Craniodiaphyseal Dysplasia

Mendelian MONDO:0021021 Pathograph 33 Show in embeddings browser Sclerosing Bone Dysplasias

Craniodiaphyseal dysplasia is an extremely rare and severe sclerosing bone dysplasia of the craniotubular group, marked by massive hyperostosis and sclerosis of the skull and facial bones (the facial distortion historically called leontiasis ossea) together with hyperostosis and sclerosis of the diaphyses of the tubular bones. The dominant form, the subject of this entry, is caused by heterozygous, usually de novo, missense variants at codon 21 of the SOST signal peptide, which greatly reduce secretion of sclerostin, the osteocyte-derived inhibitor of Wnt-driven bone formation, and are thought to act by a dominant-negative mechanism. Relentless bone deposition encroaches on the craniofacial foramina, nasal passages and the cranial cavity, producing facial diplegia, progressive conductive then mixed hearing loss, optic atrophy, choanal and nasolacrimal obstruction, raised intracranial pressure and hydrocephalus, and the course is progressive and often fatal.

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1
Inheritance
5
Pathophys.
22
Phenotypes
1
Hypotheses
33
Pathograph
1
Genes
6
Medical Actions
4
Differentials
1
Models
1
Deep Research
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Classifications

ISDS Skeletal Nosology
osteosclerotic disorders
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Inheritance

1
Autosomal Dominant HP:0000006
Dominant transmission was first proposed from an affected mother and son, and heterozygous SOST signal-peptide variants were later identified in two children with craniodiaphyseal dysplasia. Most cases appear sporadic, and an apparently mildly affected mother of a severely affected boy was suggested to carry the variant in mosaic form.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:3802557 SUPPORT Human Clinical
"Distinguishing features in these two patients as contrasted to previously described cases include a greater degree of hyperostosis and sclerosis than that described for other patients with craniodiaphyseal dysplasia, apparent dominant transmission, and significant metaphyseal involvement."
The founding mother-son report of the dominant form records apparent dominant transmission.
PMID:21221996 SUPPORT Human Clinical
"Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism."
The molecular study places the dominant form apart from the recessive SOST disorders and attributes it to a dominant-negative mechanism.
PMID:17853455 SUPPORT Human Clinical
"It is possible that the mother has somatic mosaicism for a mutation of the genes causing CDD."
Supports the statement that an apparently mildly affected parent may be mosaic, which bears on recurrence risk.
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Mechanistic Hypotheses

1
Misfolded signal-peptide sclerostin activates the unfolded protein response in osteocytes, delaying their maturation and suppressing SOST
osteocyte_upr_sost_suppression EMERGING
Evidence balance 1 support
The SOST signal-peptide variants impair protein folding and secretion. A transgenic mouse in which the unfolded protein response is activated in early osteocytes develops generalized hyperostosis with delayed osteocyte maturation and delayed or suppressed Sost expression, a phenotype the authors judge highly consistent with craniodiaphyseal dysplasia, and the hyperostosis is suppressed by a chemical chaperone. The model does not carry a SOST variant, so whether endoplasmic reticulum stress contributes to the human disease beyond the direct loss of secreted sclerostin is unresolved.
Pathograph links
SOST Signal Peptide Variant with Impaired Sclerostin Secretion -> Unfolded Protein Response in Osteocytes Misfolded signal-peptide sclerostin retained in osteocytes is proposed to activate the unfolded protein response.
Unfolded Protein Response in Osteocytes -> Loss of Sclerostin Restraint on Osteoblastic Wnt Signaling In the mouse model, UPR activation delays or suppresses Sost expression, allowing active Wnt signaling.
Show evidence (1 reference)
PMID:28973168 SUPPORT Model Organism
"As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion."
States the hypothesis and the mouse-phenotype basis on which it rests.
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Pathophysiology

5
SOST Signal Peptide Variant with Impaired Sclerostin Secretion
Heterozygous missense variants at codon 21 of SOST (c.61G>A, p.Val21Met; c.61G>T, p.Val21Leu) lie in the secretion signal peptide of sclerostin. Expressed in cultured cells, both variants greatly reduce sclerostin secretion, and the dominant inheritance of the disorder, in contrast to the recessive SOST disorders, suggests that the mutant protein interferes with secretion of the wild-type product.
Misfolded signal-peptide sclerostin activates the unfolded protein response in osteocytes, delaying their maturation and suppressing SOST
SOST hgnc:13771 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SOST (hgnc:13771). hgnc:13771 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SOST hgnc:13771 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SOST (hgnc:13771). hgnc:13771 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
Heterozygous signal-peptide missense variants p.Val21Met and p.Val21Leu, found in two children with craniodiaphyseal dysplasia; the dominant-negative mechanism is proposed by the authors from the inheritance pattern and the secretion defect.
sclerostin secretion GO:0009306 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sclerostin secretion, annotated with protein secretion (GO:0009306). GO:0009306 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss of Sclerostin Restraint on Osteoblastic Wnt Signaling Reduced secretion of sclerostin removes its inhibition of canonical Wnt signaling at the bone surface.
Unfolded Protein Response in Osteocytes Misfolded signal-peptide sclerostin retained in osteocytes is proposed to activate the unfolded protein response. Misfolded signal-peptide sclerostin activates the unfolded protein response in osteocytes, delaying their maturation and suppressing SOST
Show evidence (2 references)
PMID:21221996 SUPPORT Human Clinical
"We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD."
Identifies the heterozygous SOST signal-peptide variants in affected children.
PMID:21221996 SUPPORT In Vitro
"As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST."
Transfection experiments show that the variants greatly reduce sclerostin secretion.
Unfolded Protein Response in Osteocytes
In a transgenic mouse, activation of the unfolded protein response in early differentiating osteocytes delays their maturation, keeps them in an active bone-synthesizing state, and delays or suppresses Sost expression. Whether retained mutant sclerostin triggers this response in patients is an emerging hypothesis supported only by the mouse model.
Misfolded signal-peptide sclerostin activates the unfolded protein response in osteocytes, delaying their maturation and suppressing SOST
osteocyte CL:0000137 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteocyte (CL:0000137). CL:0000137 is a cell type from the Cell Ontology.
endoplasmic reticulum unfolded protein response GO:0030968 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endoplasmic reticulum unfolded protein response (GO:0030968). GO:0030968 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Osteocyte unfolded protein response transgenic mouse Mouse perturbs The transgene directly activates the unfolded protein response in early osteocytes, which then delays their maturation and suppresses Sost.
Downstream
Loss of Sclerostin Restraint on Osteoblastic Wnt Signaling In the mouse model, UPR activation delays or suppresses Sost expression, allowing active Wnt signaling. Misfolded signal-peptide sclerostin activates the unfolded protein response in osteocytes, delaying their maturation and suppressing SOST
Show evidence (1 reference)
PMID:28973168 SUPPORT Model Organism
"We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the..."
Mouse evidence that osteocyte UPR activation suppresses Sost, activates Wnt signaling and produces hyperostosis.
Loss of Sclerostin Restraint on Osteoblastic Wnt Signaling
Sclerostin, secreted by osteocytes, restrains osteoblast bone formation by inhibiting canonical Wnt signaling. With less sclerostin reaching the bone surface, Wnt signaling in osteoblasts is left insufficiently restrained.
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.
SOST hgnc:13771 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SOST (hgnc:13771). hgnc:13771 is a gene from the HUGO Gene Nomenclature Committee.
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
Downstream
Excessive Osteoblastic Bone Formation Unrestrained Wnt signaling drives osteoblast bone formation.
Show evidence (1 reference)
PMID:28973168 SUPPORT BACKGROUND Other
"Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling."
Background statement of the normal osteocyte-to-osteoblast sclerostin signal whose loss this node models.
Excessive Osteoblastic Bone Formation
Bone biopsies from children with craniodiaphyseal dysplasia show increased numbers of osteoblasts, consistent with net bone formation outpacing remodeling throughout the skull and the diaphyses of the tubular bones.
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.
ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Osteocyte unfolded protein response transgenic mouse Mouse partially recapitulates The mouse develops generalized hyperostosis with enhanced periosteal bone formation, which is suppressed by 4-phenylbutyrate.
Downstream
Progressive Craniofacial Hyperostosis with Foraminal Encroachment Continued bone deposition in the skull and facial bones produces progressive craniofacial hyperostosis.
Diaphyseal Sclerosis The same excess bone formation thickens and scleroses the diaphyses of the tubular bones.
Rib Sclerosis Excess bone formation scleroses and widens the ribs.
Clavicular Sclerosis Excess bone formation scleroses and widens the midshaft of the clavicles.
Show evidence (1 reference)
PMID:8733453 SUPPORT Human Clinical
"Increased numbers of osteoblasts were found in bone biopsies from both cases with craniodiaphyseal dysplasia."
Bone histology in two patients shows increased osteoblast numbers.
Progressive Craniofacial Hyperostosis with Foraminal Encroachment
Relentless bone deposition thickens the calvaria, skull base and facial bones, obliterating the paranasal sinuses and progressively narrowing the craniofacial foramina, nasal passages, nasolacrimal ducts and the cranial cavity itself. Cranial nerves, the brain and the craniocervical junction are compressed as a result.
skull UBERON:0003129 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skull (UBERON:0003129). UBERON:0003129 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cranial Hyperostosis
Macrocephaly
Hypertelorism
Obliterated Paranasal Sinuses
Facial Diplegia
Progressive Mixed Hearing Loss
Narrow Internal Auditory Canal
Optic Atrophy from Optic Nerve Compression
Choanal Stenosis
Nasolacrimal Duct Obstruction
Small Foramen Magnum
Increased Intracranial Pressure
Cervical Spinal Canal Stenosis
Show evidence (2 references)
PMID:8827383 SUPPORT BACKGROUND Human Clinical
"The clinical course is typically characterized by progressive encroachment of the craniofacial foramina and brain by the relentless deposition of bone. Compression of cranial nerves, the foramen magnum, and intracranial contents commonly leads to blindness, loss of hearing, and death."
Summarizes the progressive foraminal and intracranial encroachment and its consequences.
PMID:3802557 SUPPORT Human Clinical
"severe craniofacial hyperostosis and sclerosis with obliteration of paranasal sinuses and foramina of the skull base"
The dominant mother-son family shows craniofacial hyperostosis with obliteration of the sinuses and skull-base foramina.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Craniodiaphyseal 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.
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Phenotypes

