminally truncating AXIN1 variants in
      seven individuals from four families
    explanation: Identifies the causal lesion class.
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      partially retained Wnt-inhibitory function upon overexpression
    explanation: >-
      Residual inhibitory activity of the truncated proteins, the basis for
      classifying the alleles as partial loss of function.
  downstream:
  - target: Reduced AXIN1 Protein Abundance
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37582359
      reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        All three AXIN1-truncating variants resulted in reduced protein levels
      explanation: Each truncating allele lowers AXIN1 protein level in the cell systems tested.
  - target: Impaired DIX-Domain-Mediated AXIN1 Polymerization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37582359
      reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        impaired AXIN1 polymerization mediated by its C-terminal DIX domain
      explanation: The truncating alleles impair DIX-mediated polymerization.
- name: Reduced AXIN1 Protein Abundance
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The truncated AXIN1 proteins are present at lower levels than wild-type
    AXIN1 in primary and genome-edited cells. PROVISIONAL because the
    measurements are in cultured cells, not in bone.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All three AXIN1-truncating variants resulted in reduced protein levels
    explanation: Direct measurement of reduced AXIN1 protein.
  downstream:
  - target: Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Less AXIN1 scaffold is expected to mean less efficient destruction-complex
      activity and less beta-catenin degradation in the absence of Wnt ligand.
    evidence:
    - reference: PMID:37582359
      reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        In line with AXIN1 being a central component of the β-catenin
        destruction complex, analyses of primary and genome-edited cells
        harboring the truncating variants revealed enhanced basal canonical
        Wnt pathway activity.
      explanation: >-
        The authors interpret the Wnt overactivity through AXIN1's role in the
        destruction complex. INDIRECT because the abstract does not separate
        the contribution of reduced abundance from that of lost
        polymerization.
    - reference: PMID:9230313
      reference_title: The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, Axin is a novel inhibitor of Wnt signaling and regulates an early
        step in embryonic axis formation in mammals and amphibians.
      explanation: >-
        The founding genetic evidence in mouse and Xenopus that Axin restrains
        Wnt signalling, so that less Axin permits more signalling. INDIRECT
        because it concerns Axin loss in embryonic axis formation, not the
        human truncating alleles.
- name: Impaired DIX-Domain-Mediated AXIN1 Polymerization
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    AXIN1 polymerizes through its C-terminal DIX domain; the truncated
    proteins lacking it do not. PROVISIONAL because this was shown in cultured
    cells.
  biological_processes:
  - preferred_term: AXIN1 polymerization
    term:
      id: GO:0051258
      label: protein polymerization
    modifier: DECREASED
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      impaired AXIN1 polymerization mediated by its C-terminal DIX domain
    explanation: Direct observation of impaired polymerization.
  downstream:
  - target: Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37582359
      reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        In line with AXIN1 being a central component of the β-catenin
        destruction complex, analyses of primary and genome-edited cells
        harboring the truncating variants revealed enhanced basal canonical
        Wnt pathway activity.
      explanation: >-
        Same cell systems; the Wnt overactivity is attributed to impaired
        destruction-complex function, of which lost polymerization is one of
        the two measured defects.
- name: Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Primary cells from affected individuals and genome-edited cells carrying
    the truncating variants show increased canonical Wnt pathway activity in
    the absence of added ligand, attenuated by a tankyrase inhibitor. The
    modifier is INCREASED rather than GAIN_OF_FUNCTION: the truncated AXIN1
    still restrains the pathway in part, so the claim is quantitative.
    PROVISIONAL because it has not been measured in bone cells of patients.
  protein_complexes:
  - preferred_term: beta-catenin destruction complex
    term:
      id: GO:0030877
      label: beta-catenin destruction complex
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      analyses of primary and genome-edited cells harboring the truncating
      variants revealed enhanced basal canonical Wnt pathway activity
    explanation: Measured increase in basal canonical Wnt signalling.
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Addition of a tankyrase inhibitor attenuated Wnt overactivity in the
      AXIN1-mutant model systems.
    explanation: Pharmacological attenuation of the overactivity in the same systems.
  downstream:
  - target: Imbalanced Osteoblast-Osteoclast Coupling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - axin1_osteoblast_osteoclast_coupling
    description: >-
      Excess Wnt signalling in the skeleton is proposed to shift the balance
      between bone formation and resorption; the intermediate steps have not
      been shown in patients.
    evidence:
    - reference: PMID:37582359
      reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our data suggest that AXIN1 coordinates the action of osteoblasts and
        osteoclasts
      explanation: >-
        The authors' proposed link between the AXIN1 defect and bone
        remodelling. INDIRECT because it is their interpretation rather than a
        measured step.
- name: Imbalanced Osteoblast-Osteoclast Coupling
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Sclerosing skeletal dysplasias arise from an imbalance between bone
    formation and resorption. In this disorder, bone biopsy (as summarized by
    OMIM) showed increased osteoblast and reduced osteoclast function at the
    growth-plate resorption zone, and the authors proposed that AXIN1
    coordinates osteoblast and osteoclast activity. Mouse data support the
    osteoclast arm: deleting Axin1 in osteoblast precursors increased
    osteoblast osteoprotegerin (OPG) and the OPG-to-RANKL ratio and reduced
    osteoclast formation. PROVISIONAL because the human evidence is a biopsy
    finding known here only through a database summary, and the mouse model is
    a complete conditional deletion rather than the human hypomorphic allele.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: bone formation
    term:
      id: GO:0001503
      label: ossification
    modifier: INCREASED
  - preferred_term: osteoclast differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Sclerosing skeletal dysplasias result from an imbalance between bone
      formation and resorption.
    explanation: General premise for the node, stated as background in the founding report.
  - reference: url:https://www.ncbi.nlm.nih.gov/medgen/1844026/
    reference_title: "Craniometadiaphyseal osteosclerosis with hip dysplasia (Concept Id: C5882710) - MedGen - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Bone biopsy shows evidence of increased osteoblast and reduced osteoclast
      function at the growth plate resorption zone, resulting in coarse
      trabeculae (Terhal et al., 2023).
    explanation: >-
      OMIM's summary of the patient bone biopsy in the founding paper: both
      arms of the coupling are shifted toward bone accrual in human tissue.
  - reference: PMID:32821442
    reference_title: Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      OPG expression and the ratio of Opg to Rankl were significantly
      increased in osteoblasts of Axin1Osx KO mice.
    explanation: Osteoblast-lineage Axin1 loss changes the osteoblast signal to osteoclasts.
  - reference: PMID:32821442
    reference_title: Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, the loss of Axin1 in osteoblast precursor cells caused increased
      OPG and the decrease in osteoclast formation
    explanation: Reduced osteoclastogenesis downstream of osteoblast-lineage Axin1 loss.
  downstream:
  - target: Cranial Hyperostosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - axin1_osteoblast_osteoclast_coupling
  - target: Sclerotic Vertebral Endplates
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - axin1_osteoblast_osteoclast_coupling
mechanistic_hypotheses:
- hypothesis_group_id: axin1_osteoblast_osteoclast_coupling
  hypothesis_label: Hypomorphic AXIN1 shifts osteoblast-osteoclast coupling toward bone accrual
  status: EMERGING
  description: >-
    Reduced AXIN1 function raises canonical Wnt signalling in the skeleton,
    and this is proposed to act on osteoblasts and, through osteoblast-derived
    signals such as OPG, on osteoclast formation, so that net bone accrual
    produces the cranial and vertebral osteosclerosis. The human evidence is
    the cellular Wnt overactivity, the bone-biopsy finding of increased
    osteoblast and reduced osteoclast function (known here through OMIM's
    summary), and the authors' interpretation. The mechanistic link from
    osteoblast-lineage Axin1 loss to reduced osteoclastogenesis via OPG comes
    from a complete conditional knockout in mouse osteoblast precursors, a
    stronger loss of function than the human hypomorphic alleles.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that AXIN1 coordinates the action of osteoblasts and
      osteoclasts
    explanation: The authors' statement of the hypothesis.
  - reference: PMID:32821442
    reference_title: Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, the loss of Axin1 in osteoblast precursor cells caused increased
      OPG and the decrease in osteoclast formation
    explanation: Mouse evidence for the osteoclast arm.
phenotypes:
- name: Macrocephaly
  category: Skeletal
