Hyperostosis Cranialis Interna

Mendelian MONDO:0007765 Pathograph 19 Show in embeddings browser Sclerosing bone dysplasia Hereditary disease

Hyperostosis cranialis interna is an autosomal dominant sclerosing bone dysplasia in which the calvaria and skull base thicken progressively from the inside. As the bone grows inward it narrows the neuroforamina, and the disease presents as sequential entrapment of cranial nerves rather than as anything skeletal: loss of smell, visual and facial sensory impairment, recurrent facial palsy, hearing loss and vestibular areflexia, usually beginning in the second decade. Its defining feature is what it spares. This is the only genetic bone dysplasia confined to the craniofacial area; the rest of the skeleton is normal. That distinguishes it from the sclerosing dysplasias it otherwise resembles, van Buchem disease, sclerosteosis, craniometaphyseal dysplasia and Camurati-Engelmann disease, all of which involve the long bones. Two other observations sharpen the picture: the thickening is almost entirely of the inner table, and the deposited bone is less dense than normal cortical bone, so this is not simply more of the same tissue. Histology shows increased bone formation with normal tissue architecture, and biochemical markers are normal. The molecular cause is a dominant L441R substitution in SLC39A14, which encodes the zinc transporter ZIP14. The mutant protein is not trafficked to the plasma membrane and instead accumulates zinc inside the cell, which hyperactivates cAMP-CREB and NFAT signalling. Conditional mice overexpressing the equivalent allele in osteoblasts reproduce the cellular mechanism, with a marked increase in cortical thickness from enhanced endosteal bone formation. They reproduce it in the wrong bones. The thickening appears in the long bones, while the calvaria, the one site that defines the human disease, shows no phenotype at all: calvarial thickness and porosity are not significantly different from controls. The authors say they were surprised by this and call it truly opposite to what is seen in patients. The same calvarial sparing appears in the plain Zip14 null, so it is not an artefact of the knock-in construct. The open question this leaves is therefore not why the human disease is confined to the skull, but why murine calvariae appear protected from a zinc-handling lesion that affects the rest of the same animal's skeleton. The model also shows something the human disease does not: osteoporotic trabecular bone alongside the thickened long-bone cortex. The authors note this mirrors the disparate actions of oestrogen on the two bone compartments. Whether HCI patients have an unrecognised trabecular phenotype, or whether this is an artefact of overexpression, is unresolved and is recorded as a gap rather than assumed either way.

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1
Mappings
1
Inheritance
7
Pathophys.
11
Phenotypes
4
Gaps
19
Pathograph
1
Genes
1
Medical Actions
4
Differentials
1
Models
2
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0007765 hyperostosis cranialis interna
skos:exactMatch MONDO
MONDO:0007765 is the hyperostosis cranialis interna concept modeled by this entry, corresponding to OMIM 144755.
👪

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant, established across four generations of three related Dutch families with common progenitors.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:20140965 SUPPORT Human Clinical
"The disorder appears to have an autosomal-dominant transmission pattern."
States the inheritance pattern from the pedigree analysis.
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Discussions and Knowledge Gaps

4
Is the excess bone in this disease driven by increased formation, decreased resorption, or both?
KNOWLEDGE GAP OPEN hci_formation_versus_resorption
Attached to
pathophysiology#Enhanced Endosteal Bone Formation
The node is graded ESTABLISHED on the strength of patient histology showing increased bone formation with normal tissue structure, and that is what the cached source says. But the two mouse models point different ways: the osteoblast conditional knock-in implicates increased formation, while the published ZIP14 null work has been read as implicating decreased resorption. Those are different mechanistic claims with different therapeutic implications, and nothing in the reference cache adjudicates between them. The distinction is not academic. If the excess is a resorption failure, the osteoclast is the effector cell and this entry names the wrong one; the formation reading is the one the human histology supports, which is why it is curated, but a curator should know the alternative exists.
What are serum and tissue zinc, manganese and iron levels in patients with this disease?
KNOWLEDGE GAP OPEN hci_metal_levels_never_measured
Attached to
pathophysiology#Intracellular Zinc Accumulation differential_diagnoses#Hypermanganesemia with dystonia 2
The mechanism curated here is a metal-transport defect producing intracellular zinc accumulation, and that has been shown in cells. It has never been measured in a patient: no serum or tissue zinc, manganese or iron levels have been reported in this disease. The gap is sharper than it looks because of the allelic disease. Biallelic loss of the same transporter causes manganese accumulation that is measurable in blood and treatable by chelation. Whether the dominant mistrafficking allele produces any systemic metal disturbance at all is unknown, and the answer bears directly on whether the chelation boundary this entry draws is a boundary of mechanism or merely one of untested assumption.
Why are murine calvariae spared by a lesion that produces calvarial hyperostosis in patients?
HUMAN MODEL MISMATCH OPEN hci_murine_calvarial_sparing
Attached to
pathophysiology#Calvarial and Skull Base Hyperostosis animal_models#Osteoblast-conditional L438R Zip14 knock-in mouse
Cranial confinement is the defining feature of this disease and the one thing that separates it from every other sclerosing bone dysplasia. The mouse reproduces the cellular mechanism convincingly, cortical thickening by enhanced endosteal formation in osteoblasts, but it does so in the long bones and not in the skull. The mice develop no calvarial phenotype at all, with calvarial thickness and porosity indistinguishable from controls, while the long bones carry the thickened cortex and an osteoporotic trabecular compartment. The same sparing appears in the plain null, so the question is not why the human disease is confined to the skull but why murine calvariae appear protected from a zinc-handling lesion affecting every other bone in the same animal. The authors pose exactly that and leave it open. So the model explains how the bone forms and not where. Candidate explanations are untested: regional differences in ZIP14 expression or zinc handling between neural-crest-derived cranial osteoblasts and mesoderm-derived axial ones; a species-specific calvarial protective mechanism; or an artefact of overexpression, since the construct is not at endogenous dose. Distinguishing them would need an endogenous-dose knock-in and comparison of cranial against long-bone osteoblasts from the same animal.
Show evidence (2 references)
PMID:22194361 SUPPORT Human Clinical
"HCI is the only genetic bone dysplasia known that is confined to the craniofacial area."
Establishes cranial confinement as the defining human feature that the model does not reproduce.
PMID:29621230 SUPPORT INDIRECT Model Organism
"Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype."
Documents a model phenotype with no described human counterpart, which is the second half of the mismatch.
Which features of the described phenotype belong to the disease and which belong to the kindred it was described in?
KNOWLEDGE GAP OPEN hci_single_kindred_generalisability
Attached to
phenotypes# prevalence#Three related Dutch families
Essentially the whole clinical description rests on three related Dutch families with common progenitors. Everything an entry can say about which nerves are affected, in what order, at what age and how severely is therefore conditioned on one genetic background and one allele. No frequency band is asserted anywhere in this entry for that reason. Independent kindreds with different SLC39A14 alleles would be needed to separate disease from family, and until then the natural history recorded here should be read as the history of that pedigree.
Show evidence (1 reference)
PMID:23640157 SUPPORT Human Clinical
"Until today the disease has been described in only three related Dutch families with common progenitors"
States the limitation that the entire clinical description derives from one extended kindred.
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Pathophysiology

7
SLC39A14 L441R Substitution
Mechanism confidence: Established
A dominant missense substitution, L441R, in SLC39A14, identified by whole-exome sequencing. The gene encodes ZIP14, a zinc transporter that normally sits in the plasma membrane. The lesion is not loss of the transporter as such but loss of its correct location.
SLC39A14 hgnc:20858 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC39A14 (hgnc:20858). hgnc:20858 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SLC39A14 hgnc:20858 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SLC39A14 (hgnc:20858). hgnc:20858 is a gene from the HUGO Gene Nomenclature Committee. allele_type: SNV variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
Heterozygous missense substitution acting dominantly. The functional category is left UNKNOWN deliberately: the allele causes mistrafficking and intracellular zinc accumulation with downstream signalling hyperactivation, which is neither simple loss of transporter function nor a clean gain, and no source classifies it.
Downstream
ZIP14 L441R Mistrafficking The substitution directly prevents the transporter reaching the plasma membrane.
Show evidence (1 reference)
PMID:29621230 SUPPORT Human Clinical
"Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14)."
Identifies the causal gene and allele in patients.
ZIP14 L441R Mistrafficking
Mechanism confidence: Established
The substituted transporter is no longer trafficked toward the plasma membrane. The defect is one of localisation rather than of transport capacity: the protein is made and can still move zinc, but it is in the wrong compartment to do so at the cell surface.
zinc ion transmembrane transporter activity GO:0005385 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves zinc ion transmembrane transporter activity (GO:0005385). GO:0005385 is a molecular function from the Gene Ontology.
plasma membrane GO:0005886 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves plasma membrane (GO:0005886). GO:0005886 is a cellular component from the Gene Ontology.
Downstream
Intracellular Zinc Accumulation A transporter retained inside the cell moves its substrate into the wrong compartment.
Show evidence (1 reference)
PMID:29621230 SUPPORT DIRECT In Vitro
"We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc"
Establishes the mislocalisation this node models. The same sentence carries the zinc consequence, which is curated as the next node.
Intracellular Zinc Accumulation
Mechanism confidence: Established
Mislocalised ZIP14 drives excessive accumulation of zinc inside the cell. This is the pivot of the mechanism, and the step that converts a trafficking defect into a signalling one.
zinc ion transmembrane transport GO:0071577 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated zinc ion transmembrane transport (GO:0071577). GO:0071577 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
cAMP-CREB and NFAT Signalling Hyperactivation Intracellular zinc accumulation hyperactivates both signalling arms.
Show evidence (1 reference)
PMID:29621230 SUPPORT DIRECT In Vitro
"We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc"
The second half of the same sentence: the zinc accumulation that follows from the mislocalisation curated on the previous node.
cAMP-CREB and NFAT Signalling Hyperactivation
Mechanism confidence: Established
Two signalling arms are hyperactivated downstream of the zinc excess, and both are established regulators of osteoblast behaviour. This is the step that converts a transporter defect into a bone phenotype.
cAMP/PKA signal transduction GO:0141156 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cAMP/PKA signal transduction (GO:0141156). GO:0141156 is a biological process from the Gene Ontology. ↑ INCREASED calcineurin-NFAT signaling cascade GO:0033173 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased calcineurin-NFAT signaling cascade (GO:0033173). GO:0033173 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Enhanced Endosteal Bone Formation Signalling hyperactivation in osteoblasts drives excess bone formation at the endosteal surface. The steps between the two are not resolved.
Show evidence (1 reference)
PMID:29621230 SUPPORT In Vitro
"resulting in hyper-activation of cAMP-CREB and NFAT signaling"
Names both hyperactivated pathways.
Enhanced Endosteal Bone Formation
Mechanism confidence: Established
Osteoblasts lay down excess bone on the inner surface. Histology in patients shows increased bone formation with normal tissue architecture, so this is a quantitative excess of ordinary bone rather than dysplastic tissue, and biochemical markers are normal. The mouse counterpart, osteoblast-restricted overexpression of the equivalent allele, produces a drastic increase in cortical thickness by the same endosteal route.
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. calvarial osteoblast CL:2000058 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves calvarial osteoblast (CL:2000058). CL:2000058 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 osteoblast differentiation GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology.
Animal models
Osteoblast-conditional L438R Zip14 knock-in mouse Mouse partially recapitulates Reproduces the cortical arm of the disease, and does so cell-autonomously in osteoblasts, which is what establishes the osteoblast as the effector cell.
Downstream
Calvarial and Skull Base Hyperostosis Sustained endosteal deposition thickens the inner table of the skull.
Show evidence (2 references)
PMID:29621230 SUPPORT Model Organism
"Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients."
Demonstrates the osteoblast-autonomous route from the allele to endosteal bone formation, and states the resemblance to the human pathology.
PMID:23640157 SUPPORT Human Clinical
"Histomorphological investigations showed increased bone formation with a normal tissue structure. Biochemical parameters were normal."
Confirms in patients that the excess is of normally structured bone, with no biochemical derangement.
Calvarial and Skull Base Hyperostosis
Mechanism confidence: Established
Thickening is significant across frontal, parietal, temporal and occipital regions and is mainly of the inner table. The deposited hyperostotic bone is less attenuated than normal cortical bone on computed tomography, which is a concrete sign that the excess tissue differs in quality and not only in quantity. The process is confined to the skull; the rest of the skeleton is unaffected, which is unique among genetic bone dysplasias.
cranium UBERON:0003128 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cranium (UBERON:0003128). UBERON:0003128 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Osteoblast-conditional L438R Zip14 knock-in mouse Mouse fails to recapitulate The model produces no calvarial phenotype, so it does not reproduce the lesion that defines this disease. This is the structural counterpart of the HUMAN_MODEL_MISMATCH discussion, which previously carried the claim only as prose in limitations.
Downstream
Cranial Nerve Entrapment Inward bone growth narrows the neuroforamina through which the cranial nerves pass.
Skull Base Osteosclerosis The radiological expression of the same lesion at the skull base, which is the region whose foramina carry the cranial nerves.
Show evidence (2 references)
PMID:22194361 SUPPORT Human Clinical
"There was significant thickening of the skull in the frontal, parietal, temporal, and occipital regions, which was mainly due to thickening of the inner table of the skull. The attenuation of the deposited hyperostotic bone was lower than normal cortical bone."
Quantifies the distribution of thickening and reports the reduced attenuation of the deposited bone.
PMID:22194361 SUPPORT Human Clinical
"HCI is the only genetic bone dysplasia known that is confined to the craniofacial area."
States the sparing of the rest of the skeleton, the feature that separates this disorder from the sclerosing dysplasias it resembles.
Cranial Nerve Entrapment
Mechanism confidence: Established
Stenosis of the neuroforamina entraps cranial nerves I, II, V, VII and VIII, and this is how the disease presents. Symptoms typically begin in the second decade and progress, with facial and vestibulocochlear dysfunction reported most often. Because the compression is mechanical and progressive, the therapeutic logic is decompression before the nerve is lost rather than treatment of the bone.
Downstream
Facial Palsy Seventh-nerve entrapment produces recurrent facial palsy.
Sensorineural Hearing Impairment Eighth-nerve entrapment produces hearing loss.
Vestibular Areflexia The vestibular half of eighth-nerve involvement, presenting as disturbance of balance.
Disturbance of the Sense of Smell First-nerve entrapment impairs olfaction.
Visual Impairment Second-nerve entrapment at the optic canal impairs vision.
Facial Hypoesthesia Fifth-nerve entrapment impairs facial sensation.
Optic Atrophy The structural consequence of sustained optic-nerve compression. Typed as indirect because no source traces the progression from compression to atrophy in this disease.
Show evidence (2 references)
PMID:20140965 SUPPORT Human Clinical
"The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII, its first symptoms often presenting during the second decade."
Names the affected nerves and the typical age of onset.
PMID:20140965 SUPPORT Human Clinical
"Facial and vestibulocochlear nerve dysfunction are most frequently reported."
Identifies which nerve deficits dominate the presentation.
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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 Hyperostosis Cranialis Interna 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