22
Ear 2
Progressive Mixed Hearing Loss Mixed hearing impairment HP:0000410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive mixed hearing impairment, annotated with Mixed hearing impairment (HP:0000410), qualified as course progressive. HP:0000410 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:8733453 SUPPORT Human Clinical
"In the craniodiaphyseal dysplasia, the hearing abnormality progressed from an initial conductive to a mixed loss on serial audiometric follow up."
Serial audiometry documents progression from conductive to mixed loss.
PMID:8172537 SUPPORT Human Clinical
"The air spaces of the mastoid, external auditory canal, and middle ear cavity are reduced by hyperostotic bone. The ossicles are also deformed by the bony overgrowth."
Temporal bone histopathology shows the structural basis of the conductive component.
Narrow Internal Auditory Canal HP:0011386 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow internal auditory canal (HP:0011386). HP:0011386 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8733453 SUPPORT Human Clinical
"Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion."
CT documents narrowing of the internal auditory meatus.
Eye 2
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17456942 SUPPORT BACKGROUND Human Clinical
"The affected patients typically present in early infancy with facial abnormalities such as paranasal bossing, hypertelorism and increased head circumference."
Names hypertelorism among the typical early facial abnormalities.
PMID:17456942 SUPPORT Human Clinical
"Physical examination revealed grossly deformed head, short stature, hypertelorism and epiphora of left eye."
Hypertelorism observed in the reported patient.
Optic Atrophy from Optic Nerve Compression Optic atrophy from cranial nerve compression HP:0007958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy from cranial nerve compression (HP:0007958). HP:0007958 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17853455 SUPPORT Human Clinical
"Facial diplegia, bilateral hearing loss and optic nerve atrophy were early, severe complications of the disease."
Optic nerve atrophy as an early complication.
PMID:17456942 SUPPORT Human Clinical
"Axial computed tomogram section showing bilateral optic canal narrowing"
CT shows the optic canal narrowing that underlies the compression.
Head and Neck 8
Cranial Hyperostosis VERY_FREQUENT Craniofacial hyperostosis HP:0004493 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniofacial hyperostosis (HP:0004493), qualified as course progressive. HP:0004493 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:8827383 SUPPORT BACKGROUND Human Clinical
"characterized by massive generalized hyperostosis and sclerosis, particularly of the skull and facial bones, leading to severe deformity"
Defines craniofacial hyperostosis as the cardinal feature.
PMID:31132523 SUPPORT BACKGROUND Human Clinical
"a massive generalized hyperostosis and sclerosis, primarily involving the facial bones and the skull"
Independent description of skull and facial-bone hyperostosis.
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:17456942 SUPPORT BACKGROUND Human Clinical
"The affected patients typically present in early infancy with facial abnormalities such as paranasal bossing, hypertelorism and increased head circumference."
The case report's literature review gives increased head circumference as a typical early presentation.
Obliterated Paranasal Sinuses Abnormal paranasal sinus morphology HP:0000245 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obliterated paranasal sinuses, annotated with Abnormal paranasal sinus morphology (HP:0000245). HP:0000245 is a phenotype from the Human Phenotype Ontology.
HPO has Absent paranasal sinuses (HP:0002689), defined as aplasia, and Opacified paranasal sinuses (HP:0034494), but no term for sinuses obliterated by bone overgrowth; an OLS search of hp for "paranasal sinus" returned those and the parent Abnormal paranasal sinus morphology, which is bound here.
Show evidence (1 reference)
PMID:17456942 SUPPORT Human Clinical
"severe craniofacial hyperostosis, sclerosis, obliteration of paranasal sinuses and foramina of skull base"
Sinus obliteration documented by CT in a child with the disorder.
Facial Diplegia HP:0001349 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial diplegia (HP:0001349). HP:0001349 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17853455 SUPPORT Human Clinical
"Facial diplegia, bilateral hearing loss and optic nerve atrophy were early, severe complications of the disease."
Facial diplegia as an early complication.
PMID:3802557 SUPPORT Human Clinical
"Subsequent severe bilateral hearing loss and facial diplegia with relative sparing of the optic nerves were noted."
Facial diplegia in the dominant mother-son family.
Choanal Stenosis HP:0000452 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choanal stenosis (HP:0000452). HP:0000452 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8733453 SUPPORT Human Clinical
"Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived."
In this mixed series, Cases 1 and 2 are the two craniodiaphyseal dysplasia patients; both presented in infancy with choanal stenosis, and Case 1 had it drilled and dilated with bony re-obstruction within a year.
Nasolacrimal Duct Obstruction HP:0000579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nasolacrimal duct obstruction (HP:0000579). HP:0000579 is a phenotype from the Human Phenotype Ontology.
Sequelae: Recurrent Dacryocystitis
Show evidence (1 reference)
PMID:17456942 SUPPORT Human Clinical
"presented with abnormal facial features and recurrent dacryocystitis due to narrowing of nasolacrimal duct"
CT-documented nasolacrimal duct narrowing in a child with the disorder.
Recurrent Dacryocystitis HP:0000620 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dacryocystitis (HP:0000620), qualified as temporality recurrent. HP:0000620 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:17456942 SUPPORT Human Clinical
"Occasionally, they may present with recurrent dacryocystitis because of progressive stenosis of the nasolacrimal duct, which happened in our case."
Recurrent dacryocystitis as a presentation caused by duct stenosis.
Small Foramen Magnum HP:0002677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small foramen magnum (HP:0002677). HP:0002677 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hydrocephalus Syringomyelia
Show evidence (1 reference)
PMID:14530887 SUPPORT Human Clinical
"MR imaging exquisitely depicted cranial nerve compression, small foramen magnum, hydrocephalus, and other intracranial complications of this syndrome."
MRI documents a small foramen magnum in a 4-year-old with the disorder.
Limbs 1
Diaphyseal Sclerosis HP:0003034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diaphyseal sclerosis (HP:0003034). HP:0003034 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:3802557 SUPPORT Human Clinical
"The long bones show extreme asymmetric hyperostosis and sclerosis of the diaphyses and evidence of a modelling defect in the metaphyses."
Diaphyseal hyperostosis and sclerosis in the dominant family.
PMID:8827383 SUPPORT Human Clinical
"The tubular bones demonstrated the characteristic diaphyseal endostosis, undertubulation, and relative overgrowth on the involved side."
Diaphyseal involvement of the tubular bones in a further case.
Musculoskeletal 3
Rib Sclerosis Osteosclerosis of ribs HP:0006634 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteosclerosis of ribs (HP:0006634), qualified as course progressive. HP:0006634 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:8733453 SUPPORT Human Clinical
"Progressive marked sclerosis and widening of the ribs with obliteration of the medullary cavity by seven months of age."
The paper's table of radiological features gives this rib finding for craniodiaphyseal dysplasia, in contrast with the craniometaphyseal form.
Clavicular Sclerosis HP:0100923 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clavicular sclerosis (HP:0100923). HP:0100923 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8733453 SUPPORT Human Clinical
"Midclavicular sclerosis, hyperostosis and widening by three months sparing the manubrial and acromial ends becoming more overgrown by five years."
The paper's table of radiological features gives this clavicular finding for craniodiaphyseal dysplasia.
Cervical Spinal Canal Stenosis OCCASIONAL HP:0008445 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cervical spinal canal stenosis (HP:0008445). HP:0008445 is a phenotype from the Human Phenotype Ontology.
Sequelae: Tetraparesis
Show evidence (1 reference)
PMID:11341413 SUPPORT Human Clinical
"We report the only case of CDD in an adult, with stenosis of the cervical canal leading to quadriparesis as a late complication of hyperostosis, and describe the problems associated with its treatment."
Cervical canal stenosis from hyperostosis in an adult patient.
Nervous System 6
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14530887 SUPPORT Human Clinical
"MR imaging exquisitely depicted cranial nerve compression, small foramen magnum, hydrocephalus, and other intracranial complications of this syndrome."
MRI documents hydrocephalus alongside the small foramen magnum.
Syringomyelia OCCASIONAL HP:0003396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syringomyelia (HP:0003396). HP:0003396 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14530887 SUPPORT Human Clinical
"A syrinx of the cervical spinal cord was demonstrated."
Single-case MRI finding of a cervical syrinx.
Increased Intracranial Pressure HP:0002516 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased intracranial pressure (HP:0002516). HP:0002516 is a phenotype from the Human Phenotype Ontology.
Sequelae: Seizure Intellectual Disability
Show evidence (1 reference)
PMID:8827383 SUPPORT Human Clinical
"Significant brain compression with signs and symptoms of increased intracranial pressure was managed successfully with decompressing craniectomy at age 12 years, enlarging the anterior and middle fossae."
Documents brain compression with raised intracranial pressure.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11341413 SUPPORT BACKGROUND Human Clinical
"Hyperostosis can cause progressive foraminal stenosis leading to palsy of cranial nerves, epilepsy and mental retardation."
Names epilepsy as a consequence of the hyperostosis.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11341413 SUPPORT BACKGROUND Human Clinical
"Hyperostosis can cause progressive foraminal stenosis leading to palsy of cranial nerves, epilepsy and mental retardation."
Names intellectual disability as a consequence of the hyperostosis.
Tetraparesis OCCASIONAL HP:0002273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetraparesis (HP:0002273). HP:0002273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11341413 SUPPORT Human Clinical
"We report the only case of CDD in an adult, with stenosis of the cervical canal leading to quadriparesis as a late complication of hyperostosis, and describe the problems associated with its treatment."
Quadriparesis secondary to cervical canal stenosis.
🧬

Genetic Associations

1
SOST (Causative)
Gene: SOST hgnc:13771 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SOST (hgnc:13771). hgnc:13771 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:21221996 SUPPORT Human Clinical
"We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST."
Establishes SOST as the gene for the dominant form.
PMID:29264888 SUPPORT REVIEW SYNTHESIS Other
"Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease."
A review places craniodiaphyseal dysplasia with the other SOST-related craniotubular hyperostoses.
💊

Medical Actions

6
Decompressive Craniectomy and Reduction Osteoplasty
Action: decompressive craniectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is decompressive craniectomy, annotated with Craniectomy (NCIT:C51791). NCIT:C51791 is a clinical intervention from the NCI Thesaurus. Ontology label: Craniectomy NCIT:C51791
Platform: Surgery
Decompressive craniectomy for brain compression and raised intracranial pressure, with subsequent calvarial, midfacial and mandibular recontouring. Continued bone deposition requires close follow-up.
Mechanism Target:
Increased Intracranial Pressure — Enlarging the cranial fossae relieves brain compression.
Show evidence (1 reference)
PMID:8827383 SUPPORT Human Clinical
"Significant brain compression with signs and symptoms of increased intracranial pressure was managed successfully with decompressing craniectomy at age 12 years, enlarging the anterior and middle fossae."
Single-case report of successful decompressive craniectomy.
Choanal, Craniofacial and Lacrimal Surgery
Action: choanal, craniofacial and lacrimal surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is choanal, craniofacial and lacrimal surgery, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgery for choanal stenosis, craniofacial remodelling and dacryocystorhinostomy for nasolacrimal obstruction. Benefits are short-lived because bone deposition continues.
Mechanism Target:
Choanal Stenosis
Nasolacrimal Duct Obstruction
Show evidence (1 reference)
PMID:8733453 SUPPORT Human Clinical
"Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived."
In this mixed series, the craniodiaphyseal dysplasia patients are Cases 1 and 2; Case 1 underwent choanal surgery and two dacryocystorhinostomies and Case 2 facial recontouring, each followed by bony regrowth.
Bone-Anchored Hearing Aid
Action: bone-anchored hearing aid implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is bone-anchored hearing aid implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device bone-anchored hearing aid. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
A bone-anchored hearing aid has been used successfully for progressive hearing loss despite the skull involvement.
Mechanism Target:
Progressive Mixed Hearing Loss
Show evidence (1 reference)
PMID:31132523 SUPPORT Human Clinical
"Furthermore, we describe the first case of craniodiaphysial dysplasia rehabilitated with Bone-Anchored Hearing Aid, despite the concerns inherent to the involvement of the skull bone that characterizes the disease."
Single-case report of hearing rehabilitation with a bone-anchored aid.
Calcitriol with Low-Calcium Diet
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: calcitriol CHEBI:17823 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcitriol (CHEBI:17823). CHEBI:17823 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Calcitriol with a low-calcium diet, intended to increase bone resorption, did not alter the progression of disease in the reported cases.
Show evidence (1 reference)
PMID:8733453 REFUTE Human Clinical
"Calcitriol therapy with a low calcium diet did not alter the clinical course of progression in our cases."
Refutes efficacy of calcitriol and calcium restriction. In this mixed series both craniodiaphyseal dysplasia patients (Cases 1 and 2) received the regimen; the paper contrasts them with a craniometaphyseal case whose biochemistry did respond.
Chemical Chaperone Therapy (Preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium 4-phenylbutyrate CHEBI:41500 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium 4-phenylbutyrate, annotated with 4-phenylbutyric acid (CHEBI:41500). CHEBI:41500 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
In a mouse model in which the unfolded protein response is activated in osteocytes, the chemical chaperone sodium 4-phenylbutyrate suppressed the onset of hyperostosis. Agents that improve protein folding have been proposed as a potential treatment, but there are no human data.
Mechanism Target:
Unfolded Protein Response in Osteocytes
Show evidence (1 reference)
PMID:28973168 SUPPORT Model Organism
"A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA)."
Mouse evidence that a chemical chaperone suppresses UPR-driven hyperostosis.
Anesthetic Airway Management
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Craniofacial and mandibular hyperostosis makes tracheal intubation difficult; fibreoptic intubation guided by a laryngeal mask airway with spontaneous respiration has been used.
Show evidence (1 reference)
PMID:8732615 SUPPORT Human Clinical
"Patients with CDD present problems to the anaesthetist, specifically difficulties with airway management and tracheal intubation. This child was managed using laryngeal mask airway (LMA) guided fibreoptic intubation."
Case report of airway management for surgery in a child with the disorder.
🔬

Diagnosis

4
Radiographic Skeletal Survey
Diagnosis is principally radiological. Serial skeletal surveys show progressive craniofacial hyperostosis together with diaphyseal widening of the long bones and rib and clavicle sclerosis, which distinguishes craniodiaphyseal dysplasia from craniometaphyseal dysplasia and bears on prognosis.
radiographic skeletal survey NCIT:C38101 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:8733453 SUPPORT Human Clinical
"The diagnostic distinction can now be made radiologically by serial skeletal survey which is important for prognosis."
States that serial skeletal survey makes the diagnostic distinction.
PMID:8733453 SUPPORT Human Clinical
"The diagnosis of craniodiaphyseal dysplasia was made on skeletal survey"
The diagnosis in Case 1 was made on skeletal survey.
Temporal Bone CT
CT of the temporal bones shows narrowing of the middle ear cavity, internal auditory meatus and facial nerve canal, and is used to evaluate hearing loss and facial palsy.
temporal bone computed tomography NCIT:C17204 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:8733453 SUPPORT Human Clinical
"Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion."
Temporal bone CT documents the foraminal narrowing behind the hearing loss and facial palsy.
Brain and Craniocervical MRI
MRI depicts cranial nerve compression, a small foramen magnum, hydrocephalus and cervical syrinx, and has been proposed as a routine part of evaluation.
magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:14530887 SUPPORT Human Clinical
"We suggest that MR imaging become a routine component of the evaluation of these patients."
The authors recommend routine MRI after it revealed intracranial complications in their patient.
SOST Sequencing
Sequencing of SOST identifies heterozygous signal-peptide variants at codon 21 and confirms the dominant SOST-related form.
SOST sequence analysis NCIT:C153598 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21221996 SUPPORT Human Clinical
"We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD."
SOST sequencing identified the causal variants in two affected children.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population-based estimate exists. A 2007 case report stated that fewer than 30 cases had been reported in the English literature.
Show evidence (2 references)
PMID:17456942 SUPPORT BACKGROUND Human Clinical
"Craniodiaphyseal dysplasia is the rarest of all sclerosing bone dysplasia, so far less than 30 cases have been reported in the English literature."
Gives the reported-case count on which the ultra-rare class rests; the sentence is the case report's review of prior literature.
PMID:21221996 SUPPORT BACKGROUND Human Clinical
"an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as "leontiasis ossea""
The molecular study describes the disorder as extremely rare.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Craniodiaphyseal Dysplasia:

Sclerosteosis MONDO:0017838
Overlapping Features Recessive SOST loss-of-function disorder with cranial hyperostosis and cranial nerve entrapment, distinguished by syndactyly and tall stature and by biallelic rather than heterozygous SOST variants.
Show evidence (1 reference)
PMID:21221996 SUPPORT BACKGROUND Human Clinical
"Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene."
Places sclerosteosis in the same SOST spectrum with recessive inheritance.
Van Buchem disease MONDO:0009395
Overlapping Features Recessive SOST regulatory-deletion disorder in which mandibular enlargement predominates, head circumference is normal and facial changes appear in the second decade.
Show evidence (1 reference)
PMID:17456942 SUPPORT BACKGROUND Human Clinical
"In Van Buchem's dysplasia, mandibular enlargement is the predominant manifestation, head circumference is normal and facial changes manifest in the second decade."
Gives the clinical features distinguishing van Buchem disease.
Camurati-Engelmann disease MONDO:0007542
Overlapping Features TGFB1-related diaphyseal dysplasia in which craniofacial involvement is mild and the major changes are in the long bones.
Show evidence (1 reference)
PMID:17456942 SUPPORT BACKGROUND Human Clinical
"In Camurati-Engelmann, the degree of cranio-facial involvement is mild with major changes in long bones."
Gives the feature distinguishing Camurati-Engelmann disease.
Craniometaphyseal dysplasia MONDO:0015465
Overlapping Features Craniotubular dysplasia with similar skull changes but metaphyseal widening with club-shaped long bones, rather than the cylindrical diaphyseal widening of craniodiaphyseal dysplasia.
Show evidence (1 reference)
PMID:17456942 SUPPORT BACKGROUND Human Clinical
"In craniotubular dysplasia, there is metaphyseal widening and cortical thinning giving rise to club-shaped configuration of long bones whereas in craniodiaphyseal dysplasia the diaphyseal widening gives rise to cylindrical appearance"
Gives the long-bone contour distinguishing metaphyseal craniotubular dysplasias.
🐁

Animal Models

1
Osteocyte unfolded protein response transgenic mouse
Transgenic mouse in which the unfolded protein response is activated in early differentiating osteocytes. Osteocyte maturation is delayed, Sost expression is delayed or suppressed, Wnt signaling is active and periosteal bone formation is enhanced, giving generalized hyperostosis that the authors judge highly consistent with craniodiaphyseal dysplasia. The hyperostosis is suppressed by the chemical chaperone 4-phenylbutyrate.
Species
Mouse
Genotype
Transgene activating the unfolded protein response in early differentiating osteocytes
Publication
PMID:28973168
Pathograph links
Unfolded Protein Response in Osteocytes perturbs fidelity: low observes: cellular The transgene directly activates the unfolded protein response in early osteocytes, which then delays their maturation and suppresses Sost.
Limitations: The model carries no SOST allele: the unfolded protein response is induced by a transgene rather than by misfolded signal-peptide sclerostin, so it tests whether osteocyte ER stress can produce the phenotype, not whether the human SOST variants trigger it.
Show evidence (1 reference)
PMID:28973168 SUPPORT Model Organism
"We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the..."
Shows that the model activates the osteocyte UPR and records its consequences for Sost and Wnt signaling.
Excessive Osteoblastic Bone Formation partially recapitulates fidelity: moderate observes: organism The mouse develops generalized hyperostosis with enhanced periosteal bone formation, which is suppressed by 4-phenylbutyrate.
Limitations: The model carries no SOST allele, so the excess bone formation arises from transgene-induced ER stress rather than from the dominant signal-peptide sclerostin secretion defect. Craniofacial foraminal encroachment and cranial nerve compression, which dominate the human disease, are not reported in the abstract.
Show evidence (1 reference)
PMID:28973168 SUPPORT Model Organism
"A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA)."
Links UPR activation to hyperostosis onset in the model and shows its pharmacological suppression.
Show evidence (1 reference)
PMID:28973168 SUPPORT Model Organism
"As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion."
The authors relate the mouse phenotype to craniodiaphyseal dysplasia.
{ }