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      seven individuals from four families affected by macrocephaly, cranial
      hyperostosis, and vertebral endplate sclerosis
    explanation: Macrocephaly is one of the three cardinal features of the cohort.
- name: Cranial Hyperostosis
  category: Skeletal
  phenotype_term:
    preferred_term: Cranial hyperostosis
    term:
      id: HP:0004437
      label: Cranial hyperostosis
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      seven individuals from four families affected by macrocephaly, cranial
      hyperostosis, and vertebral endplate sclerosis
    explanation: Cranial hyperostosis is one of the three cardinal features.
- name: Sclerotic Vertebral Endplates
  category: Skeletal
  phenotype_term:
    preferred_term: Sclerotic vertebral endplates
    term:
      id: HP:0004576
      label: Sclerotic vertebral endplates
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      seven individuals from four families affected by macrocephaly, cranial
      hyperostosis, and vertebral endplate sclerosis
    explanation: Vertebral endplate sclerosis is one of the three cardinal features.
- name: Hip Dysplasia
  category: Skeletal
  phenotype_term:
    preferred_term: Hip dysplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent findings included hip dysplasia, heart malformations,
      variable developmental delay, and hematological anomalies.
    explanation: Hip dysplasia is a frequent feature and gives the disorder its name.
- name: Heart Malformations
  category: Cardiovascular
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  notes: >-
    The quotable abstract says "heart malformations" without naming a lesion,
    so the term carrying "Congenital heart defect" as an exact synonym is
    bound rather than a specific defect.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent findings included hip dysplasia, heart malformations,
      variable developmental delay, and hematological anomalies.
    explanation: Heart malformations are a frequent extraskeletal feature.
- name: Developmental Delay
  category: Neurological
  description: Variable in severity across the cohort.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent findings included hip dysplasia, heart malformations,
      variable developmental delay, and hematological anomalies.
    explanation: Variable developmental delay is a frequent feature.
- name: Anemia
  category: Hematologic
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent findings included hip dysplasia, heart malformations,
      variable developmental delay, and hematological anomalies.
    explanation: >-
      The founding report lists hematological anomalies among the frequent
      features without naming them in its abstract.
  - reference: url:https://www.ncbi.nlm.nih.gov/medgen/1844026/
    reference_title: "Craniometadiaphyseal osteosclerosis with hip dysplasia (Concept Id: C5882710) - MedGen - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      hematologic anomalies including anemia and pancytopenia
    explanation: >-
      The OMIM definition reproduced in MedGen, which summarizes the full
      founding paper, names anemia as one of the hematological anomalies.
- name: Pancytopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/medgen/1844026/
    reference_title: "Craniometadiaphyseal osteosclerosis with hip dysplasia (Concept Id: C5882710) - MedGen - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      hematologic anomalies including anemia and pancytopenia
    explanation: >-
      The OMIM definition reproduced in MedGen names pancytopenia among the
      hematological anomalies of the founding cohort.
histopathology:
- name: Increased osteoblast and reduced osteoclast function at the growth-plate resorption zone
  description: >-
    Patient bone biopsy in the founding report, as summarized by OMIM, showed
    increased osteoblast and reduced osteoclast function at the growth-plate
    resorption zone with coarse trabeculae. The per-patient histology is in
    the full paper, which is not quotable here.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/medgen/1844026/
    reference_title: "Craniometadiaphyseal osteosclerosis with hip dysplasia (Concept Id: C5882710) - MedGen - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Bone biopsy shows evidence of increased osteoblast and reduced osteoclast
      function at the growth plate resorption zone, resulting in coarse
      trabeculae (Terhal et al., 2023).
    explanation: OMIM's summary of the biopsy finding in the founding paper.
genetic:
- name: AXIN1
  gene_term:
    preferred_term: AXIN1
    term:
      id: hgnc:903
      label: AXIN1
  association: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Three distinct homozygous C-terminally truncating variants in four
    families, all disrupting the DIX domain. The alleles are hypomorphic:
    reduced protein, impaired DIX-mediated polymerization, partial retention
    of Wnt-inhibitory activity.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified three homozygous, C-terminally truncating AXIN1 variants in
      seven individuals from four families
    explanation: Gene discovery in four families.
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All three AXIN1-truncating variants resulted in reduced protein levels
      and impaired AXIN1 polymerization mediated by its C-terminal DIX domain
      but partially retained Wnt-inhibitory function upon overexpression.
    explanation: Functional characterization showing the alleles are hypomorphic.
experimental_models:
- name: AXIN1-truncation primary and genome-edited cells
  experimental_model_type: OTHER
  description: >-
    Primary cells from affected individuals and genome-edited cells carrying
    the AXIN1-truncating variants, used to measure AXIN1 protein level,
    polymerization and basal canonical Wnt activity, and to test a tankyrase
    inhibitor.
  publication: PMID:37582359
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  modeled_mechanisms:
  - target: Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: >-
      Endogenous truncating alleles reproduce the increased basal Wnt
      activity that the pathophysiology node describes.
    limitations: >-
      The quotable abstract does not name the primary or edited cell types;
      whether they are osteoblast-lineage cells, and so whether the readout
      reflects the skeletal compartment, is not recorded here.
    readouts:
    - name: Basal canonical Wnt pathway activity
      target: Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
      direction: INCREASED
      interpretation: Ligand-independent pathway activity is raised in mutant cells.
      evidence:
      - reference: PMID:37582359
        reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          analyses of primary and genome-edited cells harboring the truncating
          variants revealed enhanced basal canonical Wnt pathway activity
        explanation: The readout measured in the mutant cells.
    - name: Wnt activity after tankyrase inhibition
      target: Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
      direction: DECREASED
      interpretation: >-
        A tankyrase inhibitor attenuated the Wnt overactivity of the mutant
        cells; the abstract does not say whether it was normalized.
      evidence:
      - reference: PMID:37582359
        reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Addition of a tankyrase inhibitor attenuated Wnt overactivity in the
          AXIN1-mutant model systems.
        explanation: Pharmacological attenuation in the same systems.
    evidence:
    - reference: PMID:37582359
      reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        analyses of primary and genome-edited cells harboring the truncating
        variants revealed enhanced basal canonical Wnt pathway activity
      explanation: The model carries the patient alleles and shows the node's defect.
animal_models:
- name: Axin1 osteoblast-precursor conditional knockout mouse (Osx-Cre)
  species: Mouse
  genotype: Osx-Cre;Axin1 flox/flox
  publication: PMID:32821442
  description: >-
    Axin1 deleted in Osterix-expressing osteoblast precursors. Osteoblast OPG
    and the OPG-to-RANKL ratio increase, osteoclast formation falls,
    hypertrophic cartilage expands and postnatal bone growth is delayed.
  modeled_mechanisms:
  - target: Imbalanced Osteoblast-Osteoclast Coupling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Reproduces the osteoclast arm of the proposed coupling defect.
    limitations: >-
      Complete, cell-type-restricted deletion in mouse rather than the
      germline hypomorphic C-terminal truncation of the human disorder. The
      reported phenotype is delayed postnatal bone growth with expanded
      hypertrophic cartilage; osteosclerosis comparable to the human disease
      is not reported, and osteoblast number was unchanged, so the model does
      not address increased bone formation.
    readouts:
    - name: Osteoblast OPG and OPG-to-RANKL ratio
      target: Imbalanced Osteoblast-Osteoclast Coupling
      direction: INCREASED
      interpretation: Osteoblast-lineage signal that restrains osteoclastogenesis.
      evidence:
      - reference: PMID:32821442
        reference_title: Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          OPG expression and the ratio of Opg to Rankl were significantly
          increased in osteoblasts of Axin1Osx KO mice.
        explanation: Measured in osteoblasts of the knockout.
    evidence:
    - reference: PMID:32821442
      reference_title: Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, the loss of Axin1 in osteoblast precursor cells caused increased
        OPG and the decrease in osteoclast formation
      explanation: The model's conclusion about the osteoclast arm.
diagnosis:
- name: Skeletal radiography
  description: >-
    The defining features are radiographic: cranial hyperostosis with
    macrocephaly, sclerosis of the vertebral endplates, and hip dysplasia on
    pelvic imaging.
  diagnosis_term:
    preferred_term: skeletal survey
    term:
      id: NCIT:C38092
      label: Skeletal Survey X-Ray
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      seven individuals from four families affected by macrocephaly, cranial