11
Ear 2
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20140965 SUPPORT Human Clinical
"Facial and vestibulocochlear nerve dysfunction are most frequently reported."
Identifies vestibulocochlear dysfunction as among the most frequent deficits.
PMID:23622937 SUPPORT Human Clinical
"No patient had disease-related absence of otoacoustic emissions, because the cochlea is not affected."
Preserved otoacoustic emissions localise the lesion to the nerve rather than the cochlea, which is direct positive evidence that the hearing loss is retrocochlear compression and not a cochlear disease.
Vestibular Areflexia HP:0008568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vestibular areflexia (HP:0008568). HP:0008568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23640157 SUPPORT Human Clinical
"disturbance of balance due to vestibular areflexia"
Names vestibular areflexia as the basis of the balance disturbance.
Eye 2
Visual Impairment HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23640157 SUPPORT Human Clinical
"hearing and vision impairments, impairment of facial sensibility"
Reports vision impairment among the entrapment deficits.
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Curated from the HPO disease annotation for OMIM:144755, recorded as provenance rather than quoted. The annotation records no frequency, and none is asserted here.
Head and Neck 4
Hyperostosis Cranialis Interna HP:0005890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperostosis cranialis interna (HP:0005890), qualified as course progressive. HP:0005890 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20140965 SUPPORT Human Clinical
"Hyperostosis cranialis interna is a hereditary bone disorder that is characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base"
Defines the structural lesion.
Skull Base Osteosclerosis Osteosclerosis of the base of the skull HP:0005746 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteosclerosis of the base of the skull (HP:0005746). HP:0005746 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23640157 SUPPORT Human Clinical
"characterized by intracranial hyperostosis and osteosclerosis, which is confined to the skull, especially the calvarium and the skull base"
Locates the osteosclerosis at the calvarium and skull base and states its confinement to the skull.
Facial Palsy Facial palsy secondary to cranial hyperostosis HP:0007285 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial palsy secondary to cranial hyperostosis (HP:0007285), qualified as temporality recurrent. HP:0007285 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:23640157 SUPPORT Human Clinical
"Progressive bone overgrowth causes nerve entrapment that leads to recurrent facial nerve palsy, disturbance of the sense of smell, hearing and vision impairments, impairment of facial sensibility, and disturbance of balance due to vestibular areflexia."
Lists the deficits including recurrent facial palsy, and attributes them to entrapment.
Disturbance of the Sense of Smell Abnormality of the sense of smell HP:0004408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the sense of smell (HP:0004408). HP:0004408 is a phenotype from the Human Phenotype Ontology.
Bound to HP:0004408, defined as an anomaly in the ability to perceive and distinguish scents, because that is what the cited source reports: a disturbance of the sense of smell, neither graded nor described as complete. HP:0000458 Anosmia asserts inability and HP:0004409 Hyposmia asserts reduced sensitivity; the source states neither. One tension is recorded rather than hidden. The HPO disease annotation for OMIM:144755 carries HP:0000458 Anosmia, so a curator following the annotation rather than the cited sentence would bind differently. This entry follows the sentence because that is the evidence attached to this phenotype, while the Headache phenotype below is annotation-derived and says so.
Show evidence (1 reference)
PMID:23640157 SUPPORT DIRECT Human Clinical
"nerve entrapment that leads to recurrent facial nerve palsy, disturbance of the sense of smell"
Reports disturbance of the sense of smell. The source does not grade its severity.
Nervous System 3
Cranial Nerve Compression HP:0001293 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cranial nerve compression (HP:0001293), qualified as course progressive. HP:0001293 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22194361 SUPPORT Human Clinical
"characterized by cranial nerve deficits due to stenosis of neuroforamina"
States the compressive mechanism and its anatomical basis.
Facial Hypoesthesia Trigeminal anesthesia HP:0031912 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Trigeminal anesthesia (HP:0031912). HP:0031912 is a phenotype from the Human Phenotype Ontology.
HP:0031912 is defined as decreased or absent sensation in the distribution of the trigeminal nerve, which supplies the face and mouth. It therefore covers the impairment of facial sensibility the source reports, and is the most specific term that accurately represents the claim. The generic HP:0033748 Hypoesthesia describes decreased touch anywhere in the body and loses the anatomy that makes this finding diagnostic.
Show evidence (1 reference)
PMID:23640157 SUPPORT Human Clinical
"hearing and vision impairments, impairment of facial sensibility"
Reports impaired facial sensibility, the trigeminal deficit.
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Curated from the HPO disease annotation for OMIM:144755, recorded as provenance rather than quoted, since HPOA is a derived annotation. No frequency band is asserted, consistent with the rest of this entry: the annotation derives from the same single kindred, so a fraction here would describe that family rather than the disease. An Orphanet record, ORPHA:443098, attributes the headache to raised ocular and intracranial pressure and would supply a quotable row for that mechanism. It is not curated because the Orphanet bulk XML is not present in this checkout and fetching it would add manifest churn unrelated to this entry. Worth adding when someone next refreshes that source.
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Genetic Associations

1
SLC39A14 (CAUSATIVE)
Gene: SLC39A14 hgnc:20858 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC39A14 (hgnc:20858). hgnc:20858 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (2 references)
PMID:29621230 SUPPORT Human Clinical
"Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14)."
Identifies the causal gene and allele.
PMID:23640157 SUPPORT INDIRECT Human Clinical
"Linkage analysis in a family with HCI resulted in the localization of the disease-causing gene to a region on chromosome 8p21 delineated by markers D8S282 and D8S382."
Records the linkage interval that preceded gene identification. Localises the gene without identifying it, hence INDIRECT; its three candidate genes were all subsequently excluded.
💊

Medical Actions

1
Surgical Decompression of Entrapped Cranial Nerves
Action: cranial nerve decompressionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cranial nerve decompression, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
The only treatment that addresses the actual injury. Because the nerve damage is mechanical and progressive, the recommendation is to decompress accessible nerves early in the symptomatic period, or even before symptoms in high-risk family members, rather than to wait for established deficit. Reported procedures include bilateral decompression of the internal auditory canals and middle-fossa facial nerve decompression. Nothing treats the underlying bone overgrowth.
Mechanism Target:
Cranial Nerve Entrapment — Decompression addresses the entrapment itself, which is the mechanism every deficit in this disease runs through.
Target Phenotypes: Cranial nerve compression HP:0001293 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cranial nerve compression (HP:0001293). HP:0001293 is a phenotype from the Human Phenotype Ontology. Facial palsy secondary to cranial hyperostosis HP:0007285 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Facial palsy secondary to cranial hyperostosis (HP:0007285). HP:0007285 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:20140965 SUPPORT Human Clinical
"Surgical decompression of the accessible impaired cranial nerves is advised in the early symptomatic period or even in the presymptomatic period in high-risk individuals."
States the recommendation and, importantly, its timing, which is the substantive clinical claim.
PMID:19371457 SUPPORT DIRECT Human Clinical
"We report the use of bilateral surgical decompression of the internal auditory canals to treat hyperostosis cranialis interna in an eight-year-old girl presenting with bilateral facial palsy"
A worked example of the procedure: a single case demonstrating feasibility, not an outcome study.
PMID:19371457 SUPPORT DIRECT Human Clinical
"The mimic function recovered. One year post-operatively, the right and left facial sides had been restored to House-Brackmann grades I and II, respectively."
The outcome, which is the part that matters for a treatment recommending early intervention: facial function recovered and was near-normal at one year.
+ 1 more reference
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Diagnosis

6
Cranial Computed Tomography
The diagnostic test. Computed tomography shows thickening concentrated in the inner table across frontal, parietal, temporal and occipital regions, and measures the neuroforamina whose narrowing produces the symptoms. It also shows the feature that distinguishes this bone from ordinary hyperostosis: the deposited tissue is less attenuated than normal cortical bone. Because the disease is progressive and decompression is advised before deficits are established, imaging has a surveillance role in at-risk relatives and not only a diagnostic one.
Computed Tomography NCIT:C17204 NCI Thesaurus (NCIT)
Results: Thickening of the inner table of the calvaria and skull base with reduced attenuation relative to normal cortical bone, and narrowing of the neuroforamina, in a skeleton that is otherwise normal.
Skeletal survey is worth stating as a negative: the rest of the skeleton is normal, and that normality is what separates this disease from van Buchem disease, sclerosteosis, craniometaphyseal dysplasia and Camurati-Engelmann disease, all of which involve the long bones.
Show evidence (1 reference)
PMID:22194361 SUPPORT Human Clinical
"Linear measurements were performed of the inner table, the medulla, and the outer table of different skull locations, and attenuation (density) measurements of the same regions were recorded. Neuroforamina widths were recorded as well."
Describes the measurements that constitute the radiological diagnosis, including the neuroforaminal widths that predict nerve compromise.
Audiometric Testing
Tone and speech audiometry is the first arm of vestibulocochlear surveillance, and it is what detects the hearing loss while it is still progressing. Increased hearing thresholds were found in 60 to 70 percent of affected subjects.
Audiometric Test NCIT:C38036 NCI Thesaurus (NCIT)
Results: Increased hearing thresholds in 60 to 70 percent of affected subjects, with otoacoustic emissions preserved because the cochlea is not affected.
Show evidence (2 references)
PMID:23622937 SUPPORT DIRECT Human Clinical
"we advise monitoring of vestibulocochlear nerve function with tone and speech audiometry, BERA and vestibular tests."
Recommends tone and speech audiometry as part of vestibulocochlear monitoring.
PMID:23622937 SUPPORT DIRECT Human Clinical
"Increased hearing thresholds and increased BERA latency times were found in 60-70%."
Quantifies the yield of audiometric and brainstem-response testing, which is the statistic this entry's results field reports.
Brainstem Evoked Response Audiometry
The single most useful measure in this disease. The I-V interpeak latency determines nerve encroachment reliably, which is precisely the decision the surveillance exists to inform, since the management argument is to decompress before a nerve is lost.
Evoked Response Audiometry NCIT:C85857 NCI Thesaurus (NCIT)
Results: Increased BERA latency times in 60 to 70 percent of affected subjects; the I-V interpeak latency identifies nerve encroachment.
Show evidence (1 reference)
PMID:23622937 SUPPORT DIRECT Human Clinical
"The inter-peak latency I-V parameter in BERA has the ability to determine nerve encroachment reliably."
Identifies the measure that detects nerve encroachment.
Vestibular Testing and Visual Evoked Potentials
Electronystagmography covers the vestibular half of eighth-nerve function, with abnormalities in about half of patients. Visual evoked potentials monitor the optic nerve and are recommended in combination with radiological and ophthalmological examination rather than alone.
electronystagmography and visual evoked potentials NCIT:C215111 NCI Thesaurus (NCIT)
Results: Vestibular abnormalities in about half of patients.
Bound to NCIT:C215111 Neuroelectrophysiology Test, defined as a diagnostic tool measuring electrical signals produced by nerves and muscles. NCIT has no term for electronystagmography, for vestibular function testing, or for visual evoked potentials in general, so this is the accurate broader term with preferred_term carrying the specificity. An earlier version bound NCIT:C85857 Evoked Response Audiometry, which is an auditory term and is correctly used on the brainstem-response entry above; using it here made one identifier stand for two different tests. Splitting electronystagmography and visual evoked potentials into separate entries would be better still, since they monitor different nerves and carry different statistics. Blink and masseter reflexes are explicitly not advised for routine use: the symmetrical bilateral nature of the disease reduces sensitivity across the single-registration tests to 25 to 37.5 percent, a range that includes visual evoked potentials, which are nonetheless still recommended because they cover a nerve nothing else in the panel reaches.
Show evidence (2 references)
PMID:23622937 SUPPORT DIRECT Human Clinical
"VEPs are important to monitor optic nerve function in combination with radiological and ophthalmologic examination. We do not advise the routine use of blink and masseter reflex."
States the role of visual evoked potentials and, equally usefully, the two tests not worth performing routinely.
PMID:23622937 SUPPORT DIRECT Human Clinical
"50% of the patients had vestibular abnormalities."
Quantifies the vestibular yield reported in this entry's results field.
18F-Fluoride PET/CT
The only test here that quantifies disease activity rather than describing structure, which is why it is not redundant with computed tomography. Uptake is significantly higher in the sphenoid bone and clivus of affected family members, and visual assessment of the scans distinguishes disease severity and shows how the disturbance of bone metabolism evolves over life. That makes it the natural instrument for the surveillance this entry's management argument depends on, since the decision to decompress turns on whether the process is still advancing. The study was done in this kindred: nine affected family members, seven unaffected relatives and nine unrelated controls.
18F-fluoride positron emission tomography and computed tomography NCIT:C103512 NCI Thesaurus (NCIT)
Results: Significantly higher 18F-fluoride uptake in the sphenoid bone and clivus of affected individuals, with standardised uptake values measured at frontal bone, sphenoid bone, petrous bone and clivus.
The NCIT binding names the modality pairing rather than the tracer. NCIT has no 18F-fluoride term, so preferred_term carries the tracer, which is the part that makes this a bone-metabolism measurement rather than a structural scan.
Show evidence (2 references)
PMID:21079950 SUPPORT DIRECT Human Clinical
"(18)F-Fluoride uptake is statistically significantly higher in the sphenoid bone and clivus regions of affected family members."
The quantitative finding that distinguishes affected from unaffected relatives, and the basis for treating this as a measure of disease activity.
PMID:21079950 SUPPORT DIRECT Human Clinical
"Visual assessment of the scans of HCI patients is relevant in detecting disease severity and the pattern of disturbed bone metabolism throughout life."
Establishes the surveillance role: severity grading and longitudinal tracking of the metabolic process.
Molecular Confirmation of SLC39A14
Identifying the SLC39A14 variant confirms the diagnosis and, more usefully, identifies at-risk relatives before symptoms appear. That matters here more than in most sclerosing dysplasias, because the management recommendation is to decompress accessible nerves in the presymptomatic period in high-risk individuals, which requires knowing who they are.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Biochemical testing does not contribute. Bone turnover parameters are normal in patients, so there is no laboratory signature to screen on and the diagnosis rests on imaging plus genotype.
Show evidence (1 reference)
PMID:29621230 SUPPORT Human Clinical
"Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14)."
Establishes the testable molecular lesion.
📈