Source YAML

click to show 
name: Craniodiaphyseal Dysplasia
creation_date: '2026-09-23T19:10:23Z'
category: Mendelian
description: >
  Craniodiaphyseal dysplasia is an extremely rare and severe sclerosing bone
  dysplasia of the craniotubular group, marked by massive hyperostosis and
  sclerosis of the skull and facial bones (the facial distortion historically
  called leontiasis ossea) together with hyperostosis and sclerosis of the
  diaphyses of the tubular bones. The dominant form, the subject of this entry,
  is caused by heterozygous, usually de novo, missense variants at codon 21 of
  the SOST signal peptide, which greatly reduce secretion of sclerostin, the
  osteocyte-derived inhibitor of Wnt-driven bone formation, and are thought to
  act by a dominant-negative mechanism. Relentless bone deposition encroaches
  on the craniofacial foramina, nasal passages and the cranial cavity,
  producing facial diplegia, progressive conductive then mixed hearing loss,
  optic atrophy, choanal and nasolacrimal obstruction, raised intracranial
  pressure and hydrocephalus, and the course is progressive and often fatal.
disease_term:
  preferred_term: craniodiaphyseal dysplasia, autosomal dominant
  term:
    id: MONDO:0021021
    label: craniodiaphyseal dysplasia, autosomal dominant
synonyms:
- craniodiaphyseal dysplasia, dominant
- CDD
- Schaefer Stein Oshman syndrome
- dominantly inherited craniodiaphyseal dysplasia
- leontiasis ossea
parents:
- Sclerosing Bone Dysplasias
notes: >-
  Scope. This entry is anchored at MONDO:0021021, the autosomal dominant
  SOST-related form. MONDO also carries MONDO:0009031 (craniodiaphyseal
  dysplasia) with no causal gene, and a recessive form caused by a homozygous
  SP7 missense variant has been reported (PMID:36436818, which has no PubMed
  abstract to quote), and biallelic
  SP7 variants cause a sclerotic skeletal dysplasia partially overlapping
  craniodiaphyseal dysplasia (PMID:37918503). The SP7 forms are outside the
  scope of this SOST-anchored entry. Most published
  clinical descriptions of craniodiaphyseal dysplasia predate molecular
  diagnosis and do not state a genotype; they are cited here for the shared
  clinical and radiographic phenotype, and genotype-specific claims rest on the
  SOST study (PMID:21221996) and the transgenic mouse study (PMID:28973168).
  Unlike sclerosteosis and van Buchem disease, which are recessive SOST
  loss-of-function disorders, the dominant signal-peptide variants are proposed
  to act dominant-negatively.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Dominant transmission was first proposed from an affected mother and son,
    and heterozygous SOST signal-peptide variants were later identified in two
    children with craniodiaphyseal dysplasia. Most cases appear sporadic, and
    an apparently mildly affected mother of a severely affected boy was
    suggested to carry the variant in mosaic form.
  evidence:
  - reference: PMID:3802557
    reference_title: "Dominantly inherited craniodiaphyseal dysplasia: a new craniotubular dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distinguishing features in these two patients as contrasted to previously described cases include a greater degree of hyperostosis and sclerosis than that described for other patients with craniodiaphyseal dysplasia, apparent dominant transmission, and significant metaphyseal involvement."
    explanation: >-
      The founding mother-son report of the dominant form records apparent
      dominant transmission.
  - reference: PMID:21221996
    reference_title: "Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism."
    explanation: >-
      The molecular study places the dominant form apart from the recessive
      SOST disorders and attributes it to a dominant-negative mechanism.
  - reference: PMID:17853455
    reference_title: "A boy with severe craniodiaphyseal dysplasia and apparently normal mother."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is possible that the mother has somatic mosaicism for a mutation of the genes causing CDD."
    explanation: >-
      Supports the statement that an apparently mildly affected parent may be
      mosaic, which bears on recurrence risk.
classifications:
  isds_skeletal_category:
  - classification_value: osteosclerotic_disorders
    notes: >-
      Assigned by analogy with the other SOST-related sclerosing bone
      dysplasias (sclerosteosis, van Buchem disease) curated under the same
      ISDS value. Membership of craniodiaphyseal dysplasia in the 2023 ISDS
      Nosology table (Unger et al., PMID:36779427) has not been verified
      against the table itself.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based estimate exists. A 2007 case report stated that fewer
    than 30 cases had been reported in the English literature.
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Craniodiaphyseal dysplasia is the rarest of all sclerosing bone dysplasia, so far less than 30 cases have been reported in the English literature."
    explanation: >-
      Gives the reported-case count on which the ultra-rare class rests; the
      sentence is the case report's review of prior literature.
  - reference: PMID:21221996
    reference_title: "Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as \"leontiasis ossea\""
    explanation: >-
      The molecular study describes the disorder as extremely rare.
mechanistic_hypotheses:
- hypothesis_group_id: osteocyte_upr_sost_suppression
  hypothesis_label: >-
    Misfolded signal-peptide sclerostin activates the unfolded protein
    response in osteocytes, delaying their maturation and suppressing SOST
  status: EMERGING
  description: >-
    The SOST signal-peptide variants impair protein folding and secretion. A
    transgenic mouse in which the unfolded protein response is activated in
    early osteocytes develops generalized hyperostosis with delayed osteocyte
    maturation and delayed or suppressed Sost expression, a phenotype the
    authors judge highly consistent with craniodiaphyseal dysplasia, and the
    hyperostosis is suppressed by a chemical chaperone. The model does not
    carry a SOST variant, so whether endoplasmic reticulum stress contributes
    to the human disease beyond the direct loss of secreted sclerostin is
    unresolved.
  evidence:
  - reference: PMID:28973168
    reference_title: "Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion."
    explanation: >-
      States the hypothesis and the mouse-phenotype basis on which it rests.
pathophysiology:
- name: SOST Signal Peptide Variant with Impaired Sclerostin Secretion
  description: >
    Heterozygous missense variants at codon 21 of SOST (c.61G>A, p.Val21Met;
    c.61G>T, p.Val21Leu) lie in the secretion signal peptide of sclerostin.
    Expressed in cultured cells, both variants greatly reduce sclerostin
    secretion, and the dominant inheritance of the disorder, in contrast to the
    recessive SOST disorders, suggests that the mutant protein interferes with
    secretion of the wild-type product.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SOST
    term:
      id: hgnc:13771
      label: SOST
  genetic_context:
    gene:
      preferred_term: SOST
      term:
        id: hgnc:13771
        label: SOST
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Heterozygous signal-peptide missense variants p.Val21Met and p.Val21Leu,
      found in two children with craniodiaphyseal dysplasia; the
      dominant-negative mechanism is proposed by the authors from the
      inheritance pattern and the secretion defect.
  biological_processes:
  - preferred_term: sclerostin secretion
    modifier: DECREASED
    term:
      id: GO:0009306
      label: protein secretion
  downstream:
  - target: Loss of Sclerostin Restraint on Osteoblastic Wnt Signaling
    description: >-
      Reduced secretion of sclerostin removes its inhibition of canonical Wnt
      signaling at the bone surface.
  - target: Unfolded Protein Response in Osteocytes
    description: >-
      Misfolded signal-peptide sclerostin retained in osteocytes is proposed
      to activate the unfolded protein response.
    hypothesis_groups:
    - osteocyte_upr_sost_suppression
  evidence:
  - reference: PMID:21221996
    reference_title: "Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD."
    explanation: >-
      Identifies the heterozygous SOST signal-peptide variants in affected
      children.
  - reference: PMID:21221996
    reference_title: "Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST."
    explanation: >-
      Transfection experiments show that the variants greatly reduce sclerostin
      secretion.
- name: Unfolded Protein Response in Osteocytes
  description: >
    In a transgenic mouse, activation of the unfolded protein response in early
    differentiating osteocytes delays their maturation, keeps them in an active
    bone-synthesizing state, and delays or suppresses Sost expression. Whether
    retained mutant sclerostin triggers this response in patients is an
    emerging hypothesis supported only by the mouse model.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
  downstream:
  - target: Loss of Sclerostin Restraint on Osteoblastic Wnt Signaling
    description: >-
      In the mouse model, UPR activation delays or suppresses Sost expression,
      allowing active Wnt signaling.
    hypothesis_groups:
    - osteocyte_upr_sost_suppression
  evidence:
  - reference: PMID:28973168
    reference_title: "Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis."
    explanation: >-
      Mouse evidence that osteocyte UPR activation suppresses Sost, activates
      Wnt signaling and produces hyperostosis.
- name: Loss of Sclerostin Restraint on Osteoblastic Wnt Signaling
  description: >
    Sclerostin, secreted by osteocytes, restrains osteoblast bone formation by
    inhibiting canonical Wnt signaling. With less sclerostin reaching the bone
    surface, Wnt signaling in osteoblasts is left insufficiently restrained.
  biological_scale: CELLULAR
  genes:
  - preferred_term: SOST
    term:
      id: hgnc:13771
      label: SOST
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  downstream:
  - target: Excessive Osteoblastic Bone Formation
    description: >-
      Unrestrained Wnt signaling drives osteoblast bone formation.
  evidence:
  - reference: PMID:28973168
    reference_title: "Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling."
    explanation: >-
      Background statement of the normal osteocyte-to-osteoblast sclerostin
      signal whose loss this node models.
- name: Excessive Osteoblastic Bone Formation
  description: >
    Bone biopsies from children with craniodiaphyseal dysplasia show increased
    numbers of osteoblasts, consistent with net bone formation outpacing
    remodeling throughout the skull and the diaphyses of the tubular bones.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: ossification
    modifier: INCREASED
    term:
      id: GO:0001503
      label: ossification
  downstream:
  - target: Progressive Craniofacial Hyperostosis with Foraminal Encroachment
    description: >-
      Continued bone deposition in the skull and facial bones produces
      progressive craniofacial hyperostosis.
  - target: Diaphyseal Sclerosis
    description: >-
      The same excess bone formation thickens and scleroses the diaphyses of
      the tubular bones.
  - target: Rib Sclerosis
    description: >-
      Excess bone formation scleroses and widens the ribs.
  - target: Clavicular Sclerosis
    description: >-
      Excess bone formation scleroses and widens the midshaft of the clavicles.
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased numbers of osteoblasts were found in bone biopsies from both cases with craniodiaphyseal dysplasia."
    explanation: >-
      Bone histology in two patients shows increased osteoblast numbers.
- name: Progressive Craniofacial Hyperostosis with Foraminal Encroachment
  description: >
    Relentless bone deposition thickens the calvaria, skull base and facial
    bones, obliterating the paranasal sinuses and progressively narrowing the
    craniofacial foramina, nasal passages, nasolacrimal ducts and the cranial
    cavity itself. Cranial nerves, the brain and the craniocervical junction
    are compressed as a result.
  biological_scale: TISSUE
  locations:
  - preferred_term: skull
    term:
      id: UBERON:0003129
      label: skull
  downstream:
  - target: Cranial Hyperostosis
  - target: Macrocephaly
  - target: Hypertelorism
  - target: Obliterated Paranasal Sinuses
  - target: Facial Diplegia
  - target: Progressive Mixed Hearing Loss
  - target: Narrow Internal Auditory Canal
  - target: Optic Atrophy from Optic Nerve Compression
  - target: Choanal Stenosis
  - target: Nasolacrimal Duct Obstruction
  - target: Small Foramen Magnum
  - target: Increased Intracranial Pressure
  - target: Cervical Spinal Canal Stenosis
  evidence:
  - reference: PMID:8827383
    reference_title: "Intracranial and extracranial reduction osteoplasty for craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The clinical course is typically characterized by progressive encroachment of the craniofacial foramina and brain by the relentless deposition of bone. Compression of cranial nerves, the foramen magnum, and intracranial contents commonly leads to blindness, loss of hearing, and death."
    explanation: >-
      Summarizes the progressive foraminal and intracranial encroachment and
      its consequences.
  - reference: PMID:3802557
    reference_title: "Dominantly inherited craniodiaphyseal dysplasia: a new craniotubular dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe craniofacial hyperostosis and sclerosis with obliteration of paranasal sinuses and foramina of the skull base"
    explanation: >-
      The dominant mother-son family shows craniofacial hyperostosis with
      obliteration of the sinuses and skull-base foramina.
phenotypes:
- name: Cranial Hyperostosis
  category: Skeletal
  description: >
    Massive hyperostosis and sclerosis of the calvaria, skull base and facial
    bones, producing severe facial deformity; calvarial thickness of nearly
    4 cm has been measured.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Craniofacial hyperostosis
    term:
      id: HP:0004493
      label: Craniofacial hyperostosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:8827383
    reference_title: "Intracranial and extracranial reduction osteoplasty for craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "characterized by massive generalized hyperostosis and sclerosis, particularly of the skull and facial bones, leading to severe deformity"
    explanation: >-
      Defines craniofacial hyperostosis as the cardinal feature.
  - reference: PMID:31132523
    reference_title: "Craniodiaphyseal dysplasia: A Rare And Successful Bone-Anchored Hearing Aid Implantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "a massive generalized hyperostosis and sclerosis, primarily involving the facial bones and the skull"
    explanation: >-
      Independent description of skull and facial-bone hyperostosis.
- name: Macrocephaly
  category: Skeletal
  description: >
    Increased head circumference from calvarial thickening, often noted in
    early infancy.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The affected patients typically present in early infancy with facial abnormalities such as paranasal bossing, hypertelorism and increased head circumference."
    explanation: >-
      The case report's literature review gives increased head circumference
      as a typical early presentation.
- name: Hypertelorism
  category: Craniofacial
  description: >
    Widely spaced eyes accompanying paranasal bossing from facial bone
    overgrowth.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The affected patients typically present in early infancy with facial abnormalities such as paranasal bossing, hypertelorism and increased head circumference."
    explanation: >-
      Names hypertelorism among the typical early facial abnormalities.
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination revealed grossly deformed head, short stature, hypertelorism and epiphora of left eye."
    explanation: >-
      Hypertelorism observed in the reported patient.
- name: Diaphyseal Sclerosis
  category: Skeletal
  description: >
    Hyperostosis and sclerosis of the diaphyses of the long bones, giving
    straight, cylindrical, undermodeled shafts, often asymmetric; the ribs,
    clavicles, spine and pelvis are less severely involved.
  phenotype_term:
    preferred_term: Diaphyseal sclerosis
    term:
      id: HP:0003034
      label: Diaphyseal sclerosis
  evidence:
  - reference: PMID:3802557
    reference_title: "Dominantly inherited craniodiaphyseal dysplasia: a new craniotubular dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The long bones show extreme asymmetric hyperostosis and sclerosis of the diaphyses and evidence of a modelling defect in the metaphyses."
    explanation: >-
      Diaphyseal hyperostosis and sclerosis in the dominant family.
  - reference: PMID:8827383
    reference_title: "Intracranial and extracranial reduction osteoplasty for craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tubular bones demonstrated the characteristic diaphyseal endostosis, undertubulation, and relative overgrowth on the involved side."
    explanation: >-
      Diaphyseal involvement of the tubular bones in a further case.
- name: Rib Sclerosis
  category: Skeletal
  description: >
    Progressive marked sclerosis and widening of the ribs with obliteration of
    the medullary cavity, radiographically evident in infancy.
  phenotype_term:
    preferred_term: Osteosclerosis of ribs
    term:
      id: HP:0006634
      label: Osteosclerosis of ribs
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive marked sclerosis and widening of the ribs with obliteration of the medullary cavity by seven months of age."
    explanation: >-
      The paper's table of radiological features gives this rib finding for
      craniodiaphyseal dysplasia, in contrast with the craniometaphyseal form.
- name: Clavicular Sclerosis
  category: Skeletal
  description: >
    Sclerosis, hyperostosis and widening of the midshaft of the clavicles,
    sparing the medial and lateral ends.
  phenotype_term:
    preferred_term: Clavicular sclerosis
    term:
      id: HP:0100923
      label: Clavicular sclerosis
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Midclavicular sclerosis, hyperostosis and widening by three months sparing the manubrial and acromial ends becoming more overgrown by five years."
    explanation: >-
      The paper's table of radiological features gives this clavicular finding
      for craniodiaphyseal dysplasia.
- name: Obliterated Paranasal Sinuses
  category: Skeletal
  description: >
    The paranasal sinuses are obliterated by hyperostotic bone.
  phenotype_term:
    preferred_term: Obliterated paranasal sinuses
    term:
      id: HP:0000245
      label: Abnormal paranasal sinus morphology
  notes: >-
    HPO has Absent paranasal sinuses (HP:0002689), defined as aplasia, and
    Opacified paranasal sinuses (HP:0034494), but no term for sinuses
    obliterated by bone overgrowth; an OLS search of hp for "paranasal sinus"
    returned those and the parent Abnormal paranasal sinus morphology, which is
    bound here.
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe craniofacial hyperostosis, sclerosis, obliteration of paranasal sinuses and foramina of skull base"
    explanation: >-
      Sinus obliteration documented by CT in a child with the disorder.
- name: Facial Diplegia
  category: Neurological
  description: >
    Bilateral facial nerve palsy from narrowing of the facial nerve canals,
    often an early and severe complication.
  phenotype_term:
    preferred_term: Facial diplegia
    term:
      id: HP:0001349
      label: Facial diplegia
  evidence:
  - reference: PMID:17853455
    reference_title: "A boy with severe craniodiaphyseal dysplasia and apparently normal mother."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial diplegia, bilateral hearing loss and optic nerve atrophy were early, severe complications of the disease."
    explanation: >-
      Facial diplegia as an early complication.
  - reference: PMID:3802557
    reference_title: "Dominantly inherited craniodiaphyseal dysplasia: a new craniotubular dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent severe bilateral hearing loss and facial diplegia with relative sparing of the optic nerves were noted."
    explanation: >-
      Facial diplegia in the dominant mother-son family.
- name: Progressive Mixed Hearing Loss
  category: Neurological
  description: >
    Bilateral hearing loss that begins as conductive, from narrowing of the
    external canal and middle ear and deformity of the ossicles, and progresses
    to a mixed loss as the internal auditory canal and eighth nerve are
    compressed.
  phenotype_term:
    preferred_term: Progressive mixed hearing impairment
    term:
      id: HP:0000410
      label: Mixed hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the craniodiaphyseal dysplasia, the hearing abnormality progressed from an initial conductive to a mixed loss on serial audiometric follow up."
    explanation: >-
      Serial audiometry documents progression from conductive to mixed loss.
  - reference: PMID:8172537
    reference_title: "Temporal bone findings in craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The air spaces of the mastoid, external auditory canal, and middle ear cavity are reduced by hyperostotic bone. The ossicles are also deformed by the bony overgrowth."
    explanation: >-
      Temporal bone histopathology shows the structural basis of the
      conductive component.
- name: Narrow Internal Auditory Canal
  category: Skeletal
  description: >
    Narrowing of the internal auditory meatus and facial nerve canal on
    temporal bone CT.
  phenotype_term:
    preferred_term: Narrow internal auditory canal
    term:
      id: HP:0011386
      label: Narrow internal auditory canal
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion."