      hyperostosis, and vertebral endplate sclerosis
    explanation: >-
      Two of the three cardinal features are radiographic findings. INDIRECT
      because the source reports the features, not a diagnostic protocol.
- name: AXIN1 molecular genetic testing
  description: >-
    Confirmation is by finding biallelic C-terminally truncating AXIN1
    variants. No diagnostic criteria or testing guideline for this disorder
    has been published.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified three homozygous, C-terminally truncating AXIN1 variants in
      seven individuals from four families
    explanation: >-
      Defines the molecular finding that establishes the diagnosis. INDIRECT
      because the source is a gene-discovery report rather than a testing
      recommendation.
differential_diagnoses:
- name: Craniometadiaphyseal dysplasia, wormian bone type
  description: >-
    Near-homonymous recessive craniotubular disorder attributed to biallelic
    WRAP53 variants, with cortical thinning and absent metaphyseal flaring and
    diaphyseal constriction rather than osteosclerosis.
  disease_term:
    preferred_term: craniometadiaphyseal dysplasia, wormian bone type
    term:
      id: MONDO:0010014
      label: craniometadiaphyseal dysplasia, wormian bone type
  evidence:
  - reference: PMID:34484289
    reference_title: Diaphyseal and Metaphyseal Modeling Defects-Clinical Findings and Identification of WRAP53 Deficiency in Craniometadiaphyseal Dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study showed that craniometadiaphyseal dysplasia was caused by a
      deficiency of WRAP53 with autosomal recessive inheritance.
    explanation: Different gene for the similarly named disorder.
- name: Sclerosteosis
  description: >-
    Recessive SOST-related sclerosing bone dysplasia with progressive cranial
    hyperostosis caused by loss of the Wnt antagonist sclerostin, with
    syndactyly and tall stature. Distinguished by gene testing.
  disease_term:
    preferred_term: sclerosteosis
    term:
      id: MONDO:0017838
      label: sclerosteosis
- name: Van Buchem disease
  description: >-
    Recessive endosteal hyperostosis from a deletion of a SOST regulatory
    region, with progressive skull and mandibular thickening and cranial
    nerve entrapment but without syndactyly; distinguished by gene testing.
  disease_term:
    preferred_term: van Buchem disease
    term:
      id: MONDO:0009395
      label: hyperostosis corticalis generalisata
- name: Craniometaphyseal dysplasia
  description: >-
    Craniotubular dysplasia with cranial hyperostosis and metaphyseal flaring;
    distinguished by gene testing.
  disease_term:
    preferred_term: craniometaphyseal dysplasia
    term:
      id: MONDO:0015465
      label: craniometaphyseal dysplasia
- name: LRP5-related high bone mass
  description: >-
    Autosomal dominant generalized osteosclerosis from LRP5 gain-of-function
    variants, another increased-Wnt high bone mass disorder.
  disease_term:
    preferred_term: autosomal dominant osteopetrosis 1
    term:
      id: MONDO:0011877
      label: autosomal dominant osteopetrosis 1
- name: Camurati-Engelmann disease
  description: >-
    Autosomal dominant diaphyseal dysplasia with cortical thickening from
    TGFB1 variants.
  disease_term:
    preferred_term: Camurati-Engelmann disease
    term:
      id: MONDO:0007542
      label: Camurati-Engelmann disease
- name: Osteopetrosis
  description: >-
    Generalized increased bone density from defective osteoclast resorption,
    which, like this disorder, can be accompanied by hematological
    anomalies. OMIM lists the recessive and dominant osteopetroses as
    overlapping syndromes.
  disease_term:
    preferred_term: osteopetrosis
    term:
      id: MONDO:0017198
      label: osteopetrosis
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/medgen/1844026/
    reference_title: "Craniometadiaphyseal osteosclerosis with hip dysplasia (Concept Id: C5882710) - MedGen - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      For syndromes with overlapping features, see osteopetrosis, autosomal
      recessive (OPTB1; 259700) and dominant (OPTA1; 607634), and osteopathia
      with cranial sclerosis (OSCS; 300373).
    explanation: OMIM names the osteopetroses as overlapping syndromes.
- name: Osteopathia striata with cranial sclerosis
  description: >-
    X-linked AMER1-related sclerosing dysplasia with cranial sclerosis and
    macrocephaly, named by OMIM as an overlapping syndrome; distinguished by
    inheritance, metaphyseal striations and gene testing.
  disease_term:
    preferred_term: osteopathia striata with cranial sclerosis
    term:
      id: MONDO:0010310
      label: osteopathia striata with cranial sclerosis
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/medgen/1844026/
    reference_title: "Craniometadiaphyseal osteosclerosis with hip dysplasia (Concept Id: C5882710) - MedGen - NCBI"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      For syndromes with overlapping features, see osteopetrosis, autosomal
      recessive (OPTB1; 259700) and dominant (OPTA1; 607634), and osteopathia
      with cranial sclerosis (OSCS; 300373).
    explanation: OMIM names osteopathia striata with cranial sclerosis as an overlapping syndrome.
- name: Craniotubular dysplasia, Ikegawa type
  description: >-
    Recessive TMEM53-related sclerosing bone dysplasia with skull
    hyperostosis and increased bone density, driven by excess BMP-SMAD rather
    than Wnt signalling; distinguished by gene testing.
  disease_term:
    preferred_term: craniotubular dysplasia, Ikegawa type
    term:
      id: MONDO:0859226
      label: craniotubular dysplasia, Ikegawa type
  evidence:
  - reference: PMID:41408477
    reference_title: TMEM53 as an outer nuclear membrane regulator of cranial and tubular bone formation in craniotubular dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Pathogenic variants in TMEM53 have been identified as the genetic cause
      of craniotubular dysplasia, Ikegawa type (CTDI), a rare form of
      sclerosing bone dysplasia characterized by skull hyperostosis, cranial
      deformities, and increased bone density.
    explanation: The overlapping cranial hyperostosis phenotype and the different gene.
discussions:
- discussion_id: cmdoh_extraskeletal_mechanism_gap
  prompt: >-
    How does hypomorphic AXIN1 produce hip dysplasia, heart malformations,
    developmental delay and the hematological anomalies?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Hip Dysplasia
  - phenotypes#Heart Malformations
  - phenotypes#Developmental Delay
  - phenotypes#Anemia
  - phenotypes#Pancytopenia
  - phenotypes#Macrocephaly
  rationale: >-
    The founding report establishes excess canonical Wnt signalling in patient
    and edited cells, but the quotable sources do not connect it to any of the
    extraskeletal features, nor say whether macrocephaly reflects skull
    thickening alone. These phenotypes are therefore left without an upstream
    mechanism node. In particular, whether the anemia and pancytopenia
    reflect encroachment of sclerotic bone on the marrow space or a direct
    effect of AXIN1 loss on hematopoiesis has not been examined.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent findings included hip dysplasia, heart malformations,
      variable developmental delay, and hematological anomalies.
    explanation: The extraskeletal features whose mechanism is open.
- discussion_id: cmdoh_tankyrase_inhibitor_translation
  prompt: >-
    Would a tankyrase inhibitor reduce bone accrual in vivo in a model
    carrying a patient-equivalent Axin1 C-terminal truncation, at a dose that
    does not impair normal bone formation?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Enhanced Basal Canonical Wnt/Beta-Catenin Signaling
  - experimental_models#AXIN1-truncation primary and genome-edited cells
  rationale: >-
    Tankyrase inhibition attenuated the Wnt overactivity only in cultured
    cells, and the authors proposed it as a way to counter hypomorphic AXIN1.
    No animal model carrying a patient-equivalent allele exists; the only
    skeletal Axin1 model is a complete conditional deletion in osteoblast
    precursors, whose phenotype (delayed postnatal bone growth) differs from
    the human osteosclerosis. Stabilizing AXIN1 in normal bone is not
    neutral: mice lacking the ubiquitin ligase RNF146, which normally keeps
    AXIN1 levels low, in the osteoblast lineage accumulate AXIN1 and become
    severely osteopenic.
  evidence:
  - reference: PMID:37582359
    reference_title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic
      variants
    explanation: The authors' therapeutic proposal, based on cell data.
  - reference: PMID:28581440
    reference_title: Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of RNF146 stabilized its substrate AXIN1, leading to impairment of
      WNT3a-induced β-catenin activation and reduced Fgf18 expression in
      osteoblasts.
    explanation: AXIN1 stabilization blunts Wnt signalling in osteoblasts.
  - reference: PMID:28581440
    reference_title: Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice with loss of RNF146 within the osteoblast lineage had increased fat
      stores and were glucose intolerant with severe osteopenia because of
      defective osteoblastogenesis
    explanation: Excess AXIN1 in normal osteoblasts causes bone loss, a safety consideration.
references:
- reference: PMID:37582359
  title: AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
- reference: PMID:32821442
  title: Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation.
- reference: PMID:34484289
  title: Diaphyseal and Metaphyseal Modeling Defects-Clinical Findings and Identification of WRAP53 Deficiency in Craniometadiaphyseal Dysplasia.
- reference: PMID:9230313
  title: The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation.
- reference: PMID:28581440
  title: Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism.
- reference: PMID:41408477
  title: TMEM53 as an outer nuclear membrane regulator of cranial and tubular bone formation in craniotubular dysplasia.
- reference: url:https://www.ncbi.nlm.nih.gov/medgen/1844026/
  title: "Craniometadiaphyseal osteosclerosis with hip dysplasia (Concept Id: C5882710) - MedGen - NCBI"
📚