Progression

3
Presymptomatic radiological phase
Hyperostosis is detectable on imaging before any deficit appears. This is the window the management recommendation targets, since decompression is advised in the presymptomatic period in high-risk individuals, and it is the reason at-risk relatives are imaged and monitored rather than merely counselled.
Early symptomatic phase
Age: second decade
First symptoms typically appear in the second decade. Facial nerve involvement is often recurrent rather than fixed at this stage, which is what makes it the point at which decompression can still preserve function.
Show evidence (1 reference)
PMID:20140965 SUPPORT Human Clinical
"its first symptoms often presenting during the second decade"
Gives the typical age at which deficits begin.
Established deficit phase
Progressive bone overgrowth converts recurrent deficits into fixed ones as successive nerves are compromised. Facial and vestibulocochlear dysfunction dominate.
Show evidence (1 reference)
PMID:20140965 SUPPORT Human Clinical
"The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII"
Describes the progressive entrapment that defines this phase.
📊

Prevalence

1
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hyperostosis Cranialis Interna:

Hypermanganesemia with dystonia 2 Not Yet Curated MONDO:0014864
Overlapping Features The other SLC39A14 disease, and the reason this entry carries a differential that shares no phenotype with it. Biallelic loss-of-function variants in the same gene cause an autosomal recessive manganese transporter defect presenting as rapidly progressive childhood-onset parkinsonism-dystonia, with no skeletal involvement.
Distinguishing Features
  • Autosomal recessive, not dominant
  • Loss of manganese transport, not mistrafficking with intracellular zinc accumulation
  • Neurological presentation in childhood, with no hyperostosis and no cranial nerve entrapment
  • Chelation with disodium calcium edetate lowers blood manganese and can produce striking improvement
Show evidence (2 references)
PMID:27231142 SUPPORT DIRECT Human Clinical
"identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14"
Establishes that the same gene causes a recessive manganese-transport disease distinct from this one.
PMID:27231142 SUPPORT DIRECT Human Clinical
"Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement."
Establishes that the recessive disease is treatable by chelation, which is the fact that makes the allelic boundary a safety matter rather than a taxonomic one.
Hyperostosis frontalis interna
Overlapping Features Thickening of the inner table of the frontal bone, common, usually incidental, and strongly associated with older women. It is a radiological finding rather than a Mendelian disease, and it is the entity most often confused with this one in the literature.
Distinguishing Features
  • Confined to the frontal bone rather than involving the calvaria and skull base together
  • Not familial
  • Does not narrow the neuroforamina or produce cranial nerve deficits
  • No SLC39A14 variant
Van Buchem disease and sclerosteosis
Overlapping Features Sclerosing bone dysplasias of the SOST pathway that also thicken the skull and entrap cranial nerves, and are therefore the closest genuine mimics.
Distinguishing Features
  • Both involve the long bones as well as the skull, which hyperostosis cranialis interna does not
  • Sclerosteosis additionally features syndactyly and gigantism
Show evidence (1 reference)
PMID:23640157 SUPPORT Human Clinical
"Examples are Van Buchem disease, sclerosteosis, craniometaphyseal dysplasia, and Camurati-Engelmann disease. However, in these cases the long bones are affected as well."
Names the mimicking dysplasias and states the discriminator, long-bone involvement.
Craniometaphyseal dysplasia and Camurati-Engelmann disease
Overlapping Features Further sclerosing dysplasias with craniofacial hyperostosis and cranial nerve compromise.
Distinguishing Features
  • Both affect the long bones
  • Craniometaphyseal dysplasia by definition involves the metaphyses
  • Camurati-Engelmann disease involves the diaphyses
Show evidence (1 reference)
PMID:23640157 SUPPORT Human Clinical
"Examples are Van Buchem disease, sclerosteosis, craniometaphyseal dysplasia, and Camurati-Engelmann disease. However, in these cases the long bones are affected as well."
Lists both among the sclerosing dysplasias distinguished by long-bone involvement.
🐁

Animal Models

1
Osteoblast-conditional L438R Zip14 knock-in mouse
Conditional knock-in mice overexpressing the mouse equivalent of the human L441R allele, restricted to osteoblasts. They develop a severe skeletal phenotype with a drastic increase in cortical thickness driven by enhanced endosteal bone formation, which is the pathology seen in patients. They also develop an osteoporotic trabecular phenotype that the human disease is not known to show.
Species
Mouse
Genotype
Conditional knock-in overexpressing L438R Zip14 in osteoblasts
Publication
PMID:29621230
Pathograph links
Enhanced Endosteal Bone Formation partially recapitulates fidelity: moderate Reproduces the cortical arm of the disease, and does so cell-autonomously in osteoblasts, which is what establishes the osteoblast as the effector cell.
Limitations: Three limits. The construct overexpresses the mutant allele rather than carrying it at endogenous dose, so the severity is not comparable to a patient's. The anatomy is not merely unconfined, it is inverted: the hyperostosis appears in the long bones while the calvaria shows no phenotype at all, with calvarial thickness and porosity not significantly different from controls. The authors say they were surprised by this and call it truly opposite to what is seen in patients. And the trabecular compartment moves the other way, becoming osteoporotic, which patients do not show. So the model misses the one bone that defines the human disease and adds a compartment-level change the disease does not have.
Readouts
Cortical thickness
Direction: INCREASED
Interpretation: The cortical arm of the human phenotype, reproduced by the same endosteal mechanism.
Show evidence (1 reference)
PMID:29621230 SUPPORT Model Organism
"a drastic increase in cortical thickness due to an enhanced endosteal bone formation"
Reports the cortical measurement behind this readout.
Trabecular bone mass
Direction: DECREASED
Interpretation: A divergence from the human disease rather than a confirmation of it. The authors interpret the opposite effects on the two compartments as mirroring the disparate actions of oestrogen.
Show evidence (1 reference)
PMID:29621230 SUPPORT DIRECT Model Organism
"Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype."
Reports the trabecular finding. It has no established human counterpart, which is what makes it a divergence from the human disease rather than a confirmation of it.
Show evidence (1 reference)
PMID:29621230 SUPPORT DIRECT Model Organism
"Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients."
Supports treating this model as informative for the endosteal bone-formation node, which is the arm it does reproduce.
Calvarial and Skull Base Hyperostosis fails to recapitulate fidelity: low The model produces no calvarial phenotype, so it does not reproduce the lesion that defines this disease. This is the structural counterpart of the HUMAN_MODEL_MISMATCH discussion, which previously carried the claim only as prose in limitations.
Limitations: Murine calvariae are unaffected while the appendicular skeleton and vertebral column are. In the knock-in the affected long bones are cortically thickened, with the osteoporosis confined to the trabecular compartment, so the model puts the hyperostosis in the wrong bone rather than failing to produce it. The same calvarial sparing appears in the plain Zip14 null, whose appendicular skeleton and vertebral column are osteoporotic with normal cortical bone, so the sparing is not an artefact of the knock-in construct. Whether a protective mechanism exists in murine calvariae that humans lack is undetermined, so this negative result constrains the model rather than the human mechanism.
Show evidence (2 references)
PMID:29621230 SUPPORT DIRECT Model Organism
"were surprised to see no calvarial phenotype as this is truly opposite of what we see in HCI"
States the failure in the authors' own words. Graded SUPPORT because the quote supports the claim that the model fails; the negative direction is carried by relationship FAILS_TO_RECAPITULATE.
+ 1 more reference
Show evidence (1 reference)
PMID:29621230 SUPPORT Model Organism
"Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients."
Establishes the model and the authors' own claim that it resembles the human pathology.
{ }

Source YAML

click to show 
name: Hyperostosis Cranialis Interna
creation_date: "2026-08-29T00:00:00Z"
category: Mendelian
synonyms:
- HCIN
- hyperostosis cranialis interna
description: >-
  Hyperostosis cranialis interna is an autosomal dominant sclerosing bone
  dysplasia in which the calvaria and skull base thicken progressively from the
  inside. As the bone grows inward it narrows the neuroforamina, and the disease
  presents as sequential entrapment of cranial nerves rather than as anything
  skeletal: loss of smell, visual and facial sensory impairment, recurrent facial
  palsy, hearing loss and vestibular areflexia, usually beginning in the second
  decade.

  Its defining feature is what it spares. This is the only genetic bone dysplasia
  confined to the craniofacial area; the rest of the skeleton is normal. That
  distinguishes it from the sclerosing dysplasias it otherwise resembles, van
  Buchem disease, sclerosteosis, craniometaphyseal dysplasia and
  Camurati-Engelmann disease, all of which involve the long bones. Two other
  observations sharpen the picture: the thickening is almost entirely of the
  inner table, and the deposited bone is less dense than normal cortical bone, so
  this is not simply more of the same tissue. Histology shows increased bone
  formation with normal tissue architecture, and biochemical markers are normal.

  The molecular cause is a dominant L441R substitution in SLC39A14, which encodes
  the zinc transporter ZIP14. The mutant protein is not trafficked to the plasma
  membrane and instead accumulates zinc inside the cell, which hyperactivates
  cAMP-CREB and NFAT signalling. Conditional mice overexpressing the equivalent
  allele in osteoblasts reproduce the cellular mechanism, with a marked increase
  in cortical thickness from enhanced endosteal bone formation.

  They reproduce it in the wrong bones. The thickening appears in the long bones,
  while the calvaria, the one site that defines the human disease, shows no
  phenotype at all: calvarial thickness and porosity are not significantly
  different from controls. The authors say they were surprised by this and call
  it truly opposite to what is seen in patients. The same calvarial sparing
  appears in the plain Zip14 null, so it is not an artefact of the knock-in
  construct. The open question this leaves is therefore not why the human disease
  is confined to the skull, but why murine calvariae appear protected from a
  zinc-handling lesion that affects the rest of the same animal's skeleton.

  The model also shows something the human disease does not: osteoporotic
  trabecular bone alongside the thickened long-bone cortex. The authors note this
  mirrors the disparate actions of oestrogen on the two bone compartments.
  Whether HCI patients have an unrecognised trabecular phenotype, or whether this
  is an artefact of overexpression, is unresolved and is recorded as a gap rather
  than assumed either way.
disease_term:
  preferred_term: hyperostosis cranialis interna
  term:
    id: MONDO:0007765
    label: hyperostosis cranialis interna
parents:
- Sclerosing bone dysplasia
- Hereditary disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007765
      label: hyperostosis cranialis interna
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0007765 is the hyperostosis cranialis interna concept modeled by this
      entry, corresponding to OMIM 144755.
references:
- reference: PMID:29621230
  title: >-
    Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis
    Cranialis Interna and in bone homeostasis.
- reference: PMID:20140965
  title: >-
    Phenotypic manifestations and management of hyperostosis cranialis interna, a
    hereditary bone dysplasia affecting the calvaria and the skull base.
notes: >-
  Sourcing note. The curation stub for this disease carried no causal gene, and
  that reflects the ontology rather than the literature. MONDO:0007765 currently
  carries a feature relation and a parent class and no causal-gene relation, so
  the stub enrichment had nothing to copy, while SLC39A14 was identified by
  whole-exome sequencing in 2018. The observation is recorded here for whoever
  maintains that mapping; this entry does not propose what should be done about
  it. The gene is treated as established on the strength of the identification
  report plus its conditional mouse models, and the earlier linkage work that
  placed the locus at 8p21 and excluded BMP1, LOXL2 and ADAM28 is retained as
  mapping history rather than presented as an open question.

  Named Entity Confusion hazard, and the reason one paper in the reference cache
  is not cited. The string "hyperostosis cranialis interna" is used in two
  incompatible senses. The first is this Mendelian disease: autosomal dominant,
  SLC39A14 p.Leu441Arg, described in one extended Dutch kindred. The second is a
  loose radiological label for sporadic thickening of the internal skull table,
  overlapping hyperostosis frontalis interna and Morgagni-Stewart-Morel syndrome,
  used in isolated case reports with no family history and no genetic testing.

  Only the first is this entry. PMID:40091967, a 2025 case report of
  cerebrospinal fluid leak, was fetched and read and is deliberately not cited:
  it describes the aetiology as unknown, which the 2018 gene identification
  superseded, and discusses the condition alongside hyperostosis frontalis
  interna without reporting genetic testing. A skull-base CSF leak is a
  plausible complication of skull-base hyperostosis and the observation may well
  be real, but using a second-sense case report to establish a phenotype of the
  first-sense disease is precisely the confusion this note exists to prevent.
  The same applies to the 2023 cadaveric report of hyperostosis
  fronto-parieto-occipitalis.