    explanation: >-
      CT documents narrowing of the internal auditory meatus.
- name: Optic Atrophy from Optic Nerve Compression
  category: Neurological
  description: >
    Narrowing of the optic canals compresses the optic nerves, producing optic
    atrophy and blindness; the optic nerves are relatively spared in some
    patients.
  phenotype_term:
    preferred_term: Optic atrophy from cranial nerve compression
    term:
      id: HP:0007958
      label: Optic atrophy from cranial nerve compression
  evidence:
  - reference: PMID:17853455
    reference_title: "A boy with severe craniodiaphyseal dysplasia and apparently normal mother."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial diplegia, bilateral hearing loss and optic nerve atrophy were early, severe complications of the disease."
    explanation: >-
      Optic nerve atrophy as an early complication.
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Axial computed tomogram section showing bilateral optic canal narrowing"
    explanation: >-
      CT shows the optic canal narrowing that underlies the compression.
- name: Choanal Stenosis
  category: Respiratory
  description: >
    Bony narrowing of the posterior nasal apertures causing nasal obstruction;
    surgical relief is short-lived.
  phenotype_term:
    preferred_term: Choanal stenosis
    term:
      id: HP:0000452
      label: Choanal stenosis
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived."
    explanation: >-
      In this mixed series, Cases 1 and 2 are the two craniodiaphyseal
      dysplasia patients; both presented in infancy with choanal stenosis, and
      Case 1 had it drilled and dilated with bony re-obstruction within a year.
- name: Nasolacrimal Duct Obstruction
  category: Ophthalmologic
  description: >
    Progressive bony narrowing of the nasolacrimal duct causes epiphora and
    recurrent dacryocystitis.
  phenotype_term:
    preferred_term: Nasolacrimal duct obstruction
    term:
      id: HP:0000579
      label: Nasolacrimal duct obstruction
  sequelae:
  - target: Recurrent Dacryocystitis
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with abnormal facial features and recurrent dacryocystitis due to narrowing of nasolacrimal duct"
    explanation: >-
      CT-documented nasolacrimal duct narrowing in a child with the disorder.
- name: Recurrent Dacryocystitis
  category: Ophthalmologic
  description: >
    Recurrent infection of the lacrimal sac secondary to nasolacrimal duct
    narrowing.
  phenotype_term:
    preferred_term: Dacryocystitis
    term:
      id: HP:0000620
      label: Dacryocystitis
    temporality: RECURRENT
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Occasionally, they may present with recurrent dacryocystitis because of progressive stenosis of the nasolacrimal duct, which happened in our case."
    explanation: >-
      Recurrent dacryocystitis as a presentation caused by duct stenosis.
- name: Small Foramen Magnum
  category: Skeletal
  description: >
    Narrowing of the foramen magnum by hyperostosis, with risk of
    craniocervical compression.
  phenotype_term:
    preferred_term: Small foramen magnum
    term:
      id: HP:0002677
      label: Small foramen magnum
  sequelae:
  - target: Hydrocephalus
  - target: Syringomyelia
  evidence:
  - reference: PMID:14530887
    reference_title: "MR imaging features of craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MR imaging exquisitely depicted cranial nerve compression, small foramen magnum, hydrocephalus, and other intracranial complications of this syndrome."
    explanation: >-
      MRI documents a small foramen magnum in a 4-year-old with the disorder.
- name: Hydrocephalus
  category: Neurological
  description: >
    Hydrocephalus accompanying the small foramen magnum and intracranial
    encroachment.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:14530887
    reference_title: "MR imaging features of craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MR imaging exquisitely depicted cranial nerve compression, small foramen magnum, hydrocephalus, and other intracranial complications of this syndrome."
    explanation: >-
      MRI documents hydrocephalus alongside the small foramen magnum.
- name: Syringomyelia
  category: Neurological
  description: >
    A cervical cord syrinx has been demonstrated on MRI in association with a
    small foramen magnum.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Syringomyelia
    term:
      id: HP:0003396
      label: Syringomyelia
  evidence:
  - reference: PMID:14530887
    reference_title: "MR imaging features of craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A syrinx of the cervical spinal cord was demonstrated."
    explanation: >-
      Single-case MRI finding of a cervical syrinx.
- name: Increased Intracranial Pressure
  category: Neurological
  description: >
    Calvarial thickening reduces intracranial volume and compresses the brain,
    producing signs and symptoms of raised intracranial pressure that may
    require decompressive craniectomy.
  phenotype_term:
    preferred_term: Increased intracranial pressure
    term:
      id: HP:0002516
      label: Increased intracranial pressure
  sequelae:
  - target: Seizure
  - target: Intellectual Disability
  evidence:
  - reference: PMID:8827383
    reference_title: "Intracranial and extracranial reduction osteoplasty for craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant brain compression with signs and symptoms of increased intracranial pressure was managed successfully with decompressing craniectomy at age 12 years, enlarging the anterior and middle fossae."
    explanation: >-
      Documents brain compression with raised intracranial pressure.
- name: Seizure
  category: Neurological
  description: >
    Epilepsy has been attributed to progressive intracranial and foraminal
    encroachment.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:11341413
    reference_title: "Stenosis of the cervical canal in craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Hyperostosis can cause progressive foraminal stenosis leading to palsy of cranial nerves, epilepsy and mental retardation."
    explanation: >-
      Names epilepsy as a consequence of the hyperostosis.
- name: Intellectual Disability
  category: Neurological
  description: >
    Intellectual disability is reported in a proportion of patients and
    attributed to intracranial encroachment; intelligence is normal in others.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:11341413
    reference_title: "Stenosis of the cervical canal in craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Hyperostosis can cause progressive foraminal stenosis leading to palsy of cranial nerves, epilepsy and mental retardation."
    explanation: >-
      Names intellectual disability as a consequence of the hyperostosis.
- name: Cervical Spinal Canal Stenosis
  category: Skeletal
  description: >
    Hyperostosis of the cervical vertebrae narrows the spinal canal, a late
    complication reported in an adult.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cervical spinal canal stenosis
    term:
      id: HP:0008445
      label: Cervical spinal canal stenosis
  sequelae:
  - target: Tetraparesis
  evidence:
  - reference: PMID:11341413
    reference_title: "Stenosis of the cervical canal in craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the only case of CDD in an adult, with stenosis of the cervical canal leading to quadriparesis as a late complication of hyperostosis, and describe the problems associated with its treatment."
    explanation: >-
      Cervical canal stenosis from hyperostosis in an adult patient.
- name: Tetraparesis
  category: Neurological
  description: >
    Quadriparesis from cervical cord compression.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tetraparesis
    term:
      id: HP:0002273
      label: Tetraparesis
  evidence:
  - reference: PMID:11341413
    reference_title: "Stenosis of the cervical canal in craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the only case of CDD in an adult, with stenosis of the cervical canal leading to quadriparesis as a late complication of hyperostosis, and describe the problems associated with its treatment."
    explanation: >-
      Quadriparesis secondary to cervical canal stenosis.
genetic:
- name: SOST
  association: Causative
  gene_term:
    preferred_term: SOST
    term:
      id: hgnc:13771
      label: SOST
  notes: >
    Heterozygous missense variants at codon 21 in the signal peptide
    (c.61G>A, p.Val21Met; c.61G>T, p.Val21Leu). These differ from the biallelic
    loss-of-function coding variants of sclerosteosis and the biallelic
    downstream regulatory deletion of van Buchem disease.
  evidence:
  - reference: PMID:21221996
    reference_title: "Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST."
    explanation: >-
      Establishes SOST as the gene for the dominant form.
  - reference: PMID:29264888
    reference_title: "Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease."
    explanation: >-
      A review places craniodiaphyseal dysplasia with the other SOST-related
      craniotubular hyperostoses.
treatments:
- name: Decompressive Craniectomy and Reduction Osteoplasty
  description: >
    Decompressive craniectomy for brain compression and raised intracranial
    pressure, with subsequent calvarial, midfacial and mandibular recontouring.
    Continued bone deposition requires close follow-up.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: decompressive craniectomy
    term:
      id: NCIT:C51791
      label: Craniectomy
  target_mechanisms:
  - target: Increased Intracranial Pressure
    description: >-
      Enlarging the cranial fossae relieves brain compression.
  evidence:
  - reference: PMID:8827383
    reference_title: "Intracranial and extracranial reduction osteoplasty for craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant brain compression with signs and symptoms of increased intracranial pressure was managed successfully with decompressing craniectomy at age 12 years, enlarging the anterior and middle fossae."
    explanation: >-
      Single-case report of successful decompressive craniectomy.
- name: Choanal, Craniofacial and Lacrimal Surgery
  description: >
    Surgery for choanal stenosis, craniofacial remodelling and
    dacryocystorhinostomy for nasolacrimal obstruction. Benefits are
    short-lived because bone deposition continues.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: choanal, craniofacial and lacrimal surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Choanal Stenosis
  - target: Nasolacrimal Duct Obstruction
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived."
    explanation: >-
      In this mixed series, the craniodiaphyseal dysplasia patients are Cases 1
      and 2; Case 1 underwent choanal surgery and two dacryocystorhinostomies
      and Case 2 facial recontouring, each followed by bony regrowth.
- name: Bone-Anchored Hearing Aid
  description: >
    A bone-anchored hearing aid has been used successfully for progressive
    hearing loss despite the skull involvement.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: bone-anchored hearing aid implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: bone-anchored hearing aid
        term:
          id: NCIT:C185117
          label: Bone-anchored Hearing Aid
  target_mechanisms:
  - target: Progressive Mixed Hearing Loss
  evidence:
  - reference: PMID:31132523
    reference_title: "Craniodiaphyseal dysplasia: A Rare And Successful Bone-Anchored Hearing Aid Implantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, we describe the first case of craniodiaphysial dysplasia rehabilitated with Bone-Anchored Hearing Aid, despite the concerns inherent to the involvement of the skull bone that characterizes the disease."
    explanation: >-
      Single-case report of hearing rehabilitation with a bone-anchored aid.
- name: Calcitriol with Low-Calcium Diet
  description: >
    Calcitriol with a low-calcium diet, intended to increase bone resorption,
    did not alter the progression of disease in the reported cases.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Calcitriol therapy with a low calcium diet did not alter the clinical course of progression in our cases."
    explanation: >-
      Refutes efficacy of calcitriol and calcium restriction. In this mixed
      series both craniodiaphyseal dysplasia patients (Cases 1 and 2) received
      the regimen; the paper contrasts them with a craniometaphyseal case whose
      biochemistry did respond.
- name: Chemical Chaperone Therapy (Preclinical)
  description: >
    In a mouse model in which the unfolded protein response is activated in
    osteocytes, the chemical chaperone sodium 4-phenylbutyrate suppressed the
    onset of hyperostosis. Agents that improve protein folding have been
    proposed as a potential treatment, but there are no human data.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium 4-phenylbutyrate
      term:
        id: CHEBI:41500
        label: 4-phenylbutyric acid
  target_mechanisms:
  - target: Unfolded Protein Response in Osteocytes
  evidence:
  - reference: PMID:28973168
    reference_title: "Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA)."
    explanation: >-
      Mouse evidence that a chemical chaperone suppresses UPR-driven
      hyperostosis.
- name: Anesthetic Airway Management
  description: >
    Craniofacial and mandibular hyperostosis makes tracheal intubation
    difficult; fibreoptic intubation guided by a laryngeal mask airway with
    spontaneous respiration has been used.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:8732615
    reference_title: "Craniodiaphyseal dysplasia; another cause of difficult intubation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with CDD present problems to the anaesthetist, specifically difficulties with airway management and tracheal intubation. This child was managed using laryngeal mask airway (LMA) guided fibreoptic intubation."
    explanation: >-
      Case report of airway management for surgery in a child with the
      disorder.
diagnosis:
- name: Radiographic Skeletal Survey
  description: >-
    Diagnosis is principally radiological. Serial skeletal surveys show
    progressive craniofacial hyperostosis together with diaphyseal widening of
    the long bones and rib and clavicle sclerosis, which distinguishes
    craniodiaphyseal dysplasia from craniometaphyseal dysplasia and bears on
    prognosis.
  diagnosis_term:
    preferred_term: radiographic skeletal survey
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnostic distinction can now be made radiologically by serial skeletal survey which is important for prognosis."
    explanation: >-
      States that serial skeletal survey makes the diagnostic distinction.
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of craniodiaphyseal dysplasia was made on skeletal survey"
    explanation: >-
      The diagnosis in Case 1 was made on skeletal survey.
- name: Temporal Bone CT
  description: >-
    CT of the temporal bones shows narrowing of the middle ear cavity, internal
    auditory meatus and facial nerve canal, and is used to evaluate hearing
    loss and facial palsy.
  diagnosis_term:
    preferred_term: temporal bone computed tomography
    term:
      id: NCIT:C17204
      label: Computed Tomography
  evidence:
  - reference: PMID:8733453
    reference_title: "Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion."
    explanation: >-
      Temporal bone CT documents the foraminal narrowing behind the hearing
      loss and facial palsy.
- name: Brain and Craniocervical MRI
  description: >-
    MRI depicts cranial nerve compression, a small foramen magnum,
    hydrocephalus and cervical syrinx, and has been proposed as a routine part
    of evaluation.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:14530887
    reference_title: "MR imaging features of craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that MR imaging become a routine component of the evaluation of these patients."
    explanation: >-
      The authors recommend routine MRI after it revealed intracranial
      complications in their patient.
- name: SOST Sequencing
  description: >-
    Sequencing of SOST identifies heterozygous signal-peptide variants at codon
    21 and confirms the dominant SOST-related form.
  diagnosis_term:
    preferred_term: SOST sequence analysis
    term:
      id: NCIT:C153598
      label: DNA Sequencing
  evidence:
  - reference: PMID:21221996
    reference_title: "Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD."
    explanation: >-
      SOST sequencing identified the causal variants in two affected children.
animal_models:
- name: Osteocyte unfolded protein response transgenic mouse
  species: Mouse
  genotype: Transgene activating the unfolded protein response in early differentiating osteocytes
  publication: PMID:28973168
  description: >
    Transgenic mouse in which the unfolded protein response is activated in
    early differentiating osteocytes. Osteocyte maturation is delayed, Sost
    expression is delayed or suppressed, Wnt signaling is active and periosteal
    bone formation is enhanced, giving generalized hyperostosis that the
    authors judge highly consistent with craniodiaphyseal dysplasia. The
    hyperostosis is suppressed by the chemical chaperone 4-phenylbutyrate.
  evidence:
  - reference: PMID:28973168
    reference_title: "Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion."
    explanation: >-
      The authors relate the mouse phenotype to craniodiaphyseal dysplasia.
  modeled_mechanisms:
  - target: Unfolded Protein Response in Osteocytes
    relationship: PERTURBS
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      The transgene directly activates the unfolded protein response in early
      osteocytes, which then delays their maturation and suppresses Sost.
    limitations: >-
      The model carries no SOST allele: the unfolded protein response is
      induced by a transgene rather than by misfolded signal-peptide
      sclerostin, so it tests whether osteocyte ER stress can produce the
      phenotype, not whether the human SOST variants trigger it.
    evidence:
    - reference: PMID:28973168
      reference_title: "Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis."
      explanation: >-
        Shows that the model activates the osteocyte UPR and records its
        consequences for Sost and Wnt signaling.
  - target: Excessive Osteoblastic Bone Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The mouse develops generalized hyperostosis with enhanced periosteal bone
      formation, which is suppressed by 4-phenylbutyrate.
    limitations: >-
      The model carries no SOST allele, so the excess bone formation arises
      from transgene-induced ER stress rather than from the dominant
      signal-peptide sclerostin secretion defect. Craniofacial foraminal
      encroachment and cranial nerve compression, which dominate the human
      disease, are not reported in the abstract.
    evidence:
    - reference: PMID:28973168
      reference_title: "Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA)."
      explanation: >-
        Links UPR activation to hyperostosis onset in the model and shows its
        pharmacological suppression.
differential_diagnoses:
- name: Sclerosteosis
  description: >-
    Recessive SOST loss-of-function disorder with cranial hyperostosis and
    cranial nerve entrapment, distinguished by syndactyly and tall stature and
    by biallelic rather than heterozygous SOST variants.
  disease_term:
    preferred_term: sclerosteosis
    term:
      id: MONDO:0017838
      label: sclerosteosis
  evidence:
  - reference: PMID:21221996
    reference_title: "Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene."
    explanation: >-
      Places sclerosteosis in the same SOST spectrum with recessive
      inheritance.
- name: Van Buchem disease
  description: >-
    Recessive SOST regulatory-deletion disorder in which mandibular enlargement
    predominates, head circumference is normal and facial changes appear in
    the second decade.
  disease_term:
    preferred_term: van Buchem disease
    term:
      id: MONDO:0009395
      label: hyperostosis corticalis generalisata
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In Van Buchem's dysplasia, mandibular enlargement is the predominant manifestation, head circumference is normal and facial changes manifest in the second decade."
    explanation: >-
      Gives the clinical features distinguishing van Buchem disease.
- name: Camurati-Engelmann disease
  description: >-
    TGFB1-related diaphyseal dysplasia in which craniofacial involvement is
    mild and the major changes are in the long bones.
  disease_term:
    preferred_term: Camurati-Engelmann disease
    term:
      id: MONDO:0007542
      label: Camurati-Engelmann disease
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In Camurati-Engelmann, the degree of cranio-facial involvement is mild with major changes in long bones."
    explanation: >-
      Gives the feature distinguishing Camurati-Engelmann disease.
- name: Craniometaphyseal dysplasia
  description: >-
    Craniotubular dysplasia with similar skull changes but metaphyseal
    widening with club-shaped long bones, rather than the cylindrical
    diaphyseal widening of craniodiaphyseal dysplasia.
  disease_term:
    preferred_term: craniometaphyseal dysplasia
    term:
      id: MONDO:0015465
      label: craniometaphyseal dysplasia
  evidence:
  - reference: PMID:17456942
    reference_title: "Craniodiaphyseal dysplasia: an unusual cause of recurrent dacryocystitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In craniotubular dysplasia, there is metaphyseal widening and cortical thinning giving rise to club-shaped configuration of long bones whereas in craniodiaphyseal dysplasia the diaphyseal widening gives rise to cylindrical appearance"
    explanation: >-
      Gives the long-bone contour distinguishing metaphyseal craniotubular
      dysplasias.
📚