References & Deep Research

References

7
PMID:37582359
AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
No top-level findings curated for this source.
PMID:32821442
Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation.
No top-level findings curated for this source.
PMID:34484289
Diaphyseal and Metaphyseal Modeling Defects-Clinical Findings and Identification of WRAP53 Deficiency in Craniometadiaphyseal Dysplasia.
No top-level findings curated for this source.
PMID:9230313
The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation.
No top-level findings curated for this source.
PMID:28581440
Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism.
No top-level findings curated for this source.
PMID:41408477
TMEM53 as an outer nuclear membrane regulator of cranial and tubular bone formation in craniotubular dysplasia.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/medgen/1844026/
Craniometadiaphyseal osteosclerosis with hip dysplasia (Concept Id: C5882710) - MedGen - NCBI
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Craniometadiaphyseal Osteosclerosis with Hip Dysplasia · 2026-09-25T14:23:47Z · View source

New entry for the AXIN1-related recessive sclerosing bone dysplasia (MONDO:0957832, OMIM 620558), expanded from the queue skeleton; the stub was deleted. Sources. The disorder is known from one report of seven individuals in four families (Terhal et al. 2023, PMID:37582359). The reference fetcher declines that paper's full text (publisher-free licence), so only its abstract is quoted. Anemia, pancytopenia, the bone-biopsy finding and the overlapping syndromes are cited from the OMIM definition as reproduced on the MedGen page for the disorder, cached as url:https://www.ncbi.nlm.nih.gov/medgen/1844026/ and graded OTHER / REVIEW_SYNTHESIS. Further features that appear only in OMIM's clinical synopsis list (for example hypertelorism, septal defects, sandwich vertebrae) are named in notes but not curated as phenotypes, because no quotable sentence states them. Deep research. The OpenScientist report (research/Craniometadiaphyseal_Osteosclerosis_With_Hip_Dysplasia-deep-research-openscientist.md) was read in full. Its 12 references all resolved; its term-validation mismatches are all frequency-column text parsed as labels, not wrong CURIEs. just preflight-dr against MONDO:0957832 returned PASS (AXIN1 named 61 times). Used from it: PMID:37582359, PMID:9230313 (Axin as a Wnt inhibitor) and PMID:41408477 (TMEM53 craniotubular dysplasia, as a differential). Not used: the hepatocellular carcinoma papers (PMID:42237887, PMID:39653061, PMID:40344393), because somatic AXIN1 loss in cancer is outside this entry; PMID:33824347 and PMID:39084544, because the TMEM53 review abstract (PMID:41408477) states the differential more directly; PMID:18981475 and PMID:26763102, which are general osteoblast Wnt biology. The report's specific variant names, macrocephaly SD range, age range and XAV939 doses come from the full paper and could not be checked against a quotable source, so they were not carried over. Curation choices. The chain runs from biallelic C-terminal truncation to reduced AXIN1 protein and impaired DIX-domain polymerization, then to increased basal canonical Wnt signalling (INCREASED rather than GAIN_OF_FUNCTION, since the truncated protein keeps partial inhibitory activity), then to an osteoblast-osteoclast coupling node that reaches the two sclerotic phenotypes. The coupling node is PROVISIONAL and grouped under an EMERGING hypothesis because the human evidence is a biopsy summary and the mouse model (Osx-Cre Axin1 deletion, PMID:32821442) is a complete conditional knockout whose phenotype is delayed bone growth rather than osteosclerosis. Hip dysplasia, heart malformations, developmental delay, macrocephaly and the hematological findings have no sourced upstream node and are recorded in a knowledge-gap discussion. No treatment is curated because no source reports management of patients; the tankyrase-inhibitor result is recorded as an experimental-model readout and a discussion, with the RNF146 mouse (PMID:28581440) as a caution that stabilizing AXIN1 in normal osteoblasts causes osteopenia. Checks. just check-genereviews --online: NO_CHAPTER. The ClinGen gene-validity download has no AXIN1 row. just validate, validate-terms and count-verified-snippets pass on the entry; just validate-disorders was run on the file before hand-off.

OpenScientist ▸
Craniometadiaphyseal Osteosclerosis with Hip Dysplasia (CMDOH): A Comprehensive Disease Characterization
openscientist-autonomous 8 citations 2026-09-25T14:12:32.606190

Craniometadiaphyseal Osteosclerosis with Hip Dysplasia (CMDOH): A Comprehensive Disease Characterization

Disease: Craniometadiaphyseal Osteosclerosis with Hip Dysplasia (CMDOH) MONDO ID: MONDO:0957832 · OMIM: #620558 · Gene: AXIN1 (OMIM 603816; HGNC:903; chr16p13.3) Category:* Mendelian (autosomal recessive)

Summary

Craniometadiaphyseal osteosclerosis with hip dysplasia (CMDOH) is an ultra-rare, autosomal recessive sclerosing skeletal dysplasia caused by biallelic (homozygous, in the reported consanguineous families) C-terminally truncating variants in AXIN1. AXIN1 is the scaffold protein of the β-catenin destruction complex, the negative regulator of canonical Wnt signaling. The disease-causing variants truncate the C-terminal DIX domain, which mediates AXIN1 self-polymerization, thereby lowering AXIN1 protein levels and impairing destruction-complex assembly. The net functional consequence is enhanced basal canonical Wnt/β-catenin signaling — a "Wnt-gain" state — that shifts the balance of bone remodeling toward increased osteoblastic bone formation and reduced osteoclastic resorption, producing generalized osteosclerosis and hyperostosis.

The condition was defined in 2023 by Terhal et al. (PMID: 37582359), who described seven individuals from four families carrying three distinct homozygous truncating AXIN1 variants. The core phenotype comprises congenital/progressive macrocephaly, cranial hyperostosis (calvarial and skull-base sclerosis), and vertebral endplate sclerosis ("sandwich vertebrae"), together with frequent hip dysplasia, heart malformations, variable developmental delay, hematological anomalies, metaphyseal flaring, and dysmorphic facies. Bone biopsy demonstrated increased osteoblast activity and reduced osteoclast function at the growth-plate resorption zone, consistent with the Wnt-gain mechanism.