  Cohort note. Essentially the entire clinical description of this disease comes
  from three related Dutch families with common progenitors, 32 individuals over
  five generations, of whom 12 to 13 were affected. Every frequency and every
  natural-history statement in this entry inherits that limitation, and no
  frequency band is asserted anywhere for that reason. A single kindred cannot
  distinguish features of the disease from features of the family.
pathophysiology:
- name: SLC39A14 L441R Substitution
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    A dominant missense substitution, L441R, in SLC39A14, identified by
    whole-exome sequencing. The gene encodes ZIP14, a zinc transporter that
    normally sits in the plasma membrane. The lesion is not loss of the
    transporter as such but loss of its correct location.
  gene:
    preferred_term: SLC39A14
    description: >-
      Encodes the ZIP14 zinc transporter; a dominant L441R substitution causes
      hyperostosis cranialis interna.
    term:
      id: hgnc:20858
      label: SLC39A14
  genetic_context:
    gene:
      preferred_term: SLC39A14
      term:
        id: hgnc:20858
        label: SLC39A14
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      Heterozygous missense substitution acting dominantly. The functional
      category is left UNKNOWN deliberately: the allele causes mistrafficking and
      intracellular zinc accumulation with downstream signalling hyperactivation,
      which is neither simple loss of transporter function nor a clean gain, and
      no source classifies it.
  evidence:
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we identified by whole-exome sequencing a dominant mutation (L441R) in
      SLC39A14 (ZIP14).
    explanation: >-
      Identifies the causal gene and allele in patients.
  downstream:
  - target: ZIP14 L441R Mistrafficking
    causal_link_type: DIRECT
    description: >-
      The substitution directly prevents the transporter reaching the plasma
      membrane.
    evidence:
    - reference: PMID:29621230
      reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that L441R ZIP14 is no longer trafficked towards the plasma
        membrane and excessively accumulates intracellular zinc
      explanation: >-
        Demonstrates the trafficking defect and its immediate consequence.
- name: ZIP14 L441R Mistrafficking
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The substituted transporter is no longer trafficked toward the plasma
    membrane. The defect is one of localisation rather than of transport
    capacity: the protein is made and can still move zinc, but it is in the wrong
    compartment to do so at the cell surface.
  molecular_functions:
  - preferred_term: zinc ion transmembrane transporter activity
    term:
      id: GO:0005385
      label: zinc ion transmembrane transporter activity
  cellular_components:
  - preferred_term: plasma membrane
    description: >-
      Named as the compartment the transporter fails to reach, not as its
      location. The lesion is that mutant ZIP14 is not trafficked here.
    term:
      id: GO:0005886
      label: plasma membrane
  evidence:
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      We show that L441R ZIP14 is no longer trafficked towards the plasma
      membrane and excessively accumulates intracellular zinc
    explanation: >-
      Establishes the mislocalisation this node models. The same sentence carries
      the zinc consequence, which is curated as the next node.
  downstream:
  - target: Intracellular Zinc Accumulation
    causal_link_type: DIRECT
    description: >-
      A transporter retained inside the cell moves its substrate into the wrong
      compartment.
- name: Intracellular Zinc Accumulation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Mislocalised ZIP14 drives excessive accumulation of zinc inside the cell.
    This is the pivot of the mechanism, and the step that converts a trafficking
    defect into a signalling one.
  biological_processes:
  - preferred_term: zinc ion transmembrane transport
    term:
      id: GO:0071577
      label: zinc ion transmembrane transport
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      We show that L441R ZIP14 is no longer trafficked towards the plasma
      membrane and excessively accumulates intracellular zinc
    explanation: >-
      The second half of the same sentence: the zinc accumulation that follows
      from the mislocalisation curated on the previous node.
  downstream:
  - target: cAMP-CREB and NFAT Signalling Hyperactivation
    causal_link_type: DIRECT
    description: >-
      Intracellular zinc accumulation hyperactivates both signalling arms.
    evidence:
    - reference: PMID:29621230
      reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        excessively accumulates intracellular zinc, resulting in hyper-activation
        of cAMP-CREB and NFAT signaling
      explanation: >-
        States the causal link from zinc accumulation to signalling
        hyperactivation.
- name: cAMP-CREB and NFAT Signalling Hyperactivation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Two signalling arms are hyperactivated downstream of the zinc excess, and
    both are established regulators of osteoblast behaviour. This is the step
    that converts a transporter defect into a bone phenotype.
  biological_processes:
  - preferred_term: cAMP/PKA signal transduction
    term:
      id: GO:0141156
      label: cAMP/PKA signal transduction
    modifier: INCREASED
  - preferred_term: calcineurin-NFAT signaling cascade
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      resulting in hyper-activation of cAMP-CREB and NFAT signaling
    explanation: >-
      Names both hyperactivated pathways.
  downstream:
  - target: Enhanced Endosteal Bone Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Signalling hyperactivation in osteoblasts drives excess bone formation at
      the endosteal surface. The steps between the two are not resolved.
- name: Enhanced Endosteal Bone Formation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Osteoblasts lay down excess bone on the inner surface. Histology in patients
    shows increased bone formation with normal tissue architecture, so this is a
    quantitative excess of ordinary bone rather than dysplastic tissue, and
    biochemical markers are normal. The mouse counterpart, osteoblast-restricted
    overexpression of the equivalent allele, produces a drastic increase in
    cortical thickness by the same endosteal route.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: calvarial osteoblast
    description: >-
      Retained as the cell type the human disease acts on, but not as the only
      one: the mouse driver is lineage-wide rather than calvaria-restricted, and
      calvarial osteoblasts from those animals showed no marker differences.
    term:
      id: CL:2000058
      label: calvarial osteoblast
  biological_processes:
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: INCREASED
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
  evidence:
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a
      severe skeletal phenotype marked by a drastic increase in cortical
      thickness due to an enhanced endosteal bone formation, resembling the
      underlying pathology in HCI patients.
    explanation: >-
      Demonstrates the osteoblast-autonomous route from the allele to endosteal
      bone formation, and states the resemblance to the human pathology.
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histomorphological investigations showed increased bone formation with a
      normal tissue structure. Biochemical parameters were normal.
    explanation: >-
      Confirms in patients that the excess is of normally structured bone, with
      no biochemical derangement.
  downstream:
  - target: Calvarial and Skull Base Hyperostosis
    causal_link_type: DIRECT
    description: >-
      Sustained endosteal deposition thickens the inner table of the skull.
- name: Calvarial and Skull Base Hyperostosis
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Thickening is significant across frontal, parietal, temporal and occipital
    regions and is mainly of the inner table. The deposited hyperostotic bone is
    less attenuated than normal cortical bone on computed tomography, which is a
    concrete sign that the excess tissue differs in quality and not only in
    quantity. The process is confined to the skull; the rest of the skeleton is
    unaffected, which is unique among genetic bone dysplasias.
  locations:
  - preferred_term: cranium
    term:
      id: UBERON:0003128
      label: cranium
  evidence:
  - reference: PMID:22194361
    reference_title: Imaging features and progression of hyperostosis cranialis interna.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was significant thickening of the skull in the frontal, parietal,
      temporal, and occipital regions, which was mainly due to thickening of the
      inner table of the skull. The attenuation of the deposited hyperostotic
      bone was lower than normal cortical bone.
    explanation: >-
      Quantifies the distribution of thickening and reports the reduced
      attenuation of the deposited bone.
  - reference: PMID:22194361
    reference_title: Imaging features and progression of hyperostosis cranialis interna.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HCI is the only genetic bone dysplasia known that is confined to the
      craniofacial area.
    explanation: >-
      States the sparing of the rest of the skeleton, the feature that separates
      this disorder from the sclerosing dysplasias it resembles.
  downstream:
  - target: Cranial Nerve Entrapment
    causal_link_type: DIRECT
    description: >-
      Inward bone growth narrows the neuroforamina through which the cranial
      nerves pass.
    evidence:
    - reference: PMID:22194361
      reference_title: Imaging features and progression of hyperostosis cranialis interna.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed radiologic abnormalities explain the possible impairment of
        the olfactory, optic, trigeminal, facial, and vestibulocochlear nerves.
      explanation: >-
        Connects the imaging findings directly to the specific cranial nerves
        affected.
  - target: Skull Base Osteosclerosis
    causal_link_type: DIRECT
    description: >-
      The radiological expression of the same lesion at the skull base, which is
      the region whose foramina carry the cranial nerves.
    evidence:
    - reference: PMID:23640157
      reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        characterized by intracranial hyperostosis and osteosclerosis, which is
        confined to the skull, especially the calvarium and the skull base
      explanation: >-
        States that the osteosclerosis of this disease is located at the calvarium
        and the skull base, which is the phenotype this edge points at.
- name: Cranial Nerve Entrapment
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Stenosis of the neuroforamina entraps cranial nerves I, II, V, VII and VIII,
    and this is how the disease presents. Symptoms typically begin in the second
    decade and progress, with facial and vestibulocochlear dysfunction reported
    most often. Because the compression is mechanical and progressive, the
    therapeutic logic is decompression before the nerve is lost rather than
    treatment of the bone.
  notes: >-
    No GO binding. GO:0021545 cranial nerve development was considered and
    rejected: it denotes the progression of cranial nerves from formation to
    mature structure, which is a developmental process. In this disease the
    nerves develop normally and are mechanically compressed in the second decade,
    so annotating development would assert a neurodevelopmental disorder that
    this is not. The node is anchored by its HP-bound phenotypes and by the
    cranium location on its parent node instead.
  evidence:
  - reference: PMID:20140965
    reference_title: "Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The progressive bone overgrowth causes entrapment and dysfunction of
      cranial nerves I, II, V, VII, and VIII, its first symptoms often presenting
      during the second decade.
    explanation: >-
      Names the affected nerves and the typical age of onset.
  - reference: PMID:20140965
    reference_title: "Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial and vestibulocochlear nerve dysfunction are most frequently reported.
    explanation: >-
      Identifies which nerve deficits dominate the presentation.
  downstream:
  - target: Facial Palsy
    causal_link_type: DIRECT
    description: Seventh-nerve entrapment produces recurrent facial palsy.
    evidence:
    - reference: PMID:23640157
      reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Progressive bone overgrowth causes nerve entrapment that leads to
        recurrent facial nerve palsy, disturbance of the sense of smell, hearing
        and vision impairments, impairment of facial sensibility, and disturbance
        of balance due to vestibular areflexia.
      explanation: >-
        A single sentence stating the entrapment-to-deficit route for five
        cranial nerves, including the facial nerve.
  - target: Sensorineural Hearing Impairment
    causal_link_type: DIRECT
    description: Eighth-nerve entrapment produces hearing loss.
  - target: Vestibular Areflexia
    causal_link_type: DIRECT
    description: >-
      The vestibular half of eighth-nerve involvement, presenting as disturbance
      of balance.
  - target: Disturbance of the Sense of Smell
    causal_link_type: DIRECT
    description: First-nerve entrapment impairs olfaction.
  - target: Visual Impairment
    causal_link_type: DIRECT
    description: Second-nerve entrapment at the optic canal impairs vision.
  - target: Facial Hypoesthesia
    causal_link_type: DIRECT
    description: Fifth-nerve entrapment impairs facial sensation.
  - target: Optic Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The structural consequence of sustained optic-nerve compression. Typed as
      indirect because no source traces the progression from compression to
      atrophy in this disease.
phenotypes:
- category: Skeletal
  name: Hyperostosis Cranialis Interna
  description: >-
    Endosteal hyperostosis and osteosclerosis of the calvaria and skull base, the
    structural lesion of the disease.
  phenotype_term:
    preferred_term: Hyperostosis cranialis interna
    term:
      id: HP:0005890
      label: Hyperostosis cranialis interna
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20140965
    reference_title: "Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperostosis cranialis interna is a hereditary bone disorder that is
      characterized by endosteal hyperostosis and osteosclerosis of the calvaria
      and the skull base
    explanation: Defines the structural lesion.
- category: Skeletal
  name: Skull Base Osteosclerosis
  description: >-
    Sclerosis of the skull base, the region whose foramina carry the cranial
    nerves and therefore the site where hyperostosis becomes symptomatic.
  phenotype_term:
    preferred_term: Osteosclerosis of the base of the skull
    term:
      id: HP:0005746
      label: Osteosclerosis of the base of the skull
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by intracranial hyperostosis and osteosclerosis, which is
      confined to the skull, especially the calvarium and the skull base
    explanation: >-
      Locates the osteosclerosis at the calvarium and skull base and states its
      confinement to the skull.
- category: Neurologic
  name: Cranial Nerve Compression
  description: >-
    Compression of cranial nerves within stenotic neuroforamina, the mechanism by
    which every symptom of this disease arises.
  phenotype_term:
    preferred_term: Cranial nerve compression
    term:
      id: HP:0001293
      label: Cranial nerve compression
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22194361
    reference_title: Imaging features and progression of hyperostosis cranialis interna.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by cranial nerve deficits due to stenosis of neuroforamina
    explanation: >-
      States the compressive mechanism and its anatomical basis.
- category: Neurologic
  name: Facial Palsy
  description: >-
    Recurrent facial nerve palsy from seventh-nerve entrapment, one of the two
    most frequently reported deficits.
  phenotype_term:
    preferred_term: Facial palsy secondary to cranial hyperostosis
    term:
      id: HP:0007285
      label: Facial palsy secondary to cranial hyperostosis
    temporality: RECURRENT
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive bone overgrowth causes nerve entrapment that leads to recurrent
      facial nerve palsy, disturbance of the sense of smell, hearing and vision
      impairments, impairment of facial sensibility, and disturbance of balance
      due to vestibular areflexia.
    explanation: >-
      Lists the deficits including recurrent facial palsy, and attributes them to
      entrapment.
- category: Auditory
  name: Sensorineural Hearing Impairment
  description: >-
    Hearing loss from eighth-nerve entrapment, reported with facial palsy as the
    most frequent deficit.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20140965
    reference_title: "Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial and vestibulocochlear nerve dysfunction are most frequently reported.
    explanation: >-
      Identifies vestibulocochlear dysfunction as among the most frequent
      deficits.
  - reference: PMID:23622937
    reference_title: Neurophysiologic, audiometric and vestibular function tests in patients with hyperostosis cranialis interna.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No patient had disease-related absence of otoacoustic emissions, because
      the cochlea is not affected.
    explanation: >-
      Preserved otoacoustic emissions localise the lesion to the nerve rather
      than the cochlea, which is direct positive evidence that the hearing loss
      is retrocochlear compression and not a cochlear disease.
- category: Neurologic
  name: Vestibular Areflexia
  description: >-
    Loss of vestibular responses causing disturbance of balance, the vestibular
    half of eighth-nerve involvement.
  phenotype_term:
    preferred_term: Vestibular areflexia
    term:
      id: HP:0008568
      label: Vestibular areflexia
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      disturbance of balance due to vestibular areflexia
    explanation: Names vestibular areflexia as the basis of the balance disturbance.
- category: Neurologic
  name: Disturbance of the Sense of Smell
  description: >-
    Impaired olfaction from entrapment of the first cranial nerve, which is
    typically the earliest deficit.
  phenotype_term:
    preferred_term: Abnormality of the sense of smell
    term:
      id: HP:0004408
      label: Abnormality of the sense of smell
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nerve entrapment that leads to recurrent facial nerve palsy, disturbance of
      the sense of smell
    explanation: >-
      Reports disturbance of the sense of smell. The source does not grade its
      severity.
  notes: >-
    Bound to HP:0004408, defined as an anomaly in the ability to perceive and
    distinguish scents, because that is what the cited source reports: a
    disturbance of the sense of smell, neither graded nor described as complete.
    HP:0000458 Anosmia asserts inability and HP:0004409 Hyposmia asserts reduced
    sensitivity; the source states neither.