References & Deep Research

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: Craniodiaphyseal Dysplasia · 2026-09-23T19:53:38Z · View source

New entry for the autosomal dominant, SOST-related form of craniodiaphyseal dysplasia (MONDO:0021021). Deep research: one OpenScientist report, research/Craniodiaphyseal_Dysplasia-deep-research-openscientist.md (22 of 22 references resolved, none unresolved; term validation found no unresolved CURIEs but several HP identifiers named as different terms, so no CURIE was taken from the report; preflight-dr warned that SP7 content for the separate recessive form is mixed in, and that content was excluded). No GeneReviews or StatPearls chapter exists (check-genereviews --online). Pathograph: five pathophysiology nodes (SOST signal-peptide secretion defect, osteocyte unfolded protein response as an EMERGING mouse-based hypothesis group, loss of sclerostin restraint on Wnt signaling, excessive osteoblastic bone formation, progressive craniofacial hyperostosis with foraminal encroachment) reaching 20 HP-bound phenotypes, all causally connected. Genetics rest on Kim et al. 2011 (PMID:21221996); phenotypes rest on pre-molecular case reports that do not state a genotype, as recorded in the entry notes. Treatments are surgical and supportive; calcitriol with low-calcium diet is recorded with REFUTE evidence, and 4-phenylbutyrate is recorded as preclinical (mouse). Prevalence recorded as CASES_IN_LITERATURE / ULTRA_RARE. Validation: just validate-disorders passed (schema, terms, 51/51 snippets verified); causal-target, entity-ref, duplicate-key, snippet-length, title-snippet, snippet-grading, reference-title, coarse-phenotype and gene-term checks clean. Stub stubs/Craniodiaphyseal_Dysplasia_Autosomal_Dominant.yaml deleted.

OpenScientist ▸
Craniodiaphyseal Dysplasia (CDD): A Comprehensive Disease Characterization Report
openscientist-autonomous 21 citations 2026-09-23T19:42:31.917688

Craniodiaphyseal Dysplasia (CDD): A Comprehensive Disease Characterization Report

Target disease: Craniodiaphyseal Dysplasia MONDO: MONDO:0021021 | OMIM: 122860 (autosomal dominant) | Orphanet: ORPHA:1513 | Category: Mendelian sclerosing bone dysplasia

Summary

Craniodiaphyseal dysplasia (CDD) is an extremely rare, severe, progressive sclerosing bone dysplasia characterized by massive generalized hyperostosis and sclerosis of the skull and facial bones ("leontiasis ossea") together with diaphyseal hyperostosis and defective modeling of the long bones. The relentless deposition of bone progressively narrows the craniofacial foramina and encroaches on the brain, compressing cranial nerves, the foramen magnum, and intracranial contents. The clinical consequences — blindness, sensorineural and conductive hearing loss, facial palsy, raised intracranial pressure, seizures, and premature death — arise directly from this mechanical encroachment rather than from a metabolic or systemic derangement.

The molecular basis of the classic autosomal-dominant form is a defect in the secretion of sclerostin, the osteocyte-derived protein encoded by SOST. Heterozygous mutations in the SOST secretion signal peptide (c.61G>A, p.Val21Met; c.61G>T, p.Val21Leu) greatly reduce sclerostin secretion through a dominant-negative mechanism, which distinguishes CDD from the recessive loss-of-function SOST disorders sclerosteosis and van Buchem disease. Sclerostin normally binds the Wnt co-receptors LRP4/5/6 to antagonize canonical Wnt/β-catenin signaling in osteoblasts; when secreted sclerostin is reduced, this brake on bone formation is released, canonical Wnt signaling is de-repressed, and osteoblast-driven hyperostosis ensues. A phenotypically overlapping recessive form is caused by biallelic loss-of-function variants in SP7/Osterix, an osteoblast master transcription factor, establishing genetic heterogeneity for the CDD phenotype.

There is no approved disease-modifying pharmacotherapy. Management is symptomatic and surgical — decompressive craniectomy, staged craniofacial reduction osteoplasty, and rehabilitation of hearing loss (including bone-anchored hearing aids). The sclerostin–Wnt axis is strongly validated in the opposite (therapeutic) direction by the anti-sclerostin antibody romosozumab, which is bone-anabolic in osteoporosis — confirming the direction of CDD causality but implying that no safe pro-sclerostin ("bone-quieting") therapy yet exists. Preclinical leads include the chemical chaperone sodium 4-phenylbutyrate (4-PBA), which suppresses hyperostosis in an osteocyte unfolded-protein-response (UPR) mouse model consistent with CDD, and competitive modulation of the LRP4/6–sclerostin interface.

1. Disease Information

Overview. CDD is "a rare, sporadic form of craniotubular bone dysplasia, characterized by massive generalized hyperostosis and sclerosis, particularly of the skull and facial bones, leading to severe deformity" (PMID: 8827383). It is regarded as the most severe member of the SOST-related craniotubular hyperostosis spectrum.

Key identifiers.

Resource Identifier
MONDO MONDO:0021021
OMIM 122860 (Craniodiaphyseal dysplasia, autosomal dominant)
Orphanet ORPHA:1513 (Craniodiaphyseal dysplasia)
ICD-10 Q78.8 (Other specified osteochondrodysplasias)
ICD-11 LD24.Y / FB80.Y (skeletal dysplasia grouping)
MeSH Craniofacial / hyperostosis terms (no dedicated unique descriptor)
Gene(s) SOST (dominant); SP7/Osterix (recessive)

Synonyms / alternative names. Craniodiaphyseal dysplasia; CDD; "leontiasis ossea" is a descriptive term for the facial appearance (not a synonym for the disease as a whole).

Information source. The evidence base is derived almost entirely from aggregated disease-level resources and individual published case reports / small case series (OMIM, Orphanet, and a limited primary literature of fewer than ~two dozen reported patients), rather than from EHR-derived cohorts. This is a direct consequence of the disease's extreme rarity.

2. Etiology

Primary cause — genetic. CDD is a monogenic Mendelian disorder.

  • Autosomal-dominant CDD is caused by heterozygous missense mutations in the secretion signal peptide of SOST (sclerostin). Kim et al. (2011) identified c.61G>A (p.Val21Met) and c.61G>T (p.Val21Leu) in two unrelated children with CDD: "We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) [in] two children with CDD. As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST" (PMID: 21221996).
  • Autosomal-recessive CDD is caused by biallelic variants in SP7/Osterix, an osteoblast transcription factor (Hendrickx et al. 2023, PMID: 36436818; Gauthier et al. 2024, PMID: 37918503).

Genetic risk factors. The causal variants are themselves the risk determinants; there are no established common susceptibility loci or modifier genes for this ultra-rare Mendelian condition. Most dominant cases appear to arise de novo (sporadic), consistent with the disease's severity and reproductive impact.

Environmental risk factors. None established. CDD is not attributable to toxins, infection, nutrition, occupation, age, or sex. Family history is relevant only in the rare familial / recessive settings.

Protective factors. None identified. No protective alleles or environmental exposures are known.

Gene–environment interactions. None documented. The osteocyte UPR (endoplasmic reticulum stress) has been proposed as an intracellular contributory amplifier of the phenotype (see Section 6), but this is a cell-biological mechanism rather than an environmental exposure.

3. Phenotypes

CDD phenotypes are predominantly physical/skeletal manifestations and clinical signs, with secondary neurological signs from bony encroachment. Onset is in early childhood, severity is severe, and the course is progressive.

Phenotype Type Suggested HPO Onset / severity / course Notes & evidence
Cranial hyperostosis / sclerosis Physical/imaging HP:0004493 (Thickened calvaria); HP:0004437 (Cranial hyperostosis) Childhood; severe; progressive Calvarial thickness "nearly 4 cm" (PMID: 8827383)
Facial hyperostosis / distortion ("leontiasis ossea") Physical sign HP:0011856 (facial bone hyperostosis) Childhood; severe; progressive Massive facial bone deposition (PMID: 8827383)
Macrocephaly Physical sign HP:0000256 Childhood (PMID: 14564212)
Diaphyseal hyperostosis / defective long-bone modeling (undertubulation) Imaging HP:0100670 (Diaphyseal sclerosis); HP:0005791 (Undertubulation) Childhood; progressive (PMID: 1987972; PMID: 14564212)
Clavicular / rib / axial sclerosis Imaging HP:0100692 (Sclerotic clavicle) Childhood; progressive (PMID: 14564212)
Optic atrophy / visual loss / blindness Neurological sign HP:0000648 (Optic atrophy); HP:0000618 (Blindness) Childhood–adolescence; progressive Cranial-nerve II compression (PMID: 8827383)
Hearing loss (sensorineural + conductive) Sign HP:0000407 (SNHL); HP:0000405 (conductive) Childhood; progressive (PMID: 8827383; PMID: 31132523)
Facial nerve palsy Sign HP:0010628 (Facial palsy) Childhood; progressive Foraminal narrowing (PMID: 8827383)
Raised intracranial pressure Sign HP:0002516 Childhood; progressive (PMID: 8827383; PMID: 1987972)
Seizures Sign HP:0001250 Variable (PMID: 1987972)

Frequency. Because reported cases number only in the low tens, phenotype frequencies are qualitative. Craniofacial hyperostosis, facial distortion, and diaphyseal long-bone involvement are essentially universal (defining features); cranial-nerve compression syndromes (visual loss, hearing loss, facial palsy) and raised ICP are common and progressive.

Quality-of-life impact. Severe and multi-domain: progressive sensory loss (blindness, deafness), facial disfigurement, chronic headache from raised ICP, and neurological morbidity substantially impair daily functioning. No formal EQ-5D/SF-36/PROMIS data exist for this ultra-rare disease.

4. Genetic / Molecular Information

Causal genes.

Gene HGNC / locus Inheritance OMIM Role
SOST (sclerostin) HGNC:13771; 17q21.31 Autosomal dominant 122860 (CDD); 605740 (SOST) Osteocyte-secreted Wnt antagonist
SP7 / Osterix HGNC:17321; 12q13.13 Autosomal recessive 606633 (SP7) Osteoblast master transcription factor

Pathogenic variants (dominant SOST).

  • c.61G>A (p.Val21Met) and c.61G>T (p.Val21Leu) — missense substitutions within the secretion signal peptide. Both were shown to greatly reduce SOST secretion in transfected 293E cells (PMID: 21221996).
  • Variant type/class: missense, signal-peptide.
  • Functional consequence: dominant-negative reduction of extracellular sclerostin (not simple haploinsufficiency). Kim et al. conclude: "Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits[, CDD] seem to be caused by a dominant negative mechanism" (PMID: 21221996).
  • Classification (ACMG/AMP): pathogenic (functional secretion assay + segregation with severe phenotype).
  • Allele frequency: absent from population databases (gnomAD) — private, disease-causing variants.
  • Origin: germline; dominant cases frequently de novo.

Pathogenic variants (recessive SP7). Gauthier et al. reported biallelic loss-of-function variants — c.359_362del (p.Asp120Valfs*11) and c.1163_1174delinsT (p.Pro388Leufs*33) — producing a sclerotic skeletal dysplasia overlapping juvenile Paget's disease and CDD: "SP7 variants may also cause sclerotic skeletal dysplasias (SSD), partially overlapping with Juvenile Paget's disease and craniodiaphyseal dysplasia, characterized by skull hyperostosis, long bones sclerosis, large ribs and clavicles, and possible recurrent fractures" (PMID: 37918503). These are biallelic frameshift loss-of-function variants.

Modifier genes. None formally established. The wider Wnt/sclerostin axis genes (LRP4, LRP5, LRP6) are mechanistically adjacent (Section 6) and were explicitly excluded in a mild adult CDD-like case (Janssens et al. 2003, PMID: 14564212).