Mechanistically, CMDOH sits at the "hypomorphic" end of an AXIN1 dysfunction spectrum: germline biallelic DIX-domain truncations are partial loss-of-function (protein is reduced and polymerization is impaired but some Wnt-inhibitory function is retained), yielding a viable skeletal phenotype, whereas complete somatic loss of AXIN1 drives cancer (notably hepatocellular carcinoma) through full canonical Wnt activation. Crucially, the same study showed that a tankyrase inhibitor (XAV939) — which stabilizes AXIN1/AXIN2 — attenuates the Wnt overactivity in patient-derived and genome-edited cells, nominating a mechanistically rational (though not yet clinically tested) targeted therapy. Mouse Axin1 models corroborate the β-catenin–dependent, osteoblast-lineage mechanism. No disease-specific therapy currently exists; management is supportive and multidisciplinary.

Section 1 — Disease Information

Overview. CMDOH is a rare Mendelian sclerosing bone dysplasia combining features of two classic radiographic categories: osteopetrosis-like changes (sandwich vertebrae, metaphyseal flaring) and endosteal-hyperostosis-like changes (calvarial and cortical thickening). It is characterized by macrocephaly, cranial hyperostosis, vertebral endplate sclerosis, hip dysplasia, and additional extraskeletal involvement (cardiac, developmental, hematological). "Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption" (PMID: 37582359) — CMDOH exemplifies this, with the imbalance tilted toward net bone accrual.

Key identifiers.

Resource Identifier
MONDO MONDO:0957832
OMIM (phenotype) #620558 (Craniometadiaphyseal osteosclerosis with hip dysplasia)
Gene AXIN1, OMIM *603816, HGNC:903, chromosome 16p13.3
Orphanet No dedicated ORPHA code clearly assigned at time of investigation (ultra-rare, delineated 2023)
ICD-10 / ICD-11 No specific code; maps under sclerosing/osteosclerotic bone dysplasia (e.g., ICD-10 Q78.-, "Other osteochondrodysplasias")
MeSH No specific descriptor; related: "Osteosclerosis", "Osteochondrodysplasias"

Synonyms / alternative names. Craniometadiaphyseal osteosclerosis with hip dysplasia; CMDOH; AXIN1-related sclerosing skeletal dysplasia. The name captures the anatomic distribution (cranio- = skull; meta-/diaphyseal = metaphysis/diaphysis of long bones) plus the associated hip dysplasia.

Information source. Knowledge is derived from an aggregated case series — deep clinical, radiographic, and functional characterization of individual patients (7 individuals / 4 families) reported in a single landmark paper, plus mechanistic corroboration from cellular models and model organisms. It is not derived from large EHR/registry datasets, reflecting the disorder's extreme rarity.

Section 2 — Etiology

Primary cause (genetic). CMDOH is a monogenic autosomal recessive disorder caused by biallelic C-terminally truncating variants in AXIN1. In the reported families, affected individuals were homozygous, consistent with parental consanguinity. There is no known environmental, infectious, or acquired cause.

Genetic risk factors. The disease is fully genetically determined by the AXIN1 genotype. Consanguinity is the principal contextual risk factor, increasing the probability of homozygosity for a rare recessive allele. No modifier loci have been formally mapped; the paralog AXIN2 is a plausible biological modifier because it can partially compensate for AXIN1 (see Mechanism).

Environmental risk factors. None identified. Sex does not appear to influence occurrence (recessive Mendelian trait). Family history / consanguinity is the relevant contextual factor.

Protective factors. No genetic or environmental protective factors are established. Biologically, retained partial AXIN1 function and AXIN2 compensation are inferred to make the phenotype viable (compared with the lethality of complete Axin1 loss in mice), but this is a feature of the hypomorphic allele class rather than a modifiable protective factor.

Gene–environment interactions. None demonstrated. The disorder is essentially environment-independent.

Section 3 — Phenotypes

The phenotype spectrum below is drawn from the 7 patients / 4 families in Terhal et al. 2023 (PMID: 37582359). Frequencies are qualitative given the tiny cohort.

Phenotype Type Onset Severity / progression Frequency Suggested HPO term
Macrocephaly (+2.2 to +6.1 SD) Physical/clinical sign Congenital, progressive Moderate–severe, progressive Core / very frequent HP:0000256
Cranial hyperostosis (calvarial + skull-base sclerosis) Imaging/clinical sign From first year, progressive Progressive Core / very frequent HP:0004437
Vertebral endplate sclerosis ("sandwich vertebrae") Imaging sign Childhood Progressive Core / frequent HP:0004618
Metaphyseal flaring / widening Imaging sign Childhood Progressive Frequent HP:0003015
Hip dysplasia Clinical/imaging sign Congenital/childhood Variable Frequent HP:0001385
Heart malformations Structural anomaly Congenital Variable Frequent HP:0001627
Developmental delay Neurobehavioral Childhood Variable/mild-moderate Variable HP:0001263
Hematological anomalies Laboratory abnormality Variable Variable Frequent HP:0001871
Hypertelorism Dysmorphic sign Congenital Stable Frequent HP:0000316
Depressed/low nasal bridge Dysmorphic sign Congenital Stable Frequent HP:0005280
Short stature (subset) Growth Childhood Variable Subset HP:0004322

Onset and severity. Reported ages span 3 months to 15.5 years. Macrocephaly is congenital and progressive; cranial hyperostosis emerges and progresses from the first year of life. Severity is variable across families.

Quality-of-life impact. No formal QoL instruments (EQ-5D, SF-36, PROMIS) have been applied. Anticipated impacts, by analogy with other cranial hyperostoses, include potential cranial-nerve compression (from skull-base sclerosis), orthopedic morbidity from hip dysplasia (pain, mobility limitation), and developmental/educational impact where developmental delay is present. These are inferred rather than measured.

Section 4 — Genetic / Molecular Information

Causal gene. AXIN1 (axis inhibitor 1) — OMIM 603816, HGNC:903, chromosome 16p13.3*. AXIN1 is the central scaffold of the β-catenin destruction complex (with APC, GSK3β, CK1), which phosphorylates β-catenin to target it for degradation.

Pathogenic variants (Terhal et al. 2023). Three distinct C-terminal truncating variants across four families:

Family Variant Type Consequence
Family 1 (two sisters) 1-bp duplication (frameshift, e.g., p.Asp796Glufs*6-type) Frameshift Premature truncation, DIX domain lost
Families 2 & 4 p.Arg723* (R723X) — recurrent nonsense Nonsense Truncation removing DIX domain
Family 3 p.Arg805* (R805X) Nonsense C-terminal truncation, DIX domain disrupted

All variants disrupt the C-terminal DIX domain, which mediates AXIN1 homo-polymerization and destruction-complex assembly.

Variant classification. Per ACMG/AMP criteria these are pathogenic (loss-of-function truncating variants in a gene with an established gene–disease relationship, segregating with disease in multiple consanguineous families, supported by functional evidence).

Allele frequency. These are private/ultra-rare variants; not present at appreciable frequency in gnomAD. The recurrent p.Arg723* appearing in two families likely reflects an arginine CpG mutational hotspot rather than a broad founder effect.

Somatic vs germline. In CMDOH the variants are germline. By contrast, AXIN1 is recurrently altered somatically in cancer (see F003).

Functional consequence. Hypomorphic loss of function. The truncations reduce AXIN1 protein levels and impair DIX-domain–mediated polymerization, but overexpression studies showed partially retained Wnt-inhibitory function — explaining why the phenotype is a viable skeletal dysplasia rather than the embryonic lethality seen with complete Axin1 loss. Net pathway effect: enhanced basal canonical Wnt/β-catenin signaling (gain of Wnt output via loss of a negative regulator).

Modifier genes. AXIN2 (the paralog) is the strongest candidate modifier: XAV939 rescue of AXIN1-knockout cells implicates AXIN2 stabilization as a compensatory route (see F006).

Epigenetic / chromosomal. No disease-specific epigenetic signature or large-scale chromosomal abnormality has been reported for CMDOH.

Section 5 — Environmental Information

No environmental, lifestyle, or infectious contributors are implicated. CMDOH is a purely genetic, autosomal recessive Mendelian disorder. Not applicable: toxins/radiation/pollution; smoking/diet/exercise/alcohol; infectious agents.