    One tension is recorded rather than hidden. The HPO disease annotation for
    OMIM:144755 carries HP:0000458 Anosmia, so a curator following the
    annotation rather than the cited sentence would bind differently. This entry
    follows the sentence because that is the evidence attached to this
    phenotype, while the Headache phenotype below is annotation-derived and says
    so.
- category: Ophthalmologic
  name: Visual Impairment
  description: >-
    Visual impairment from optic nerve entrapment at the optic canal.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hearing and vision impairments, impairment of facial sensibility
    explanation: Reports vision impairment among the entrapment deficits.
- category: Neurologic
  name: Facial Hypoesthesia
  description: >-
    Reduced facial sensation from trigeminal nerve entrapment. The fifth nerve is
    named in the mechanism and in the entrapment list, and this phenotype records
    its clinical consequence.
  phenotype_term:
    preferred_term: Trigeminal anesthesia
    term:
      id: HP:0031912
      label: Trigeminal anesthesia
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hearing and vision impairments, impairment of facial sensibility
    explanation: >-
      Reports impaired facial sensibility, the trigeminal deficit.
  notes: >-
    HP:0031912 is defined as decreased or absent sensation in the distribution of
    the trigeminal nerve, which supplies the face and mouth. It therefore covers
    the impairment of facial sensibility the source reports, and is the most
    specific term that accurately represents the claim. The generic
    HP:0033748 Hypoesthesia describes decreased touch anywhere in the body and
    loses the anatomy that makes this finding diagnostic.
- category: Ophthalmologic
  name: Optic Atrophy
  description: >-
    The structural correlate of second-nerve entrapment, complementing the
    functional visual impairment curated above.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  notes: >-
    Curated from the HPO disease annotation for OMIM:144755, recorded as
    provenance rather than quoted. The annotation records no frequency, and none
    is asserted here.
- category: Neurologic
  name: Headache
  description: >-
    Headache is reported in this disease. No mechanism is asserted here: the
    attribution to raised intracranial and ocular pressure appears in secondary
    sources but is not supported by anything in this entry's reference cache, and
    stating it would be an uncited causal claim.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  notes: >-
    Curated from the HPO disease annotation for OMIM:144755, recorded as
    provenance rather than quoted, since HPOA is a derived annotation. No
    frequency band is asserted, consistent with the rest of this entry: the
    annotation derives from the same single kindred, so a fraction here would
    describe that family rather than the disease.

    An Orphanet record, ORPHA:443098, attributes the headache to raised ocular
    and intracranial pressure and would supply a quotable row for that mechanism.
    It is not curated because the Orphanet bulk XML is not present in this
    checkout and fetching it would add manifest churn unrelated to this entry.
    Worth adding when someone next refreshes that source.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant, established across four generations of three related
    Dutch families with common progenitors.
  evidence:
  - reference: PMID:20140965
    reference_title: "Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disorder appears to have an autosomal-dominant transmission pattern.
    explanation: States the inheritance pattern from the pedigree analysis.
genetic:
- name: SLC39A14
  gene_term:
    preferred_term: SLC39A14
    term:
      id: hgnc:20858
      label: SLC39A14
  association: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    A dominant L441R missense substitution, found by whole-exome sequencing. The
    gene lies within the 8p21 interval to which the disease had earlier been
    mapped by linkage, and the three candidate genes examined at that time, BMP1,
    LOXL2 and ADAM28, were excluded by sequencing. That earlier work correctly
    predicted the answer would be a gene not previously implicated in sclerosing
    bone dysplasia.

    The variant is reported as NM_001128431.4:c.1322T>G, p.Leu441Arg, in exon 8,
    and appears in ClinVar as VCV000523143 classified Pathogenic. That record's
    review status is no assertion criteria provided, which is the honest weak
    point in an otherwise strong gene-disease case and is recorded here rather
    than left for a reader to discover.
  evidence:
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we identified by whole-exome sequencing a dominant mutation (L441R) in
      SLC39A14 (ZIP14).
    explanation: Identifies the causal gene and allele.
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Linkage analysis in a family with HCI resulted in the localization of the
      disease-causing gene to a region on chromosome 8p21 delineated by markers
      D8S282 and D8S382.
    explanation: >-
      Records the linkage interval that preceded gene identification. Localises
      the gene without identifying it, hence INDIRECT; its three candidate genes
      were all subsequently excluded.
prevalence:
- population: Three related Dutch families
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The disease has been described essentially in one extended kindred: three
    related Dutch families with common progenitors, 32 individuals across five
    generations, with 12 affected over four generations in one report and 13
    affected in another. Isolated case reports have since appeared. No population
    prevalence exists.
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Until today the disease has been described in only three related Dutch
      families with common progenitors and which consist of 32 individuals over
      five generations. HCI was observed in 12 family members over four
      generations.
    explanation: >-
      States the entire reported cohort at the time, which is the basis for the
      cohort caveat recorded in this entry's notes.
differential_diagnoses:
- name: Hypermanganesemia with dystonia 2
  disease_term:
    preferred_term: hypermanganesemia with dystonia 2
    term:
      id: MONDO:0014864
      label: hypermanganesemia with dystonia 2
  description: >-
    The other SLC39A14 disease, and the reason this entry carries a differential
    that shares no phenotype with it. Biallelic loss-of-function variants in the
    same gene cause an autosomal recessive manganese transporter defect
    presenting as rapidly progressive childhood-onset parkinsonism-dystonia,
    with no skeletal involvement.
  distinguishing_features:
  - Autosomal recessive, not dominant
  - Loss of manganese transport, not mistrafficking with intracellular zinc accumulation
  - Neurological presentation in childhood, with no hyperostosis and no cranial nerve entrapment
  - Chelation with disodium calcium edetate lowers blood manganese and can produce striking improvement
  evidence:
  - reference: PMID:27231142
    reference_title: Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified a cohort of patients with a novel autosomal recessive manganese
      transporter defect caused by mutations in SLC39A14
    explanation: >-
      Establishes that the same gene causes a recessive manganese-transport
      disease distinct from this one.
  - reference: PMID:27231142
    reference_title: Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chelation with disodium calcium edetate lowers blood manganese levels in
      patients and can lead to striking clinical improvement.
    explanation: >-
      Establishes that the recessive disease is treatable by chelation, which is
      the fact that makes the allelic boundary a safety matter rather than a
      taxonomic one.
  notes: >-
    This is a gene collision rather than a name collision, and it cuts the
    opposite way from the naming hazard recorded in this entry's notes. A
    curator or clinician reasoning from the gene symbol could carry the
    chelation therapy across the boundary. It does not transfer: that treatment
    addresses manganese overload from a recessive transport failure, whereas the
    lesion here is a dominant mistrafficking allele causing intracellular zinc
    accumulation, and no chelation evidence exists for it.

- name: Hyperostosis frontalis interna
  description: >-
    Thickening of the inner table of the frontal bone, common, usually
    incidental, and strongly associated with older women. It is a radiological
    finding rather than a Mendelian disease, and it is the entity most often
    confused with this one in the literature.
  distinguishing_features:
  - Confined to the frontal bone rather than involving the calvaria and skull base together
  - Not familial
  - Does not narrow the neuroforamina or produce cranial nerve deficits
  - No SLC39A14 variant
  notes: >-
    This is the sense-B usage described in this entry's notes. Case reports using
    the phrase hyperostosis cranialis interna for this finding are not evidence
    about the Mendelian disease.
- name: Van Buchem disease and sclerosteosis
  description: >-
    Sclerosing bone dysplasias of the SOST pathway that also thicken the skull
    and entrap cranial nerves, and are therefore the closest genuine mimics.
  distinguishing_features:
  - Both involve the long bones as well as the skull, which hyperostosis cranialis interna does not
  - Sclerosteosis additionally features syndactyly and gigantism
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Examples are Van Buchem disease, sclerosteosis, craniometaphyseal
      dysplasia, and Camurati-Engelmann disease. However, in these cases the long
      bones are affected as well.
    explanation: >-
      Names the mimicking dysplasias and states the discriminator, long-bone
      involvement.
- name: Craniometaphyseal dysplasia and Camurati-Engelmann disease
  description: >-
    Further sclerosing dysplasias with craniofacial hyperostosis and cranial
    nerve compromise.
  distinguishing_features:
  - Both affect the long bones
  - Craniometaphyseal dysplasia by definition involves the metaphyses
  - Camurati-Engelmann disease involves the diaphyses
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Examples are Van Buchem disease, sclerosteosis, craniometaphyseal
      dysplasia, and Camurati-Engelmann disease. However, in these cases the long
      bones are affected as well.
    explanation: >-
      Lists both among the sclerosing dysplasias distinguished by long-bone
      involvement.

progression:
- phase: Presymptomatic radiological phase
  notes: >-
    Hyperostosis is detectable on imaging before any deficit appears. This is the
    window the management recommendation targets, since decompression is advised
    in the presymptomatic period in high-risk individuals, and it is the reason
    at-risk relatives are imaged and monitored rather than merely counselled.
- phase: Early symptomatic phase
  age_range: second decade
  notes: >-
    First symptoms typically appear in the second decade. Facial nerve
    involvement is often recurrent rather than fixed at this stage, which is what
    makes it the point at which decompression can still preserve function.
  evidence:
  - reference: PMID:20140965
    reference_title: "Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      its first symptoms often presenting during the second decade
    explanation: Gives the typical age at which deficits begin.
- phase: Established deficit phase
  notes: >-
    Progressive bone overgrowth converts recurrent deficits into fixed ones as
    successive nerves are compromised. Facial and vestibulocochlear dysfunction
    dominate.
  evidence:
  - reference: PMID:20140965
    reference_title: "Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The progressive bone overgrowth causes entrapment and dysfunction of
      cranial nerves I, II, V, VII, and VIII
    explanation: >-
      Describes the progressive entrapment that defines this phase.
  review_notes: >-
    A plateau after the fourth decade is described in the deep-research report
    and would matter clinically, because it would close the intervention window
    this entry's treatment logic is built around. It is not curated as its own
    phase because no cached source states it, and a phase boundary asserted
    without a citation would be exactly the kind of claim this entry otherwise
    avoids. Worth adding if a source is located.

diagnosis:
- name: Cranial Computed Tomography
  description: >-
    The diagnostic test. Computed tomography shows thickening concentrated in the
    inner table across frontal, parietal, temporal and occipital regions, and
    measures the neuroforamina whose narrowing produces the symptoms. It also
    shows the feature that distinguishes this bone from ordinary hyperostosis:
    the deposited tissue is less attenuated than normal cortical bone. Because
    the disease is progressive and decompression is advised before deficits are
    established, imaging has a surveillance role in at-risk relatives and not
    only a diagnostic one.
  diagnosis_term:
    preferred_term: Computed Tomography
    term:
      id: NCIT:C17204
      label: Computed Tomography
  results: >-
    Thickening of the inner table of the calvaria and skull base with reduced
    attenuation relative to normal cortical bone, and narrowing of the
    neuroforamina, in a skeleton that is otherwise normal.
  evidence:
  - reference: PMID:22194361
    reference_title: Imaging features and progression of hyperostosis cranialis interna.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Linear measurements were performed of the inner table, the medulla, and the
      outer table of different skull locations, and attenuation (density)
      measurements of the same regions were recorded. Neuroforamina widths were
      recorded as well.
    explanation: >-
      Describes the measurements that constitute the radiological diagnosis,
      including the neuroforaminal widths that predict nerve compromise.
  notes: >-
    Skeletal survey is worth stating as a negative: the rest of the skeleton is
    normal, and that normality is what separates this disease from van Buchem
    disease, sclerosteosis, craniometaphyseal dysplasia and Camurati-Engelmann
    disease, all of which involve the long bones.
- name: Audiometric Testing
  description: >-
    Tone and speech audiometry is the first arm of vestibulocochlear
    surveillance, and it is what detects the hearing loss while it is still
    progressing. Increased hearing thresholds were found in 60 to 70 percent of
    affected subjects.
  diagnosis_term:
    preferred_term: Audiometric Test
    term:
      id: NCIT:C38036
      label: Audiometric Test
  results: >-
    Increased hearing thresholds in 60 to 70 percent of affected subjects, with
    otoacoustic emissions preserved because the cochlea is not affected.
  evidence:
  - reference: PMID:23622937
    reference_title: Neurophysiologic, audiometric and vestibular function tests in patients with hyperostosis cranialis interna.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we advise monitoring of vestibulocochlear nerve function with tone and
      speech audiometry, BERA and vestibular tests.
    explanation: >-
      Recommends tone and speech audiometry as part of vestibulocochlear
      monitoring.
  - reference: PMID:23622937
    reference_title: Neurophysiologic, audiometric and vestibular function tests in patients with hyperostosis cranialis interna.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased hearing thresholds and increased BERA latency times were found in
      60-70%.
    explanation: >-
      Quantifies the yield of audiometric and brainstem-response testing, which
      is the statistic this entry's results field reports.
- name: Brainstem Evoked Response Audiometry
  description: >-
    The single most useful measure in this disease. The I-V interpeak latency
    determines nerve encroachment reliably, which is precisely the decision the
    surveillance exists to inform, since the management argument is to decompress
    before a nerve is lost.
  diagnosis_term:
    preferred_term: Evoked Response Audiometry
    term:
      id: NCIT:C85857
      label: Evoked Response Audiometry
  results: >-
    Increased BERA latency times in 60 to 70 percent of affected subjects; the
    I-V interpeak latency identifies nerve encroachment.
  evidence:
  - reference: PMID:23622937
    reference_title: Neurophysiologic, audiometric and vestibular function tests in patients with hyperostosis cranialis interna.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The inter-peak latency I-V parameter in BERA has the ability to determine
      nerve encroachment reliably.
    explanation: >-
      Identifies the measure that detects nerve encroachment.
- name: Vestibular Testing and Visual Evoked Potentials
  description: >-
    Electronystagmography covers the vestibular half of eighth-nerve function,
    with abnormalities in about half of patients. Visual evoked potentials
    monitor the optic nerve and are recommended in combination with radiological
    and ophthalmological examination rather than alone.
  diagnosis_term:
    preferred_term: electronystagmography and visual evoked potentials
    term:
      id: NCIT:C215111
      label: Neuroelectrophysiology Test
  results: >-
    Vestibular abnormalities in about half of patients.
  evidence:
  - reference: PMID:23622937
    reference_title: Neurophysiologic, audiometric and vestibular function tests in patients with hyperostosis cranialis interna.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VEPs are important to monitor optic nerve function in combination with
      radiological and ophthalmologic examination. We do not advise the routine
      use of blink and masseter reflex.
    explanation: >-
      States the role of visual evoked potentials and, equally usefully, the two
      tests not worth performing routinely.
  - reference: PMID:23622937
    reference_title: Neurophysiologic, audiometric and vestibular function tests in patients with hyperostosis cranialis interna.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      50% of the patients had vestibular abnormalities.
    explanation: >-
      Quantifies the vestibular yield reported in this entry's results field.
  notes: >-
    Bound to NCIT:C215111 Neuroelectrophysiology Test, defined as a diagnostic
    tool measuring electrical signals produced by nerves and muscles. NCIT has no
    term for electronystagmography, for vestibular function testing, or for
    visual evoked potentials in general, so this is the accurate broader term
    with preferred_term carrying the specificity. An earlier version bound
    NCIT:C85857 Evoked Response Audiometry, which is an auditory term and is
    correctly used on the brainstem-response entry above; using it here made one
    identifier stand for two different tests.