Epigenetic information. No disease-specific DNA-methylation or histone data for CDD. At the mechanistic level, osteocyte ER stress/UPR modulates SOST transcription (Section 6), but this is regulatory rather than a documented epigenetic mark.

Chromosomal abnormalities. None; CDD is a single-gene disorder without characteristic aneuploidy, translocation, or copy-number signature.

5. Environmental Information

  • Environmental factors: None identified. CDD is not linked to toxins, radiation, or occupational exposure.
  • Lifestyle factors: None. Not related to smoking, diet, exercise, or alcohol.
  • Infectious agents: Not applicable; CDD is non-infectious.

(The osteocyte UPR mechanism (Section 6) is an intrinsic cell-stress pathway, not an environmental exposure, though in principle it could be modulated pharmacologically.)

6. Mechanism / Pathophysiology

Ordered causal chain

  1. A heterozygous SOST signal-peptide mutation (p.Val21Met / p.Val21Leu) is present in osteocytes → impairs trafficking/secretion of sclerostin (demonstrated in 293E cells) via a dominant-negative effect (PMID: 21221996).
  2. Reduced secretion leads to decreased extracellular sclerostin available at the bone surface.
  3. Because sclerostin normally binds LRP4/5/6 to antagonize canonical Wnt/β-catenin signaling, its deficiency results in de-repression (activation) of Wnt/β-catenin signaling in osteoblasts (PMID: 19936252; PMID: 35099616).
  4. Activated Wnt signaling drives osteoblast commitment, differentiation, and enhanced periosteal/endosteal bone formation → generalized hyperostosis (PMID: 28973168).
  5. (Inferred amplifier branch) Osteocyte ER stress / unfolded protein response (UPR) can independently delay osteocyte maturation and suppress SOST expression, converging on the same "low sclerostin → active Wnt → hyperostosis" output (PMID: 28973168).
  6. Sustained bone deposition produces craniofacial + diaphyseal hyperostosis that narrows the skull foramina and the foramen magnum.
  7. Foraminal narrowing compresses cranial nerves and the brainstem, which results in optic atrophy/blindness, sensorineural + conductive hearing loss, facial palsy, raised intracranial pressure, and death (PMID: 8827383).

Convergent recessive branch: biallelic loss of SP7/Osterix disrupts osteoblast transcriptional programming and leads to an overlapping sclerotic skeletal phenotype (PMID: 36436818; PMID: 37918503).

 SOST signal-peptide mutation (dominant-negative)          SP7/Osterix biallelic LOF
      |                                                      |
   impaired sclerostin secretion                          disrupted osteoblast
      |                                            transcriptional program
     ↓ extracellular sclerostin                                     |
      |                                                     |
   de-repressed Wnt/β-catenin  ←── (osteocyte UPR suppresses SOST)  |
      |                                                     |
     ↑ osteoblast bone formation  ←─────────────────────────────────┘
      |
   generalized HYPEROSTOSIS (cranium, face, diaphyses)
      |
   narrowing of skull foramina / foramen magnum
      |
   cranial-nerve & brainstem compression → blindness, deafness,
   facial palsy, ↑ICP, death

Detail by category

  • Molecular pathways: Canonical Wnt/β-catenin signaling is the central pathway; sclerostin is its physiologic osteocyte-derived antagonist acting at LRP4/5/6 co-receptors. Sclerostin also modulates BMP signaling (PMID: 19936252).
  • Cellular processes: Osteoblast commitment, differentiation, matrix formation/mineralization; osteocyte maturation. GO suggestions: GO:0001649 (osteoblast differentiation), GO:0060348 (bone development), GO:0045668 (negative regulation of osteoblast differentiation — normally exerted by sclerostin), GO:0016055 (Wnt signaling pathway), GO:0030282 (bone mineralization), GO:0030968 (endoplasmic reticulum unfolded protein response).
  • Protein dysfunction: Sclerostin (UniProt Q9BQB4) is a secreted glycoprotein; the signal-peptide mutation impairs its secretion, reducing the extracellular pool — a functional loss at the tissue level achieved through a dominant-negative cellular mechanism.
  • Metabolic changes: No characteristic systemic metabolic derangement in CDD. (Osteocyte bioenergetics/PPARG links to sclerostin exist in the broader literature but are not CDD-specific.)
  • Immune system involvement: None; CDD is not an immunologic or inflammatory disease.
  • Tissue-damage mechanisms: Injury is mechanical/compressive — bony encroachment on neural foramina causing compression neuropathy of cranial nerves and brainstem, plus raised ICP — rather than oxidative, fibrotic, or necrotic.
  • Biochemical abnormalities: Deficiency of functional extracellular sclerostin at the osteocyte–osteoblast interface.
  • Epigenetic changes: Not established for CDD.
  • Molecular profiling: No human transcriptomic/proteomic/metabolomic CDD datasets; mechanistic data derive from mouse models and in vitro assays.

Cell types involved (CL suggestions): osteocyte (CL:0000137), osteoblast (CL:0000062), osteoprogenitor/mesenchymal stem cell (CL:0000134). Anatomical/UBERON: cranium/skull (UBERON:0003128 / UBERON:0000209), facial bone, diaphysis of long bone (UBERON:0004769), periosteum (UBERON:0002515), foramen magnum.

7. Anatomical Structures Affected

Organ level. - Primary: Bone — skull/calvaria, facial bones, mandible; long-bone diaphyses; clavicles, ribs, axial skeleton (macrocephaly; near-4-cm calvarial thickness; PMID: 8827383; PMID: 14564212). - Secondary: Nervous system — cranial nerves (II optic, VII facial, VIII vestibulocochlear), brainstem, and brain, through foraminal narrowing and raised ICP (PMID: 8827383); special-sense organs (visual and auditory systems). - Body systems: skeletal (primary); nervous and sensory (secondary).

Tissue and cell level. Connective tissue — bone. Cellular effectors: osteoblasts (excessive bone formation) driven by loss of the osteocyte-derived sclerostin brake (CL:0000062, CL:0000137).

Subcellular level. Endoplasmic reticulum / secretory pathway — the signal-peptide mutation impairs ER-to-extracellular trafficking of sclerostin; osteocyte ER stress/UPR is implicated as an amplifier. GO cellular-component suggestions: GO:0005783 (endoplasmic reticulum), GO:0005576 (extracellular region), GO:0005615 (extracellular space).

Localization / lateralization. Bilateral and symmetric skeletal involvement. Temporal-bone CT in the SOST hyperostosis spectrum shows "diffuse osteosclerosis affecting the bilateral ossicular chains and internal auditory meatus, as well as stenosis of the bilateral internal auditory meatus" (PMID: 40605263).

8. Temporal Development

  • Onset: Early childhood; congenital predisposition with clinical manifestation in the first years of life. Reported probands are children (Kim's two patients; a 10-year-old with hearing loss, PMID: 31132523; a patient requiring decompression at age 12, PMID: 8827383). Rare milder cases are diagnosed in adulthood (56-year-old woman, PMID: 14564212).
  • Onset pattern: insidious, chronic.
  • Progression: relentless and progressive — "progressive encroachment of the craniofacial foramina and brain by the relentless deposition of bone" (PMID: 8827383). No spontaneous remission.
  • Disease course: chronic, lifelong, progressive; not episodic or relapsing-remitting.
  • Critical periods: Childhood and adolescence — the window in which bony overgrowth compromises neural foramina and interventions (decompression) can preserve vision, hearing, and life.

9. Inheritance and Population

Epidemiology. Extremely rare — described as "extremely rare" (PMID: 21221996) and "a rare, sporadic form of craniotubular bone dysplasia" (PMID: 8827383). Orphanet lists an estimated prevalence <1/1,000,000; fewer than ~two dozen cases are reported worldwide. Precise incidence/prevalence figures cannot be reliably estimated.

Genetic etiology. - Inheritance: Autosomal dominant (SOST signal-peptide mutations), typically de novo/sporadic; autosomal recessive (biallelic SP7/Osterix). - Penetrance / expressivity: Dominant SOST cases are severe and appear highly penetrant; expressivity is variable across the SOST hyperostosis spectrum (severe classic CDD to milder adult-diagnosed cases). - Genetic anticipation: Not applicable (no repeat-expansion mechanism). - Germline mosaicism / founder effects / consanguinity: No documented founder effect for CDD; consanguinity is relevant to the recessive SP7 form. (By contrast, the related recessive disorder sclerosteosis shows a well-known Afrikaner founder effect: minimum prevalence ~1/75,000, gene frequency ~0.0035, PMID: 187366 — but this is a distinct disease.) - Carrier frequency: Not applicable for the dominant form; not established for recessive SP7.

Population demographics. No ethnic predilection established for CDD; cases are geographically scattered. Sex ratio approximately equal (autosomal inheritance); reported in both sexes, with pregnancies managed in an affected woman (PMID: 1987972). Age distribution skews to pediatric diagnosis.

10. Diagnostics

Clinical/imaging (the diagnostic cornerstone). - Radiography/CT: massive skull and facial-bone hyperostosis/sclerosis with facial distortion and macrocephaly; long-bone diaphyseal endostosis with undertubulation (loss of normal metaphyseal modeling); sclerotic clavicles, ribs, and axial skeleton (PMID: 8827383; PMID: 1987972; PMID: 14564212). Janssens et al.: "marked sclerosis and hyperostosis of the skull bones is present resulting in macrocephaly. Most tubular bones of the limbs, as well as the clavicles, are affected by sclerosis" (PMID: 14564212). - Temporal-bone CT (SOST spectrum): "diffuse osteosclerosis affecting the bilateral ossicular chains and internal auditory meatus, as well as stenosis of the bilateral internal auditory meatus" (PMID: 40605263). - MRI: skull thickening with loss of the diploic marrow signal. - Laboratory tests / biomarkers: No specific diagnostic blood/urine biomarker. Serum sclerostin could in principle be low; bone-turnover markers reflect bone formation but are non-specific. No validated CDD biomarker exists. - Audiometry / ophthalmology: to detect and monitor cranial-nerve compression (hearing loss, optic atrophy).

Genetic testing (confirmatory). - Recommended approach: targeted single-gene SOST sequencing for suspected dominant CDD; WES/WGS or a sclerosing bone dysplasia gene panel when the phenotype overlaps other craniotubular disorders, which also captures recessive SP7/Osterix (PMID: 21221996; PMID: 36436818). - CMA / karyotype / FISH / mtDNA / repeat-expansion testing are not indicated (single-gene, non-structural, non-mitochondrial, non-repeat disorder).

Clinical criteria / differential diagnosis. Diagnosis rests on the characteristic craniofacial + diaphyseal radiographic pattern plus molecular confirmation. CDD must be differentiated from other craniotubular hyperostoses:

Condition Gene Inheritance Distinguishing features vs CDD
Craniodiaphyseal dysplasia SOST (signal peptide) / SP7 AD / AR Most severe; massive facial hyperostosis; no syndactyly
Sclerosteosis SOST (LOF) AR Syndactyly of 2nd/3rd fingers, gigantism (PMID: 1259284; PMID: 187366)
Van Buchem disease SOST (regulatory) AR Milder; no syndactyly
Craniometaphyseal dysplasia ANKH/GJA1 AD/AR Metaphyseal (not diaphyseal) flaring; can be misdiagnosed as CDD (PMID: 40639871)
Camurati-Engelmann disease TGFB1 AD Diaphyseal dysplasia; TGFB1 excluded in a CDD case (PMID: 14564212)

The three SOST-related craniotubular hyperostoses are grouped mechanistically: "Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease" (PMID: 29264888). The recessive disorder sclerosteosis is set apart by additional limb findings: "Sclerosteosis is a unique autosomal recessive condition in which skeletal overgrowth is associated with syndactyly and digital malformation" (PMID: 1259284).

Screening. No population newborn or carrier screening (ultra-rare, mostly de novo dominant). Cascade/prenatal testing is possible in families with a known variant.

11. Outcome / Prognosis

  • Survival / mortality: Guarded. The natural course leads to "compression of cranial nerves, the foramen magnum, and intracranial contents [that] commonly leads to blindness, loss of hearing, and death" (PMID: 8827383). No formal 5-/10-year survival statistics exist owing to rarity; premature death from brainstem/foramen-magnum compression or raised ICP is a recognized outcome.
  • Morbidity / disability: High and progressive — blindness, deafness, facial palsy, chronic headache, facial disfigurement, neurological impairment. Substantial lifelong disability.
  • Quality of life: Severely affected across sensory, functional, and psychosocial domains; no disease-specific QoL instruments applied.
  • Complications: Cranial-nerve palsies, raised intracranial pressure, seizures, and (in the recessive SP7 form) recurrent fractures (PMID: 37918503).
  • Recovery potential: No spontaneous recovery; surgical decompression can preserve function and life but does not halt the underlying bone deposition.
  • Prognostic factors: Severity and rate of foraminal narrowing; timeliness of decompressive surgery; degree of cranial-nerve involvement at presentation. No molecular prognostic biomarker validated.

12. Treatment

No approved disease-modifying pharmacotherapy exists. Management is symptomatic, surgical, and rehabilitative.

Surgical / interventional (mainstay). - Decompressive craniectomy for raised ICP: "Significant brain compression with signs and symptoms of increased intracranial pressure was managed successfully with decompressing craniectomy at age 12 years, enlarging the anterior and middle fossae. Calvarial thickness measured nearly 4 cm" (PMID: 8827383). - Staged craniofacial / mandibular reduction osteoplasty (recontouring) for deformity and foraminal decompression (PMID: 8827383). (NCIT: cranial decompression; craniofacial reconstructive surgery.) - Decompression of specific neural foramina (e.g., optic canal, internal auditory meatus) to preserve vision and hearing.