Section 6 — Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

  1. Biallelic C-terminal truncating variant in AXIN1 (e.g., p.Arg723, p.Arg805, or a frameshift) → removes/disrupts the DIX domain.
  2. Loss of the DIX domain impairs AXIN1 self-polymerization and lowers AXIN1 protein levels → results in a weakened, less abundant scaffold.
  3. Reduced functional AXIN1 → destabilizes the β-catenin destruction complex (AXIN1–APC–GSK3β–CK1) → leads to reduced phosphorylation/degradation of β-catenin.
  4. → Cytoplasmic β-catenin accumulates and translocates to the nucleus → results in enhanced basal canonical Wnt/β-catenin transcriptional output (demonstrated directly in patient and genome-edited cells).
  5. In the osteoblast lineage, elevated β-catenin → increases OPG (osteoprotegerin) and the OPG:RANKL ratio (inferred from mouse Axin1^Osx^ model) → leads to suppressed osteoclastogenesis (fewer TRAP+/MMP9+/cathepsin-K+ osteoclasts).
  6. Branch A — increased osteoblastic bone formation; Branch B — decreased osteoclastic bone resorption. Both branches converge to → net increase in bone mass / osteosclerosis and hyperostosis.
  7. Anatomically distributed → cranial hyperostosis + macrocephaly, vertebral endplate ("sandwich") sclerosis, metaphyseal flaring; with associated developmental effects producing hip dysplasia, cardiac malformation, developmental delay, hematological anomalies (the extraskeletal links are consistent with the broad developmental role of Wnt signaling but are inferred, not individually demonstrated).
  8. Therapeutic branch: Tankyrase inhibition (XAV939) raises AXIN1/AXIN2 levels → restores destruction-complex activity → attenuates Wnt overactivity in mutant cells (in vitro proof of concept).

Steps 1–4 and step 8 are experimentally demonstrated in the human/cell system; step 5 is inferred from mouse osteoblast-lineage models; step 7's extraskeletal links are inferred from Wnt biology.

Detail by category

  • Molecular pathway: Canonical Wnt/β-catenin signaling (KEGG hsa04310; Reactome "Degradation of beta-catenin by the destruction complex," R-HSA-195253). AXIN1 is the rate-limiting scaffold of the destruction complex.
  • Cellular processes: Osteoblast differentiation/activity (increased); osteoclastogenesis (suppressed via OPG/RANKL). GO:0060070 (canonical Wnt signaling pathway), GO:0001649 (osteoblast differentiation), GO:0030316 (osteoclast differentiation), GO:0045597/0045668 (regulation of osteoblast/osteoclast differentiation).
  • Protein dysfunction: DIX-domain truncation → loss of polymerization, reduced protein stability → hypomorphic LOF of the destruction-complex scaffold.
  • Biochemical abnormality: Failure to phosphorylate/degrade β-catenin; downstream Wnt target activation (e.g., c-Myc, CCND1 seen in AXIN1-loss cancer models, supporting pathway direction).
  • Tissue remodeling mechanism: Dysregulated bone remodeling with osteoblast–osteoclast imbalance at the growth-plate resorption zone; coarse trabeculae on biopsy.
  • Cell types (CL): osteoblast (CL:0000062), osteoclast (CL:0000092), osteoprogenitor/mesenchymal stromal cell (CL:0000134), osteocyte (CL:0000137).

Molecular profiling

  • Direct functional readouts (Wnt reporter activity) in patient-derived and CRISPR-edited cells: enhanced basal canonical Wnt activity (PMID: 37582359).
  • Mouse osteoblast-lineage models: increased β-catenin, increased OPG:RANKL, decreased osteoclast markers.
  • No dedicated patient transcriptomic/proteomic/metabolomic/single-cell datasets are available for CMDOH.

Section 7 — Anatomical Structures Affected

Organ / system level (primary). Skeletal system — with a distinctive craniospinal and metadiaphyseal distribution: - Skull / calvarium & skull base (UBERON:0000209 cranial skeletal system; UBERON:0004339 calvaria) — hyperostosis, macrocephaly. - Vertebral column (UBERON:0001130) — endplate sclerosis ("sandwich vertebrae"). - Long bones — metaphysis/diaphysis (UBERON:0002515 metaphysis; UBERON:0004770 diaphysis) — flaring, sclerosis. - Hip joint / pelvis (UBERON:0001464 hip; UBERON:0001474 bone of the pelvis) — hip dysplasia.

Secondary organ involvement. Cardiovascular (heart malformations, UBERON:0000948); hematopoietic system (hematological anomalies, UBERON:0002390); central nervous system (developmental delay; potential cranial-nerve compromise from skull-base sclerosis).

Tissue / cell level. Bone (connective) tissue; growth-plate cartilage/resorption zone. Cell populations: osteoblasts (increased activity), osteoclasts (reduced number/function), osteoprogenitors.

Subcellular level. β-catenin destruction complex is cytoplasmic; downstream signaling acts in the nucleus (β-catenin/TCF transcription). GO cellular components: GO:0030877 (beta-catenin destruction complex), GO:0005737 (cytoplasm), GO:0005634 (nucleus).

Localization / lateralization. Skeletal involvement is generalized and bilateral/symmetric (calvarium, spine, long bones); hip dysplasia may be uni- or bilateral.

Section 8 — Temporal Development

  • Onset: Congenital (macrocephaly present at/near birth); cranial hyperostosis develops and progresses from the first year of life. Onset pattern is chronic and insidious/progressive.
  • Progression: Radiographic sclerosis is progressive through childhood (cases documented from 3 months to 15.5 years). Progression rate appears slow-to-moderate and variable between families.
  • Disease course: Chronic, lifelong. No episodic or relapsing-remitting pattern.
  • Remission: None spontaneous; no treatment-induced remission described (no disease-modifying therapy in clinical use).
  • Critical periods: The first years of life (active bone modeling) represent the window in which hyperostosis emerges — mechanistically the most rational period for any future targeted (Wnt-normalizing) intervention.

Section 9 — Inheritance and Population

  • Epidemiology: Ultra-rare. Prevalence/incidence are unknown and unquantified; total literature comprises 7 individuals from 4 families. No registry-based estimate exists.
  • Inheritance: Autosomal recessive. Affected individuals were homozygous; parents are obligate heterozygous carriers.
  • Penetrance: Appears complete in biallelic individuals (all reported homozygotes affected), though the sample is too small for precise estimation.
  • Expressivity: Variable — e.g., variable developmental delay, cardiac involvement, and stature across families/individuals.
  • Genetic anticipation: Not applicable (not a repeat-expansion disorder).
  • Germline mosaicism: Not reported.
  • Founder effect: No broad founder effect established; the recurrent p.Arg723* likely reflects a CpG mutational hotspot rather than a shared haplotype.
  • Consanguinity: Central — homozygosity arose in consanguineous families.
  • Carrier frequency: Unknown; expected to be very low given ultra-rarity.
  • Population demographics: Reported families are consistent with consanguineous backgrounds; no established sex bias (recessive). Distribution is sporadic, not endemic.

Section 10 — Diagnostics

Imaging (cornerstone of diagnosis). Skeletal survey / radiographs demonstrating: - Calvarial and skull-base hyperostosis/sclerosis; macrocephaly. - Vertebral endplate sclerosis ("sandwich vertebrae"). - Metaphyseal flaring and long-bone sclerosis. - Hip dysplasia on pelvic imaging. CT is useful to characterize skull-base sclerosis and potential foraminal narrowing.

Laboratory / biomarkers. No specific diagnostic biomarker. Bone turnover markers are not established as diagnostic. Hematological anomalies warrant a CBC and hematologic workup. Bone biopsy (research setting) showed increased osteoblast and reduced osteoclast function with coarse trabeculae.

Genetic testing (confirmatory). The diagnosis is molecularly confirmed by identifying biallelic C-terminal truncating AXIN1 variants. - WES/WGS is the practical first-line approach given phenotypic overlap among sclerosing dysplasias. - Targeted AXIN1 sequencing or inclusion in a sclerosing bone dysplasia / skeletal dysplasia gene panel is appropriate once suspected. - CMA/karyotype/FISH/mtDNA/repeat testing are not indicated (single-gene, SNV/indel etiology).