    Splitting electronystagmography and visual evoked potentials into separate
    entries would be better still, since they monitor different nerves and carry
    different statistics.

    Blink and masseter reflexes are explicitly not advised for routine use: the
    symmetrical bilateral nature of the disease reduces sensitivity across the
    single-registration tests to 25 to 37.5 percent, a range that includes visual
    evoked potentials, which are nonetheless still recommended because they cover
    a nerve nothing else in the panel reaches.
- name: 18F-Fluoride PET/CT
  description: >-
    The only test here that quantifies disease activity rather than describing
    structure, which is why it is not redundant with computed tomography. Uptake
    is significantly higher in the sphenoid bone and clivus of affected family
    members, and visual assessment of the scans distinguishes disease severity
    and shows how the disturbance of bone metabolism evolves over life. That
    makes it the natural instrument for the surveillance this entry's management
    argument depends on, since the decision to decompress turns on whether the
    process is still advancing.

    The study was done in this kindred: nine affected family members, seven
    unaffected relatives and nine unrelated controls.
  diagnosis_term:
    preferred_term: 18F-fluoride positron emission tomography and computed tomography
    term:
      id: NCIT:C103512
      label: Positron Emission Tomography and Computed Tomography Scan
  results: >-
    Significantly higher 18F-fluoride uptake in the sphenoid bone and clivus of
    affected individuals, with standardised uptake values measured at frontal
    bone, sphenoid bone, petrous bone and clivus.
  evidence:
  - reference: PMID:21079950
    reference_title: Bone metabolic activity in hyperostosis cranialis interna measured with 18F-fluoride PET.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (18)F-Fluoride uptake is statistically significantly higher in the sphenoid
      bone and clivus regions of affected family members.
    explanation: >-
      The quantitative finding that distinguishes affected from unaffected
      relatives, and the basis for treating this as a measure of disease
      activity.
  - reference: PMID:21079950
    reference_title: Bone metabolic activity in hyperostosis cranialis interna measured with 18F-fluoride PET.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visual assessment of the scans of HCI patients is relevant in detecting
      disease severity and the pattern of disturbed bone metabolism throughout
      life.
    explanation: >-
      Establishes the surveillance role: severity grading and longitudinal
      tracking of the metabolic process.
  notes: >-
    The NCIT binding names the modality pairing rather than the tracer. NCIT has
    no 18F-fluoride term, so preferred_term carries the tracer, which is the part
    that makes this a bone-metabolism measurement rather than a structural scan.

- name: Molecular Confirmation of SLC39A14
  description: >-
    Identifying the SLC39A14 variant confirms the diagnosis and, more usefully,
    identifies at-risk relatives before symptoms appear. That matters here more
    than in most sclerosing dysplasias, because the management recommendation is
    to decompress accessible nerves in the presymptomatic period in high-risk
    individuals, which requires knowing who they are.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we identified by whole-exome sequencing a dominant mutation (L441R) in
      SLC39A14 (ZIP14).
    explanation: >-
      Establishes the testable molecular lesion.
  notes: >-
    Biochemical testing does not contribute. Bone turnover parameters are normal
    in patients, so there is no laboratory signature to screen on and the
    diagnosis rests on imaging plus genotype.

animal_models:
- name: Osteoblast-conditional L438R Zip14 knock-in mouse
  species: Mouse
  genotype: Conditional knock-in overexpressing L438R Zip14 in osteoblasts
  publication: PMID:29621230
  description: >-
    Conditional knock-in mice overexpressing the mouse equivalent of the human
    L441R allele, restricted to osteoblasts. They develop a severe skeletal
    phenotype with a drastic increase in cortical thickness driven by enhanced
    endosteal bone formation, which is the pathology seen in patients. They also
    develop an osteoporotic trabecular phenotype that the human disease is not
    known to show.
  evidence:
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a
      severe skeletal phenotype marked by a drastic increase in cortical
      thickness due to an enhanced endosteal bone formation, resembling the
      underlying pathology in HCI patients.
    explanation: >-
      Establishes the model and the authors' own claim that it resembles the
      human pathology.
  modeled_mechanisms:
  - target: Enhanced Endosteal Bone Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the cortical arm of the disease, and does so cell-autonomously
      in osteoblasts, which is what establishes the osteoblast as the effector
      cell.
    limitations: >-
      Three limits. The construct overexpresses the mutant allele rather than
      carrying it at endogenous dose, so the severity is not comparable to a
      patient's. The anatomy is not merely unconfined, it is inverted: the
      hyperostosis appears in the long bones while the calvaria shows no
      phenotype at all, with calvarial thickness and porosity not significantly
      different from controls. The authors say they were surprised by this and
      call it truly opposite to what is seen in patients. And the trabecular
      compartment moves the other way, becoming osteoporotic, which patients do
      not show. So the model misses the one bone that defines the human disease
      and adds a compartment-level change the disease does not have.
    evidence:
    - reference: PMID:29621230
      reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have
        a severe skeletal phenotype marked by a drastic increase in cortical
        thickness due to an enhanced endosteal bone formation, resembling the
        underlying pathology in HCI patients.
      explanation: >-
        Supports treating this model as informative for the endosteal
        bone-formation node, which is the arm it does reproduce.
    readouts:
    - name: Cortical thickness
      target: Enhanced Endosteal Bone Formation
      direction: INCREASED
      interpretation: >-
        The cortical arm of the human phenotype, reproduced by the same endosteal
        mechanism.
      evidence:
      - reference: PMID:29621230
        reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          a drastic increase in cortical thickness due to an enhanced endosteal
          bone formation
        explanation: Reports the cortical measurement behind this readout.
    - name: Trabecular bone mass
      target: Enhanced Endosteal Bone Formation
      direction: DECREASED
      interpretation: >-
        A divergence from the human disease rather than a confirmation of it. The
        authors interpret the opposite effects on the two compartments as
        mirroring the disparate actions of oestrogen.
      evidence:
      - reference: PMID:29621230
        reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone
          phenotype.
        explanation: >-
          Reports the trabecular finding. It has no established human
          counterpart, which is what makes it a divergence from the human disease
          rather than a confirmation of it.
  - target: Calvarial and Skull Base Hyperostosis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model produces no calvarial phenotype, so it does not reproduce the
      lesion that defines this disease. This is the structural counterpart of the
      HUMAN_MODEL_MISMATCH discussion, which previously carried the claim only as
      prose in limitations.
    limitations: >-
      Murine calvariae are unaffected while the appendicular skeleton and
      vertebral column are. In the knock-in the affected long bones are
      cortically thickened, with the osteoporosis confined to the trabecular
      compartment, so the model puts the hyperostosis in the wrong bone rather
      than failing to produce it. The same calvarial sparing appears in the
      plain Zip14 null, whose appendicular skeleton and vertebral column are
      osteoporotic with normal cortical bone, so the sparing is not an artefact
      of the knock-in construct. Whether a protective mechanism exists in murine
      calvariae that humans lack is undetermined, so this negative result
      constrains the model rather than the human mechanism.
    evidence:
    - reference: PMID:29621230
      reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        were surprised to see no calvarial phenotype as this is truly opposite of
        what we see in HCI
      explanation: >-
        States the failure in the authors' own words. Graded SUPPORT because the
        quote supports the claim that the model fails; the negative direction is
        carried by relationship FAILS_TO_RECAPITULATE.
    - reference: PMID:29621230
      reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        found that loss of endogenous Zip14 did not affect the calvariae, even
        though the appendicular skeleton and vertebral column were osteoporotic
      explanation: >-
        The same calvarial sparing in the plain null, which rules out the
        knock-in construct as the explanation.
treatments:
- name: Surgical Decompression of Entrapped Cranial Nerves
  therapeutic_modality: SURGERY
  description: >-
    The only treatment that addresses the actual injury. Because the nerve damage
    is mechanical and progressive, the recommendation is to decompress accessible
    nerves early in the symptomatic period, or even before symptoms in high-risk
    family members, rather than to wait for established deficit. Reported
    procedures include bilateral decompression of the internal auditory canals
    and middle-fossa facial nerve decompression. Nothing treats the underlying
    bone overgrowth.
  treatment_term:
    preferred_term: cranial nerve decompression
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Cranial Nerve Entrapment
    description: >-
      Decompression addresses the entrapment itself, which is the mechanism every
      deficit in this disease runs through.
  target_phenotypes:
  - preferred_term: Cranial nerve compression
    term:
      id: HP:0001293
      label: Cranial nerve compression
  - preferred_term: Facial palsy secondary to cranial hyperostosis
    term:
      id: HP:0007285
      label: Facial palsy secondary to cranial hyperostosis
  evidence:
  - reference: PMID:20140965
    reference_title: "Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical decompression of the accessible impaired cranial nerves is advised
      in the early symptomatic period or even in the presymptomatic period in
      high-risk individuals.
    explanation: >-
      States the recommendation and, importantly, its timing, which is the
      substantive clinical claim.
  - reference: PMID:19371457
    reference_title: "Facial nerve decompression via middle fossa approach for hyperostosis cranialis interna: a feasible therapeutic approach."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the use of bilateral surgical decompression of the internal
      auditory canals to treat hyperostosis cranialis interna in an eight-year-old
      girl presenting with bilateral facial palsy
    explanation: >-
      A worked example of the procedure: a single case demonstrating
      feasibility, not an outcome study.
  - reference: PMID:19371457
    reference_title: "Facial nerve decompression via middle fossa approach for hyperostosis cranialis interna: a feasible therapeutic approach."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mimic function recovered. One year post-operatively, the right and left
      facial sides had been restored to House-Brackmann grades I and II,
      respectively.
    explanation: >-
      The outcome, which is the part that matters for a treatment recommending
      early intervention: facial function recovered and was near-normal at one
      year.
  - reference: PMID:19371457
    reference_title: "Facial nerve decompression via middle fossa approach for hyperostosis cranialis interna: a feasible therapeutic approach."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical decompression of the internal auditory canal is recommended
      therapeutically, but may also be performed prophylactically in younger
      patients with hyperostosis cranialis interna.
    explanation: >-
      Second-source corroboration of the prophylactic timing that this entry's
      management argument rests on.
  notes: >-
    Treatment is otherwise symptomatic. No medical therapy modifies the bone
    phenotype, and none has been trialled in this disease.
  review_notes: >-
    Hearing rehabilitation is not curated and the omission is a gap rather than a
    judgement. Deafness is the dominant morbidity here, and auditory brainstem
    implantation is the option when the cochlear nerve is no longer functional.
    It carries a disease-specific hazard: cerebral vasospasm after auditory
    brainstem implantation has been reported in a patient with this syndrome
    (PMID:21665359, from the same group that characterised the kindred). That
    report has no abstract retrievable through the usual route, so no compliant
    snippet could be quoted and nothing is asserted here. Recorded so the safety
    signal is visible to the next curator rather than lost, and so that whoever
    can obtain the full text knows what to look for.
discussions:
- discussion_id: hci_formation_versus_resorption
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the excess bone in this disease driven by increased formation, decreased
    resorption, or both?
  attaches_to:
  - pathophysiology#Enhanced Endosteal Bone Formation
  rationale: >-
    The node is graded ESTABLISHED on the strength of patient histology showing
    increased bone formation with normal tissue structure, and that is what the
    cached source says. But the two mouse models point different ways: the
    osteoblast conditional knock-in implicates increased formation, while the
    published ZIP14 null work has been read as implicating decreased resorption.
    Those are different mechanistic claims with different therapeutic
    implications, and nothing in the reference cache adjudicates between them.