Supportive / rehabilitative. - Bone-anchored hearing aid (BAHA) for hearing rehabilitation: "we describe the first case of craniodiaphysial dysplasia rehabilitated with Bone-Anchored Hearing Aid, despite the concerns inherent to the involvement of the skull bone that characterizes the disease" (PMID: 31132523). (NCIT: hearing aid; auditory rehabilitation.) - Ophthalmologic and audiologic surveillance; symptomatic management of headache and seizures.

Pharmacotherapy / advanced therapeutics. None approved. The sclerostin–Wnt axis is pharmacologically validated in the opposite direction: the anti-sclerostin antibody romosozumab is bone-anabolic — "Romosozumab, a sclerostin inhibitor with both anabolic and antiresorptive effects" (PMID: 42761068) — increasing spine and hip BMD in osteoporosis (lumbar spine +14.47 ± 8.74%, p<0.001; total hip +4.15 ± 5.92%, p<0.001; PMID: 42417976). This confirms that lowering sclerostin drives bone gain (the CDD direction) but implies there is no safe pro-sclerostin ("bone-quieting") therapy currently available. A theoretical CDD therapy would need to restore Wnt inhibition (e.g., sclerostin replacement/mimetic or LRP6 modulation) — the reverse of osteoporosis drug development.

Experimental / preclinical leads. - Chemical chaperone sodium 4-phenylbutyrate (4-PBA): suppressed hyperostosis in the osteocyte-UPR mouse model consistent with CDD — "A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA)" (PMID: 28973168). - LRP4–sclerostin interface modulation: competitive blocking studied for anabolism (PMID: 35099616) — conceptually reversible for CDD.

Personalized/genotype-guided care. Distinguishing dominant SOST from recessive SP7 CDD informs recurrence-risk counseling and prognosis but does not yet change pharmacologic management.

13. Prevention

  • Primary prevention: Not possible — a genetic disorder, largely de novo. No modifiable risk factors.
  • Secondary prevention: Early diagnosis (radiographic + molecular) and surveillance of vision, hearing, and ICP to time decompressive surgery before irreversible cranial-nerve damage — the principal opportunity for prevention of morbidity.
  • Tertiary prevention: Surgical decompression and reduction osteoplasty to prevent blindness, deafness, and death from foraminal/brainstem compression; hearing rehabilitation.
  • Immunization / public-health / environmental interventions: Not applicable.
  • Genetic counseling: Central. For dominant SOST CDD, counsel on de novo occurrence and 50% transmission risk from an affected parent; for recessive SP7 CDD, counsel on 25% recurrence and consanguinity. Prenatal / preimplantation genetic testing is feasible when the familial variant is known.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring companion-animal or wildlife equivalent of CDD is documented in OMIA. Disease knowledge derives from engineered laboratory models (Section 15).
  • Orthologous genes: Sost (mouse, NCBI Gene 74499; Mus musculus, NCBI:txid10090); Sp7/Osterix (mouse). Both are conserved and functionally validated (below).
  • Comparative biology: Sost-deficient mice recapitulate the high-bone-mass consequence of sclerostin loss, and "Sost/SOST deficiency induces lifelong bone gain in mice and humans" (PMID: 23901037) — demonstrating strong evolutionary conservation of the sclerostin–Wnt bone-formation mechanism.
  • Transmission / zoonosis: Not applicable (non-infectious genetic disease).

15. Model Organisms

Mammalian (mouse) models are the principal system.

Model Type Key phenotype Relevance to CDD Evidence
Sost−/− (global KO) Knockout High bone mass via increased bone formation; elevated femoral-neck BV/TV Models the sclerostin-deficiency → high-bone-mass output PMID: 33339872; PMID: 31437568
Sost/SOST deficiency (mouse + human) Genetic Lifelong bone gain Cross-species validation of mechanism PMID: 23901037
AAV8-Sp7-Cre postnatal Sost KO Conditional/somatic Increased bone anabolism in adults; decreased canalicular density Confirms postnatal role of Sost in bone homeostasis PMID: 36462771
Osteocyte-UPR transgenic Transgenic (gain of ER stress) Generalized hyperostosis; SOST suppressed; Wnt activated; rescued by 4-PBA Phenotype "highly consistent with craniodiaphyseal dysplasia" — closest CDD-specific model PMID: 28973168

Phenotype recapitulation. Sost-loss models faithfully reproduce the high-bone-mass / hyperostosis endpoint central to CDD ("Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes", PMID: 33339872), and the osteocyte-UPR transgenic reproduces generalized hyperostosis explicitly likened to CDD with a druggable rescue: "As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients" (PMID: 28973168).

Limitations. No mouse carries the exact human SOST signal-peptide (p.Val21Met/Leu) dominant-negative allele; existing KOs model loss of function rather than the dominant-negative secretion defect. Murine models capture bone overgrowth but incompletely reproduce the human craniofacial "leontiasis ossea" and cranial-nerve compression syndrome. A caution flag from the literature: Sost haploinsufficiency combined with glucocorticoid excess produced lethal cardiac tamponade in mice (PMID: 30664862), highlighting potential off-target cardiovascular effects of sclerostin-axis manipulation.

Resources: MGI (mouse Sost, Sp7); IMPC/KOMP for conditional alleles.

Mechanistic Model / Interpretation

CDD is best understood as a "loss-of-the-brake" bone disease. Sclerostin is the physiologic osteocyte-derived antagonist that restrains Wnt-driven osteoblast bone formation by binding LRP4/5/6. In dominant CDD, a signal-peptide mutation blocks sclerostin from leaving the cell (a dominant-negative secretion defect), so the extracellular brake is lost, canonical Wnt/β-catenin signaling runs unchecked, and osteoblasts deposit bone relentlessly across the skull, face, and diaphyses. Because the skull is a closed compartment perforated by fixed foramina, the pathology's clinical severity comes not from any metabolic toxicity but from mechanical geometry: bone fills the foramina and cranial cavity, strangling cranial nerves II/VII/VIII and the brainstem. The osteocyte UPR provides a plausible intracellular amplifier that further suppresses SOST and can, on its own, generate a CDD-like phenotype in mice. A parallel recessive route through SP7/Osterix loss reaches an overlapping sclerotic phenotype by disrupting the osteoblast transcriptional program upstream/parallel to the sclerostin–Wnt node.

The therapeutic corollary is striking and well-supported: pharmaceutical companies deliberately inhibit sclerostin (romosozumab) to build bone in osteoporosis. CDD is essentially the endogenous, lifelong version of that intervention. This confirms the causal direction beyond doubt but also explains why no drug exists for CDD — the field has optimized tools to lower sclerostin, whereas CDD needs the opposite (restore Wnt inhibition), a direction with no approved agent and the added hazard, seen in mice, of cardiovascular effects from sclerostin-axis perturbation.

Evidence Base

PMID Title (abbrev.) Contribution
21221996 SOST signal-peptide mutations in AD CDD Landmark — identifies causal p.Val21Met/Leu; demonstrates reduced secretion; establishes dominant-negative mechanism
8827383 Reduction osteoplasty for CDD Core clinical phenotype, progression, cranial-nerve compression, surgical decompression
28973168 Osteocyte UPR causes CDD-consistent hyperostosis UPR→SOST suppression→Wnt→hyperostosis; 4-PBA rescue; CDD-like mouse model
19936252 Lrp4, receptor for sclerostin Sclerostin binds LRP5/6 and inhibits Wnt — normal function whose loss drives CDD
35099616 Blocking LRP4–sclerostin interface Confirms LRP4/6–sclerostin mechanism; reversible-modulation concept
36436818 Recessive CDD from SP7/Osterix Establishes genetic heterogeneity (recessive form)
37918503 SP7-related bone disorder follow-up Biallelic SP7 LOF variants; CDD-overlapping sclerotic dysplasia
29264888 Sclerostin mechanisms/disorders Groups CDD with sclerosteosis & van Buchem (SOST spectrum)
1259284 / 187366 Sclerosteosis clinical features Differential diagnosis: recessive, syndactyly, founder effect
40639871 CMD misdiagnosed as CDD Differential: craniometaphyseal dysplasia
14564212 Mild CDD case Milder/adult phenotype; excluded TGFB1/LRP5; radiographic features
40605263 SOST LOF, sclerosteosis-1 Temporal-bone CT findings in SOST hyperostosis spectrum
31132523 BAHA in CDD Hearing rehabilitation option
1987972 Pregnancy in CDD Raised ICP, cranial-nerve palsies, seizures, long-bone modeling defects
23901037 Reversing SOST-deficiency disorders Cross-species: SOST deficiency → lifelong bone gain
33339872 / 31437568 / 36462771 Sost KO mouse models High-bone-mass phenotype validating the mechanism
42761068 / 42417976 Romosozumab Anti-sclerostin antibody is bone-anabolic — validates CDD causal direction
30664862 Sost haploinsufficiency → cardiac tamponade Safety caution for sclerostin-axis manipulation

Evidence-source mix: human clinical case reports/series (phenotype, surgery, genetics), in vitro secretion assay (293E cells), and model-organism (mouse) studies. No large human cohorts, omics datasets, or randomized trials exist for CDD itself.

Limitations and Knowledge Gaps

  1. Tiny evidence base. Fewer than ~two dozen reported CDD cases; almost all knowledge is from case reports. Prevalence, incidence, penetrance, and QoL are estimated qualitatively, not measured.
  2. Genotype–phenotype spectrum incompletely defined. Only two dominant SOST signal-peptide alleles and a few recessive SP7 variants are described; the full mutational spectrum and modifiers are unknown.
  3. Dominant-negative mechanism partly inferred. Reduced secretion is demonstrated in a cell line; how mutant sclerostin dominantly interferes with wild-type protein at the tissue level is not fully resolved. The UPR amplifier is a plausible but not yet human-confirmed contributor.
  4. No faithful animal model of the human allele. Existing mice model loss-of-function or ER stress, not the specific dominant-negative signal-peptide defect, and do not fully reproduce craniofacial/cranial-nerve pathology.
  5. No disease-modifying therapy or trials. Management is entirely symptomatic/surgical; the required "pro-sclerostin/Wnt-inhibition" direction has no approved drug and carries potential cardiovascular risk.
  6. No CDD-specific omics. No transcriptomic, proteomic, metabolomic, or epigenomic patient datasets exist.

Proposed Follow-up Experiments / Actions

  1. Generate a knock-in mouse carrying the human SOST p.Val21Met (or p.Val21Leu) allele to model the dominant-negative secretion defect and test whether it reproduces craniofacial hyperostosis and cranial-nerve compression.
  2. Test sclerostin-restoring / Wnt-inhibiting strategies preclinically — recombinant/engineered sclerostin mimetics, LRP6 antagonism, or DKK1 pathway modulation — to establish proof-of-concept for slowing bone deposition, monitoring for the cardiovascular signal flagged in PMID: 30664862.
  3. Evaluate chemical chaperones (4-PBA) and broader UPR modulators in CDD-relevant models, building on PMID: 28973168, toward a repurposing rationale.
  4. Establish an international CDD registry / natural-history study pooling SOST and SP7 cases to quantify onset, progression rate, cranial-nerve outcomes, surgical timing/efficacy, and survival.
  5. Standardize molecular diagnosis via a sclerosing bone dysplasia gene panel (including SOST, SP7, ANKH, TGFB1, LRP5) with functional secretion assays for novel SOST variants.
  6. Patient-derived iPSC osteocyte/organoid models to study the dominant-negative secretion defect and UPR in a human genetic background and to screen candidate therapeutics.
  7. Prospective surveillance protocols (serial vision, audiometry, ICP/imaging) to define optimal timing of decompressive surgery — the current best lever on morbidity and mortality.

Report compiled from 12 confirmed findings across 33 reviewed papers over 5 investigation iterations. Evidence types: human clinical (case reports/series), in vitro (secretion assays), and model-organism (mouse). CDD remains an ultra-rare disorder where mechanistic understanding substantially outpaces therapeutic options.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 22
Resolved 22
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 22
On topic 12
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:187366 (5 mentions) - Sclerosteosis - an autosomal recessive disorder
  • shared terms: recessive

Weighed against this report's own most characteristic terms: cdd, bone, sost, sp7, sclerostin, disease, recessive, hyperostosis, loss, mechanism, dysplasia, secretion, upr, phenotype, dominant, osteocyte, genetic, wnt, craniofacial, model.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 34
Resolved 30
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 3
Terms whose name was checked 7
Terms named correctly 1
Terms named as a different term 6

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:0021021 (3 mentions) - the report calls it "if available", "MONDO"; MONDO calls it craniodiaphyseal dysplasia, autosomal dominant
  • HP:0011856 (1 mention) - the report calls it "facial bone hyperostosis"; HP calls it Pica
  • HP:0000256 (1 mention) - the report calls it "Physical sign"; HP calls it Macrocephaly
  • HP:0100692 (1 mention) - the report calls it "Sclerotic clavicle"; HP calls it Increased corneal curvature
  • HP:0002516 (1 mention) - the report calls it "Sign"; HP calls it Increased intracranial pressure
  • HP:0001250 (1 mention) - the report calls it "Sign"; HP calls it Seizure

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0021021 - called "if available", "MONDO"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.