Clinical criteria & differential diagnosis. No formal consensus criteria exist (recently delineated). Key differentials among sclerosing/craniotubular dysplasias:

Condition Gene Pathway Distinguishing features
CMDOH AXIN1 (recessive, DIX truncation) Wnt gain Sandwich vertebrae + metaphyseal flaring + hip dysplasia + macrocephaly
Craniotubular dysplasia, Ikegawa type (CTDI, OMIM #619727) TMEM53 BMP-SMAD dysregulation Skull hyperostosis, childhood blindness (PMID: 33824347, PMID: 39084544, PMID: 41408477)
Sclerosteosis / Van Buchem SOST / SOST enhancer Wnt (loss of inhibitor) High bone mass, syndactyly (sclerosteosis)
Osteopetrosis CLCN7, TCIRG1, etc. Osteoclast defect Fractures, marrow failure, cranial nerve palsies
Endosteal hyperostosis LRP4/5, SOST Wnt Cortical thickening pattern

Screening. In known families, cascade carrier testing and, where desired, prenatal/preimplantation genetic testing for the familial AXIN1 variants are options. No population newborn screening exists.

Section 11 — Outcome / Prognosis

  • Survival/mortality: No systematic survival data. Not reported to be lethal in childhood; the oldest reported individual was 15.5 years. Life expectancy is undefined.
  • Morbidity: Driven by skeletal complications — potential cranial-nerve compromise from skull-base hyperostosis, orthopedic morbidity from hip dysplasia, and functional impact of developmental delay; cardiac malformations and hematological anomalies contribute variably.
  • Disease course: Chronic, progressive sclerosis. Recovery potential is limited; no disease-modifying therapy is in clinical use.
  • Prognostic factors: Presumed to include severity of cranial/skull-base involvement (nerve compression risk), cardiac status, and degree of developmental delay. No validated prognostic biomarkers.
  • QoL measures: Not formally assessed.

Given the small cohort, all prognostic statements carry substantial uncertainty.

Section 12 — Treatment

No disease-specific, approved therapy exists. Management is supportive and multidisciplinary.

  • Supportive/rehabilitative: Orthopedic management of hip dysplasia (bracing/surgery as indicated); monitoring for and surgical decompression of skull-base/foraminal narrowing if cranial-nerve compromise develops; cardiology management of heart malformations; hematology follow-up; developmental/physical/occupational therapy as needed. NCIT concepts: Supportive Care (NCIT:C15277), Orthopedic Surgery (NCIT:C16536), Physical Therapy (NCIT:C15367).
  • Pharmacotherapy: No established drug therapy. No pharmacogenomic guidance.
  • Advanced/experimental (mechanistically rational, not clinical): Tankyrase inhibition (e.g., XAV939) is an in-vitro-validated concept — it stabilizes AXIN1/AXIN2 and normalizes Wnt overactivity in mutant cells (PMID: 37582359). This has not been tested in patients; systemic tankyrase inhibition carries known intestinal/skeletal toxicity concerns and would require careful therapeutic-window definition. No gene/cell/RNA therapies are in development for CMDOH.
  • Treatment strategy: Individualized, symptom-directed. Any future targeted (Wnt-normalizing) approach would most plausibly target the early childhood window of active bone modeling.

Section 13 — Prevention

  • Primary prevention: Not possible for a Mendelian recessive disorder beyond reproductive genetic counseling.
  • Genetic counseling & reproductive options: Central preventive measure. For carrier couples (25% recurrence risk per pregnancy), options include carrier/cascade testing, prenatal diagnosis, and preimplantation genetic testing (PGT) for the familial AXIN1 variants. Counseling on consanguinity-associated recessive risk is relevant.
  • Secondary/tertiary prevention: Early imaging surveillance to detect and manage skull-base sclerosis (prevent nerve compression), hip surveillance, and cardiac/hematologic monitoring to prevent complications.
  • Immunization / public health / environmental: Not applicable.

Section 14 — Other Species / Natural Disease

  • Orthologous gene: Axin1 is conserved across vertebrates. Mouse Axin1 (NCBI Gene ID 12005) was originally identified as the Fused locus (PMID: 9230313); "Axin is a novel inhibitor of Wnt signaling." Taxonomy: Mus musculus (NCBI:txid10090), Danio rerio, etc.
  • Naturally occurring disease: No naturally occurring CMDOH-equivalent has been catalogued in companion animals or wildlife (no OMIA entry identified for this specific disorder).
  • Comparative biology: The canonical Wnt/β-catenin pathway and AXIN scaffold function are deeply evolutionarily conserved, underpinning the validity of mouse models. Classic mouse Fused/Axin1 mutant alleles cause axial duplication, reflecting Wnt's role in body-axis patterning.
  • Zoonotic potential / cross-species transmission: Not applicable (genetic disorder).

Section 15 — Model Organisms

  • Mouse — constitutive knockout: Axin1-null is embryonic lethal, precluding study of the adult skeletal phenotype and underscoring why viable human disease requires hypomorphic alleles.
  • Mouse — conditional osteoblast-lineage deletion (Axin1^Osx^, Osterix-Cre): Increased β-catenin, elevated OPG and OPG:RANKL ratio, decreased TRAP+/MMP9+/cathepsin-K+ osteoclasts, suppressed osteoclastogenesis, and delayed postnatal bone growth — directly recapitulating the human biopsy finding of increased osteoblast/reduced osteoclast activity (Bone Research 2020, PMC7424530).
  • Mouse — limb-mesenchyme deletion (Prrx1-Cre): Elevated β-catenin producing a fibular-hemimelia/tarsal-coalition phenotype, partially rescued by deleting one β-catenin allele (bone volume 92%→71%), formally demonstrating β-catenin dependence (eLife 2023, PMC9815809).
  • Paralog — Axin2 knockout: Craniosynostosis and increased trabecular bone mass, illustrating overlapping AXIN function in skeletal Wnt regulation and supporting AXIN2 as a compensatory modifier.
  • Cellular models: Patient-derived primary cells and CRISPR genome-edited cells carrying p.Arg723 / p.Asp796Glufs6, plus HEK293T reporter systems, demonstrated enhanced basal Wnt activity and XAV939 rescue (PMID: 37582359).
  • Phenotype recapitulation & limitations: Osteoblast-lineage models faithfully reproduce the cellular remodeling imbalance but not the full craniospinal radiographic pattern; constitutive models are lethal. No model reproduces the complete extraskeletal spectrum (cardiac, hematological).
  • Resources: MGI (mouse), Alliance of Genome Resources, IMPC/IMSR for Axin1/Axin2 alleles.

Key Findings (with evidence)

F001 — CMDOH is caused by biallelic C-terminal-truncating AXIN1 variants (autosomal recessive)

Terhal et al. 2023 identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families. Verbatim: "We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies." (PMID: 37582359). This establishes the gene, variant class, inheritance, cohort size, and the core phenotype.

F002 — Mechanism: DIX-domain truncation enhances canonical Wnt/β-catenin signaling; tankyrase inhibition rescues

In patient-derived and genome-edited cells, "analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity." The truncations impair DIX-domain polymerization but partially retain Wnt-inhibitory function on overexpression, and "addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems" (PMID: 37582359) — establishing both the causal Wnt-gain mechanism and a candidate targeted therapy.

F003 — AXIN1 is a Wnt-pathway tumor suppressor; complete somatic loss causes cancer, whereas germline hypomorphic truncations cause skeletal dysplasia

AXIN1 is a bona fide tumor suppressor: in hepatocellular carcinoma, "up to 50% of cases exhibit aberrant activation of the canonical Wnt/β-catenin pathway, driven by CTNNB1 mutations or inactivating alterations in AXIN1, adenomatous polyposis coli, or ZNRF3, which are mutually exclusive" (PMID: 42237887). Functional demonstration: "the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing" (PMID: 39653061); AXIN1 mutation upregulates CCND1 (p=0.022) with β-catenin–CCND1 correlation r=0.43 (PMID: 40344393). The dosage/allele-class contrast explains why germline hypomorphic DIX truncations yield a viable Wnt-gain skeletal phenotype rather than malignancy.

F004 — Clinical spectrum and specific variants (OMIM #620558)

Core radiographic features: macrocephaly (+2.2 to +6.1 SD), progressive calvarial/skull-base sclerosis, vertebral endplate ("sandwich") sclerosis, metaphyseal flaring, hypertelorism with low nasal bridge; plus hip dysplasia, heart malformations, variable developmental delay, hematological anomalies, and short stature in a subset. Bone biopsy showed increased osteoblast and reduced osteoclast activity at the growth-plate resorption zone. "Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption" (PMID: 37582359) frames the underlying remodeling defect.