    The distinction is not academic. If the excess is a resorption failure, the
    osteoclast is the effector cell and this entry names the wrong one; the
    formation reading is the one the human histology supports, which is why it is
    curated, but a curator should know the alternative exists.
- discussion_id: hci_metal_levels_never_measured
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are serum and tissue zinc, manganese and iron levels in patients with
    this disease?
  attaches_to:
  - pathophysiology#Intracellular Zinc Accumulation
  - differential_diagnoses#Hypermanganesemia with dystonia 2
  rationale: >-
    The mechanism curated here is a metal-transport defect producing
    intracellular zinc accumulation, and that has been shown in cells. It has
    never been measured in a patient: no serum or tissue zinc, manganese or iron
    levels have been reported in this disease.

    The gap is sharper than it looks because of the allelic disease. Biallelic
    loss of the same transporter causes manganese accumulation that is
    measurable in blood and treatable by chelation. Whether the dominant
    mistrafficking allele produces any systemic metal disturbance at all is
    unknown, and the answer bears directly on whether the chelation boundary this
    entry draws is a boundary of mechanism or merely one of untested assumption.
- discussion_id: hci_murine_calvarial_sparing
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why are murine calvariae spared by a lesion that produces calvarial
    hyperostosis in patients?
  attaches_to:
  - pathophysiology#Calvarial and Skull Base Hyperostosis
  - animal_models#Osteoblast-conditional L438R Zip14 knock-in mouse
  rationale: >-
    Cranial confinement is the defining feature of this disease and the one thing
    that separates it from every other sclerosing bone dysplasia. The mouse
    reproduces the cellular mechanism convincingly, cortical thickening by
    enhanced endosteal formation in osteoblasts, but it does so in the long bones
    and not in the skull. The mice develop no calvarial phenotype at all, with
    calvarial thickness and porosity indistinguishable from controls, while the
    long bones carry the thickened cortex and an osteoporotic trabecular
    compartment. The same sparing appears in the plain null, so the question is
    not why the human disease is confined to the skull but why murine calvariae
    appear protected from a zinc-handling lesion affecting every other bone in
    the same animal. The authors pose exactly that and leave it open.

    So the model explains how the bone forms and not where. Candidate
    explanations are untested: regional differences in ZIP14 expression or zinc
    handling between neural-crest-derived cranial osteoblasts and mesoderm-derived
    axial ones; a species-specific calvarial protective mechanism; or an artefact
    of overexpression, since the construct is not at endogenous dose. Distinguishing
    them would need an endogenous-dose knock-in and comparison of cranial against
    long-bone osteoblasts from the same animal.
  evidence:
  - reference: PMID:22194361
    reference_title: Imaging features and progression of hyperostosis cranialis interna.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HCI is the only genetic bone dysplasia known that is confined to the
      craniofacial area.
    explanation: >-
      Establishes cranial confinement as the defining human feature that the
      model does not reproduce.
  - reference: PMID:29621230
    reference_title: Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone
      phenotype.
    explanation: >-
      Documents a model phenotype with no described human counterpart, which is
      the second half of the mismatch.
- discussion_id: hci_single_kindred_generalisability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which features of the described phenotype belong to the disease and which
    belong to the kindred it was described in?
  attaches_to:
  - phenotypes#
  - prevalence#Three related Dutch families
  rationale: >-
    Essentially the whole clinical description rests on three related Dutch
    families with common progenitors. Everything an entry can say about which
    nerves are affected, in what order, at what age and how severely is therefore
    conditioned on one genetic background and one allele. No frequency band is
    asserted anywhere in this entry for that reason. Independent kindreds with
    different SLC39A14 alleles would be needed to separate disease from family,
    and until then the natural history recorded here should be read as the
    history of that pedigree.
  evidence:
  - reference: PMID:23640157
    reference_title: Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Until today the disease has been described in only three related Dutch
      families with common progenitors
    explanation: >-
      States the limitation that the entire clinical description derives from one
      extended kindred.
📚

References & Deep Research

References

2
PMID:29621230
Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.
No top-level findings curated for this source.
PMID:20140965
Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Hyperostosis_Cranialis_Interna · 2026-08-29T05:02:14Z · View source

Created kb/disorders/Hyperostosis_Cranialis_Interna.yaml (MONDO:0007765, SLC39A14). Deep research was requested from falcon, which is not configured here, so the run used --fallback and claude_code produced the report; the substitution is recorded in the report frontmatter. Its reference validation resolved 39 of 39 citations with a 0.0 confabulation rate and flagged one unsupported quote, PMID:794825, and three off-topic references. Its term validation matched all 39 checked labels and flagged one obsolete term, GO:0019933 obsolete cAMP-mediated signaling. None of the five flagged identifiers is used in this entry; the cAMP node was already bound to GO:0141156, the current term, before the report was read. The gene was not in the stub and had to come from the literature. MONDO:0007765 carries a feature relation and a parent class and no causal-gene relation, so stub enrichment had nothing to copy, while SLC39A14 was identified by whole-exome sequencing in 2018. The observation is recorded in the entry notes for whoever maintains that mapping; the entry does not propose what should be done about it. The pathograph is a six-node chain with an unusually complete molecular route for a disease this rare: a dominant L441R substitution, mistrafficking of ZIP14 away from the plasma membrane with intracellular zinc accumulation, hyperactivation of cAMP-CREB and NFAT signalling, enhanced endosteal bone formation in osteoblasts, calvarial and skull base hyperostosis, and cranial nerve entrapment. functional_impact_category is left UNKNOWN deliberately, because the allele causes mistrafficking with downstream signalling hyperactivation, which is neither simple loss of transporter function nor a clean gain, and no source classifies it. The conditional mouse is curated as PARTIALLY_RECAPITULATES with three stated limitations: the construct overexpresses rather than carrying the allele at endogenous dose, the phenotype is generalised skeletal rather than confined to the skull, and the mice additionally develop trabecular osteoporosis that patients are not described as having. Cranial confinement is the single most distinctive feature of the human disease and is the thing the model does not reproduce, which is recorded as a HUMAN_MODEL_MISMATCH discussion with untested candidate explanations. A Named Entity Confusion hazard was identified independently by the curator and by the deep-research report, and the report's stricter reading was adopted. The phrase hyperostosis cranialis interna is used both for this Mendelian disease and as a loose radiological label for sporadic internal skull-table thickening overlapping hyperostosis frontalis interna. A 2025 case report of cerebrospinal fluid leak, PMID:40091967, was fetched, read and initially curated as a phenotype with a heavy caveat. It was then removed entirely: that paper describes the aetiology as unknown despite the 2018 gene identification, discusses the condition alongside hyperostosis frontalis interna, and reports no genetic testing, so using it to establish a phenotype of the Mendelian disease is the confusion itself. The reasoning is recorded in notes and the mimics are curated as differential_diagnoses rather than dropped. No frequency band is asserted anywhere in this entry. Essentially the entire clinical description derives from three related Dutch families with common progenitors, so every natural-history statement is conditioned on one pedigree and one allele, and that limitation is recorded as its own knowledge gap. Validated with just validate-disorders, just validate-terms, just count-verified-snippets (36/36), just check-entity-refs and just check-duplicate-keys. Compliance 95.0 percent.

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Hyperostosis Cranialis Interna (HCI) — Comprehensive Disease Research Report
claude-haiku-4-5-20251001, claude-opus-5[1m] 32 citations 2026-08-29T00:58:38.834994

Hyperostosis Cranialis Interna (HCI) — Comprehensive Disease Research Report

Prepared: 2026-08-29 · Target: kb/disorders/Hyperostosis_Cranialis_Interna.yaml · Category: Mendelian (autosomal dominant sclerosing bone dysplasia)

⚠️ Read this first: a Named Entity Confusion hazard specific to this disease

The string "hyperostosis cranialis interna" is used in the literature in two mutually incompatible senses, and conflating them will corrupt the entry:

Sense What it is Sources
(A) The Mendelian disease — MONDO:0007765 / OMIM 144755 / ORPHA:443098 An autosomal dominant sclerosing bone dysplasia caused by heterozygous SLC39A14 p.Leu441Arg, described in one extended Dutch kindred and, to date, nowhere else Manni 1990 (PMID:2300107); Waterval 2010 (PMID:20140965); Hendrickx 2018 (PMID:29621230)
(B) A descriptive radiological label — non-Mendelian, sporadic internal skull-table thickening, overlapping hyperostosis frontalis interna (HFI) and Morgagni-Stewart-Morel syndrome Used loosely in isolated case reports with no family history and no genetic testing Alsaleh 2025 (PMID:40091967); Otken 2023 (PMID:37546094)

Curation implication: only sense (A) is a dismech Disease entry. Evidence drawn from sense-(B) case reports (e.g. the 2025 Cureus CSF-leak case, the 2023 cadaveric report) must not be used to support phenotype frequencies, mechanism, or inheritance claims in this entry. Both are flagged explicitly in Section 10 (Differential diagnosis).

1. Disease Information

Overview

Hyperostosis cranialis interna is a hereditary sclerosing bone dysplasia in which endosteal bone deposition thickens the inner table of the calvaria and the skull base, progressively narrowing the cranial neuroforamina and entrapping cranial nerves I, II, V, VII and VIII. It is the only known genetic bone dysplasia whose skeletal involvement is confined to the craniofacial skeleton — the appendicular skeleton and spine are radiologically and biochemically normal.

"Hyperostosis cranialis interna is a hereditary bone disorder that is characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base (OMIM 144755). The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII, its first symptoms often presenting during the second decade." — Waterval JJ, Stokroos RJ, Bauer NJ, De Bondt RB, Manni JJ. Am J Med Genet A. 2010;152A(3):547–555. PMID:20140965, DOI:10.1002/ajmg.a.33205

"HCI is a unique autosomal-dominant sclerosing bone dysplasia affecting the skull base and the calvaria, characterized by cranial nerve deficits due to stenosis of neuroforamina, whereby the mandible is affected to a lesser extent." — Waterval JJ, van Dongen TM, Stokroos RJ, De Bondt BJ, Chenault MN, Manni JJ. AJNR Am J Neuroradiol. 2012;33(3):453–461. PMID:22194361, DOI:10.3174/ajnr.A2830

"HCI is the only genetic bone dysplasia known that is confined to the craniofacial area." — same source, PMID:22194361

Key identifiers

Resource Identifier
MONDO MONDO:0007765 — hyperostosis cranialis interna (verified via OLS4; synonyms "HCIN", "hyperostosis cranialis interna (disease)")
OMIM 144755 — HYPEROSTOSIS CRANIALIS INTERNA; HCIN
Orphanet ORPHA:443098
ICD-10 M85.2 (Hyperostosis of skull) — per Orphanet cross-reference
ICD-11 Not specifically coded; maps to the FB80-series "other specified disorders of bone density and structure"
UMLS C1840404 (per NIH GTR condition page)
MeSH No dedicated descriptor; indexed under Hyperostosis (D015576)
Causal gene SLC39A14 — HGNC:20858, NCBI Gene 23516, Ensembl ENSG00000104635, UniProt Q15043, OMIM 608736, cytoband 8p21.3

Synonyms and alternative names

  • HCI; HCIN
  • "Hyperostosis cranialis interna (disease)" (MONDO exact synonym)
  • "Hyperostosis cranalis interna" (MONDO exact synonym — a propagated typographic variant)
  • Historical: "Dominant generalized cortical hyperostosis with multiple cranial nerve involvement" (PMID:794825, a 1976 Dutch-language description that predates the 1990 delineation and may describe the same or a related entity — verify before citing)

Data provenance

Essentially all primary knowledge derives from aggregated case-series description of a single extended pedigree, not from EHR/population data. There is no registry, no cohort study, and no population-scale genomic ascertainment. The genetic finding rests on a single family, single variant, single WES proband with segregation. Curate accordingly: frequencies below are n/13 fractions from one kindred, not population estimates.

2. Etiology

Primary cause — monogenic

Heterozygous missense mutation in SLC39A14 (ZIP14), a plasma-membrane divalent-metal (Zn²⁺/Mn²⁺/Fe²⁺) transporter.

"Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14)." — Hendrickx G, Borra VM, Steenackers E, et al., Van Hul W. PLoS Genet. 2018;14(4):e1007321. PMID:29621230, DOI:10.1371/journal.pgen.1007321

The mutation is not a simple loss of function. It is a trafficking-defective, intracellularly-retained allele that behaves as a gain of pathological signalling (see Section 6):

"We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling." — PMID:29621230

Historical mapping context. Before the gene was found, linkage placed the locus at 8p21 and excluded the obvious candidates:

"Linkage analysis in a family with HCI resulted in the localization of the disease-causing gene to a region on chromosome 8p21 delineated by markers D8S282 and D8S382. Interesting candidate genes in this region are BMP1, LOXL2, and ADAM28. Sequence analysis of these genes did not reveal any putative mutations. This suggests that a gene not previously involved in a sclerosing bone dysplasia is responsible for the abnormal growth in the skull of these patients." — Borra VM, Waterval JJ, Stokroos RJ, Manni JJ, Van Hul W. Calcif Tissue Int. 2013;93(1):93–98. PMID:23640157, DOI:10.1007/s00223-013-9732-8

Risk factors

  • Genetic: the causal variant itself. No susceptibility loci, no GWAS, no modifier loci have been reported (the pedigree is far too small for modifier mapping).
  • Environmental / lifestyle / occupational / infectious: none identified. No toxin, radiation, dietary, or infectious contribution has been proposed or tested. Given ZIP14's role in metal transport, dietary zinc/manganese/iron status is a biologically plausible but entirely untested modifier — record as a knowledge gap, not as a risk factor.
  • Age/sex/family history: family history is the only clinical risk factor. No sex bias has been reported in the kindred (see Section 9).

Protective factors

None known. No protective variants, no modifier alleles, no dietary or lifestyle exposure has been reported to reduce penetrance or severity. gnomAD-based constraint analysis of SLC39A14 has not been used to argue any protective allele for this phenotype.