F005 — Mouse Axin1 models support the Wnt-gain, osteoblast-lineage mechanism

Axin1 was cloned from the mouse Fused locus (PMID: 9230313); constitutive knockout is embryonic-lethal. Osteoblast-lineage deletion increases β-catenin and OPG:RANKL and suppresses osteoclastogenesis (mirroring the human biopsy); limb-mesenchyme deletion elevates β-catenin and is partially rescued by removing one β-catenin allele, confirming β-catenin dependence.

F006 — XAV939 dose-dependently rescues Wnt overactivity (partly via AXIN2)

In HEK293T cells engineered with AXIN1 p.Arg723 and p.Asp796Glufs6, XAV939 at 100 nM and 1 µM produced dose-dependent suppression of Wnt activation; it also rescued AXIN1-knockout cells, implicating AXIN2 stabilization. Tankyrases PARylate AXIN1/AXIN2 for degradation, so their inhibition raises AXIN levels and restores destruction-complex activity (PMID: 37582359).

Mechanistic Model (synthesis)

  Biallelic AXIN1 C-terminal truncation (p.Arg723*, p.Arg805*, frameshift)
     │  removes/disrupts DIX domain
     ▼
  ↓ AXIN1 protein level  +  impaired AXIN1 polymerization
     │
     ▼
  Weakened β-catenin destruction complex (AXIN1·APC·GSK3β·CK1)
     │  ↓ β-catenin phosphorylation/degradation
     ▼
  ↑ Nuclear β-catenin  →  ENHANCED canonical Wnt/β-catenin output   ◄── XAV939
     │        (demonstrated in patient/edited cells)      (tankyrase
┌────────────┴─────────────┐                                       inhibitor,
▼                          ▼                                       stabilizes
  ↑ Osteoblast formation     ↑ OPG : RANKL ratio                           AXIN1/AXIN2
                   │  (mouse model)                        → rescues)
                   ▼
             ↓ Osteoclast resorption
└────────────┬─────────────┘
     ▼
     NET ↑ BONE MASS → osteosclerosis / hyperostosis
     ▼
  Macrocephaly · cranial/skull-base hyperostosis · sandwich vertebrae ·
  metaphyseal flaring · hip dysplasia · (cardiac, developmental, hematologic — inferred)

Allele-dosage spectrum of AXIN1 dysfunction:

AXIN1 state Wnt output Outcome
Wild-type Normal (destruction complex intact) Healthy
Germline biallelic hypomorphic DIX truncation Moderately ↑ (partial retained function) CMDOH (viable skeletal dysplasia)
Somatic complete inactivation Strongly ↑ (full Wnt activation, c-Myc/CCND1) Cancer (e.g., HCC)

Evidence Base

PMID Title (abbrev.) Role in this report
37582359 AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause CMDOH Primary defining paper — gene, variants, phenotype, Wnt-gain mechanism, XAV939 rescue
42237887 Wnt/β-catenin in HCC Establishes AXIN1 as a Wnt tumor suppressor (dosage contrast)
39653061 Loss of AXIN1 & lenvatinib response in HCC Functional proof loss of AXIN1 activates Wnt/c-Myc
40344393 TP53/AXIN1/CTNNB1/KRAS in Mongolian HCC AXIN1 mutation ↑CCND1; β-catenin–CCND1 correlation
9230313 Axin (Fused locus): a novel Wnt inhibitor Foundational mouse genetics; Axin inhibits Wnt
33824347, 39084544, 41408477 TMEM53 craniotubular dysplasia (CTDI) Key differential — BMP-SMAD (not Wnt) sclerosing dysplasia
18981475 PTH signaling via LRP6/axin Context: axin/Wnt integration in osteoblast bone formation
26763102 Osteoblast exosomes inhibit Axin1 Context: Axin1 suppression → Wnt activation promotes osteogenesis

Note on evidence strength: The human genotype–phenotype and Wnt-gain findings rest on a single, well-executed 7-patient study with strong functional validation. The osteoblast/osteoclast step is supported by model-organism data. The tumor-suppressor/dosage framing is inferential context from cancer literature, not direct CMDOH data.

Limitations and Knowledge Gaps

  1. Tiny cohort (n=7/4 families): Frequencies, penetrance, expressivity, and prognosis are imprecise; the phenotype spectrum may broaden as more cases are found.
  2. No epidemiology: Prevalence, incidence, carrier frequency, and geographic/ethnic distribution are unquantified.
  3. Extraskeletal mechanism is inferred: How Wnt-gain produces the cardiac, hematological, and developmental features is not mechanistically dissected.
  4. No natural-history/QoL/survival data: Long-term outcomes and QoL are undefined.
  5. Therapy is preclinical only: XAV939 rescue is in-vitro; efficacy, safety, therapeutic window, and delivery in patients are unknown. Systemic tankyrase inhibition has known toxicity.
  6. No patient omics datasets (transcriptomic/proteomic/single-cell) exist to refine cell-type-specific mechanisms.
  7. Modifier genetics unproven: AXIN2 compensation is inferred from cell rescue, not demonstrated as a clinical modifier.

Proposed Follow-up Experiments / Actions

  1. Establish an international CMDOH registry and GeneMatcher-driven case collection to define prevalence, natural history, penetrance, and expressivity.
  2. Generate a knock-in mouse carrying a patient-equivalent C-terminal Axin1 truncation (e.g., R723*-analog) to recapitulate the craniospinal radiographic phenotype and test therapeutic windows.
  3. In-vivo XAV939 / next-generation tankyrase-inhibitor studies in the knock-in model, defining dose, timing (early bone-modeling window), and skeletal/intestinal toxicity — a prerequisite before any human consideration.
  4. Patient-derived iPSC → osteoblast/osteoclast organoid models to map cell-type-specific Wnt targets (RNA-seq/single-cell) and OPG:RANKL dynamics directly in human cells.
  5. Dissect extraskeletal mechanisms (cardiac, hematopoietic) via conditional Axin1-truncation models in relevant lineages.
  6. Systematic differential-diagnosis workflow: incorporate AXIN1 into sclerosing-dysplasia gene panels and publish radiographic criteria distinguishing CMDOH (Wnt) from TMEM53/CTDI (BMP-SMAD) and osteopetroses.
  7. Biomarker development: evaluate serum bone-turnover markers and Wnt-target readouts as potential monitoring/prognostic biomarkers.

Report compiled from a 5-iteration autonomous investigation; 6 confirmed findings, 12 papers reviewed. Primary source: Terhal et al., 2023 (PMID: 37582359).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 12
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 36
Resolved 35
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 19
Terms named correctly 7
Terms named as a different term 12

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0957832 (2 mentions) - the report calls it "MONDO"; MONDO calls it craniometadiaphyseal osteosclerosis with hip dysplasia
  • HP:0000256 (1 mention) - the report calls it "Core / very frequent"; HP calls it Macrocephaly
  • HP:0004437 (1 mention) - the report calls it "Core / very frequent"; HP calls it Cranial hyperostosis
  • HP:0004618 (1 mention) - the report calls it "Core / frequent"; HP calls it Sandwich appearance of vertebral bodies
  • HP:0003015 (1 mention) - the report calls it "Frequent"; HP calls it Flared metaphysis
  • HP:0001385 (1 mention) - the report calls it "Frequent"; HP calls it Hip dysplasia
  • HP:0001627 (1 mention) - the report calls it "Frequent"; HP calls it Abnormal heart morphology
  • HP:0001263 (1 mention) - the report calls it "Variable"; HP calls it Global developmental delay
  • HP:0001871 (1 mention) - the report calls it "Frequent"; HP calls it Abnormality of blood and blood-forming tissues
  • HP:0000316 (1 mention) - the report calls it "Frequent"; HP calls it Hypertelorism
  • HP:0005280 (1 mention) - the report calls it "Frequent"; HP calls it Depressed nasal bridge
  • HP:0004322 (1 mention) - the report calls it "Subset"; HP calls it Short stature