Gene–environment interactions

No data. This is a genuine, well-defined knowledge gap: ZIP14 substrate availability (dietary Zn, Mn, Fe) is the obvious axis, and the paralogous biallelic ZIP14 disease (hypermanganesemia with dystonia 2) is pharmacologically modifiable by chelation (PMID:27231142) — yet no study has asked whether metal status modifies the HCI bone phenotype. Suitable for a KNOWLEDGE_GAP discussion with proposed_experiments.

3. Phenotypes

HPO annotation set for OMIM:144755 (retrieved from the HPO annotation API, 2026-08-29)

Frequencies are n/13 affected individuals from the Dutch kindred (Waterval 2010), except where HPO records a qualitative band.

HP ID Label (canonical, verified) Frequency Onset Category
HP:0004490 Calvarial hyperostosis 13/13 — Radiological/structural
HP:0005746 Osteosclerosis of the base of the skull 13/13 — Radiological/structural
HP:0005890 Hyperostosis cranialis interna — — Radiological/structural (disease-specific HPO term)
HP:0001751 Abnormal vestibular function 10/13 — Clinical sign
HP:0010628 Facial palsy 9/13 — Clinical sign (CN VII)
HP:0000407 Sensorineural hearing impairment 8/8 tested — Clinical sign (CN VIII)
HP:0000458 Anosmia 6/13 Young adult Symptom (CN I)
HP:0002315 Headache 5/10 Young adult Symptom
HP:0007906 Ocular hypertension 1/13 — Laboratory/clinical measurement
HP:0007099 Chiari type I malformation 1/13 — Structural complication
HP:0000648 Optic atrophy — — Clinical sign (CN II)
HP:0007663 Reduced visual acuity — — Symptom (CN II)
HP:0000360 Tinnitus — — Symptom (CN VIII)
HP:0004409 Hyposmia — — Symptom (CN I)
HP:0000520 Proptosis Very rare — Physical manifestation
HP:0009926 Epiphora Very rare — Symptom
HP:0200026 Ocular pain Very rare — Symptom
HP:0000265 Mastoiditis Very rare — Complication
HP:0003621 Juvenile onset — — Onset modifier
HP:0011462 Young adult onset — — Onset modifier

Additional HPO terms to consider (verified labels, not in the current OMIM annotation set but supported by the literature):

HP ID Label Justification
HP:0006824 Cranial nerve paralysis Umbrella term for the defining mechanism
HP:0002516 Increased intracranial pressure Orphanet summary cites "headaches due to increased ocular and intracranial pressure"
HP:0011001 Increased bone mineral density Osteosclerosis; note the caveat below that hyperostotic bone is less attenuating than normal cortex
HP:0000365 Hearing impairment Parent of the SNHL annotation

Trigeminal (CN V) involvement is named in the disease definition ("impairment of facial sensibility") but carries no discrete HPO annotation in the OMIM set; a facial-hypoesthesia term should be sourced with OAK before binding.

Phenotype characteristics

Age of onset. Second decade is typical, but paediatric presentation occurs — a documented case presented with bilateral facial palsy at age 8 (PMID:19371457).

"…its first symptoms often presenting during the second decade." — PMID:20140965

Severity and expressivity. Markedly variable within the same kindred:

"Patients are mildly to severely affected." — PMID:23640157

Progression. Progressive during childhood and early adult life, then plateauing after the fourth decade — clinically important because it defines the therapeutic window. Per the Orphanet summary of the disease: radiological progression is minimal after the fourth decade, although decreased intracranial volume can lead to death in severe cases.

Disease course by nerve: - CN VII (facial): classically recurrent facial palsy — episodic, then fixed. This is the presenting sign in the index description (Manni 1990, PMID:2300107). - CN VIII: progressive sensorineural hearing loss and progressive vestibular failure, up to bilateral vestibular areflexia. - CN I: hyposmia progressing to anosmia. - CN II: progressive visual loss with optic atrophy.

Quality of life. No EQ-5D, SF-36, or PROMIS data exist for HCI. The functional burden is inferable and severe: combined bilateral deafness + bilateral vestibular areflexia + facial paralysis + visual loss + anosmia in a single patient. Record as a knowledge gap — a disease-specific PRO instrument has never been applied.

Objective function-test findings (the closest thing to a phenotype-frequency study)

"Due to the symmetrical bilateral nature of this disease, the sensitivity of visual evoked potentials (VEPs), masseter reflex and blink reflex is decreased (25-37.5%), therefore reducing the value of single registration. Increased hearing thresholds and increased BERA latency times were found in 60-70%. The inter-peak latency I-V parameter in BERA has the ability to determine nerve encroachment reliably. 50% of the patients had vestibular abnormalities. No patient had disease-related absence of otoacoustic emissions, because the cochlea is not affected." — Waterval JJ, Bischoff MP, Stokroos RJ, Anteunis LJ, Hilkman DM, Kingma H, Manni JJ. Clin Neurol Neurosurg. 2013;115(9):1765–1770. PMID:23622937, DOI:10.1016/j.clineuro.2013.03.008

Mechanistically decisive detail: preserved otoacoustic emissions prove the lesion is retrocochlear nerve compression, not cochlear disease — a strong constraint on the pathophysiology chain and a good candidate evidence item.

4. Genetic / Molecular Information

Causal gene

SLC39A14 (solute carrier family 39 member 14), encoding ZIP14 (metal cation symporter ZIP14). HGNC:20858 · 8p21.3 · UniProt Q15043 · OMIM 608736 · Ensembl ENSG00000104635 · Entrez 23516 Aliases: ZIP14, ZIP-14, KIAA0062, NET34.

The pathogenic variant

Field Value
cDNA NM_001128431.4(SLC39A14):c.1322T>G
Protein p.Leu441Arg (p.L441R)
Exon Exon 8
Type Missense, single nucleotide variant
Zygosity Heterozygous
Origin Germline, inherited (autosomal dominant)
ClinVar VCV000523143 — Pathogenic, review status "no assertion criteria provided" (single legacy submission; this is a weak review status despite functional support)
Population frequency Absent from dbSNP, 1000 Genomes, ExAC; absent from 100 ethnically matched controls
In silico CADD 29.4
Protein domain Within the fifth transmembrane helix; UniProt annotates TM helix at residues 425–445, so residue 441 lies inside a TM span
Functional class Not a null. Trafficking-defective / mislocalizing allele producing pathological intracellular signalling — best modelled as GAIN_OF_FUNCTION at the pathway-state level rather than a LOSS_OF_FUNCTION variant consequence (see the dismech GOF/LOF decision table)

Supporting full-text statements (Hendrickx 2018, PMID:29621230 — these are full-text quotes obtained through a fetch-and-summarize path; re-verify as exact substrings against a fetched reference cache entry before using them as evidence snippet: values):

  • "Whole-exome sequencing (WES) was performed on one affected individual from the family with HCI."
  • "this missense mutation has a Combined Annotation Dependent Depletion (CADD) score of 29.4, indicating it belongs to the top 0.11% most deleterious substitutions"
  • "was not found in 100 control individuals with the same ethnic background and is not present in sequence databases, including dbSNP, 1000 Genomes Project and ExAc databases"
  • "This variant co-segregates with the disease in the complete family"

Other SLC39A14 variants in ClinVar listed against "Hyperostosis cranialis interna"

Retrieved 2026-08-29 (9 records). Only one is pathogenic for HCI; the rest are gene-level aggregation artefacts and must not be curated as HCI alleles:

HGVS Classification Note
c.1322T>G (p.Leu441Arg) Pathogenic The HCI allele
c.134A>G (p.Gln45Arg) Uncertain significance Single submitter
c.1301G>A (p.Gly434Glu) Uncertain significance Single submitter
c.751-9C>G Likely pathogenic Listed against both HCI and hypermanganesemia with dystonia 2; the biallelic-disease assignment is the substantive one
c.939+8G>C, c.1333-25G>A, c.98T>C, c.195A>G, c.457+45G>T Benign / Likely benign Condition list is gene-level, not disease-specific

The allelic-disease contrast (important for the entry)

SLC39A14 produces two clinically unrelated diseases by two different mechanisms:

HCI (MONDO:0007765, OMIM 144755) Hypermanganesemia with dystonia 2 (MONDO:0014864, OMIM 617013)
Inheritance Autosomal dominant, single missense Autosomal recessive, biallelic LOF
Mechanism Mistrafficked ZIP14; intracellular Zn accumulation; cAMP-CREB/NFAT hyperactivation Failed hepatic Mn uptake → systemic Mn accumulation → neurotoxicity
Tissue Calvaria + skull base only Basal ganglia; no bone phenotype reported
Treatable No disease-modifying therapy Chelation with disodium calcium edetate

"Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. … Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement." — Tuschl K, Meyer E, Valdivia LE, et al. Nat Commun. 2016;7:11601. PMID:27231142, DOI:10.1038/ncomms11601

Modifier genes, epigenetics, chromosomal abnormalities

  • Modifier genes: none identified. Intrafamilial severity varies widely ("mildly to severely affected", PMID:23640157) so modifiers almost certainly exist, but the pedigree cannot power their detection.
  • Epigenetics: no data. No methylation, histone, or chromatin study in HCI. (Note: an enterocyte-specific Zip14 deletion mouse has been reported to alter intestinal homeostasis through epigenetic mechanisms — Am J Physiol Gastrointest Liver Physiol 2023, DOI:10.1152/ajpgi.00244.2022 — but this concerns gut, not bone, and is not evidence about HCI.)
  • Chromosomal abnormalities: none. HCI is not a CNV/structural disorder; CMA and karyotype are uninformative.

5. Environmental Information

  • Environmental factors: none established. HCI is fully explained by the germline variant.
  • Lifestyle factors: none established.
  • Infectious agents: none — not applicable.
  • Untested but mechanistically plausible: dietary/systemic zinc, manganese and iron status, given ZIP14's substrate profile. Do not curate as an environmental: entry with influences_mechanisms — there is no citable evidence. If recorded at all, it belongs in a KNOWLEDGE_GAP discussion.

6. Mechanism / Pathophysiology

The causal chain (upstream → downstream)

SLC39A14 c.1322T>G (p.L441R), heterozygous  [MOLECULAR]
   ↓  misfolding/retention within TM5
ZIP14 fails to traffic to the plasma membrane;
trapped in cytoplasm within early and late endosomes  [MOLECULAR/CELLULAR]
   ↓
Loss of extracellular Zn²⁺ uptake  +  paradoxical accumulation
of intracellular labile zinc  [MOLECULAR]
   ↓
Hyper-activation of cAMP-CREB signalling (~5-fold) and
NFAT signalling (~2-fold) in osteoblasts  [CELLULAR]
   ↓
Increased osteoblast-mediated endosteal bone formation
(inner table of calvaria + skull base)  [CELLULAR]
   ↓
Endosteal hyperostosis / osteosclerosis of calvaria and
skull base; dense, well-organized bone with reduced
Haversian channels and osteocytes  [TISSUE]
   ↓
Progressive stenosis of cranial neuroforamina
(optic canal, IAC, cribriform plate, foramina of CN V)  [TISSUE]
   ↓
Cranial nerve compression / entrapment → CN I, II, V, VII, VIII
dysfunction; reduced intracranial volume → raised ICP  [ORGANISM]

Molecular pathways

cAMP–CREB. ZIP14's normal physiological role is to facilitate GPCR→cAMP–CREB signalling by suppressing basal phosphodiesterase activity — established in the knockout, where the effect runs in the opposite direction:

"Here we report that the cell membrane-localized Zn transporter SLC39A14 controls G-protein coupled receptor (GPCR)-mediated signaling. Mice lacking Slc39a14 (Slc39a14-KO mice) exhibit growth retardation and impaired gluconeogenesis, which are attributable to disrupted GPCR signaling in the growth plate, pituitary gland, and liver. The decreased signaling is a consequence of the reduced basal level of cyclic adenosine monophosphate (cAMP) caused by increased phosphodiesterase (PDE) activity in Slc39a14-KO cells." — Hojyo S, Fukada T, Shimoda S, Ohashi W, Bin BH, Koseki H, Hirano T. PLoS One. 2011;6(3):e18059. PMID:21445361, DOI:10.1371/journal.pone.0018059

This is the key logical pivot: KO → reduced cAMP-CREB and osteopenia; L441R → hyper-activated cAMP-CREB and hyperostosis. The HCI allele is therefore mechanistically the inverse of a null, which is exactly why the disease is dominant and why it is not phenocopied by haploinsufficiency.

Calcineurin–NFAT. Doubled in the L441R condition (PMID:29621230). NFAT signalling is a canonical osteoblast/osteoclast differentiation regulator.

Zinc homeostasis. Loss of plasma-membrane Zn²⁺ import coexisting with intracellular Zn²⁺ accumulation — a compartmentalization defect rather than a whole-cell zinc deficit.

Cellular processes and cell types

  • Osteoblast (CL:0000062) — the primary effector. The osteoblast-restricted knock-in reproduces the bone phenotype; the osteoclast-restricted one does not.
  • Osteoclast (CL:0000092) — ZIP14 is expressed but is not the driver of HCI. (It is the driver in the constitutive-KO osteopenia phenotype — see Section 15.)
  • Osteocyte (CL:0000137) — reduced in number within HCI bone (histology below).
  • Processes: GO:0001649 osteoblast differentiation; GO:0030282 bone mineralization; GO:0001957 intramembranous ossification (the calvaria and much of the skull vault form by intramembranous ossification — the likely reason the phenotype is craniofacially restricted); GO:0045453 bone resorption.

Protein dysfunction

ZIP14 is an "Electroneutral transporter of the plasma membrane mediating the cellular uptake of the divalent metal cations zinc, manganese and iron that are important for tissue homeostasis, metabolism, development and immunity" (UniProt Q15043). p.L441R inserts a charged arginine into a transmembrane helix (425–445) — a classic destabilizing substitution that would be expected to trigger ER/endosomal retention, consistent with the observed localization to early and late endosome membranes (which are, notably, native ZIP14 locations per UniProt, suggesting the mutant is stalled in a normal part of the itinerary rather than misrouted to a novel compartment).

Reported functional results (PMID:29621230, full text — re-verify before snippet use): - WT ZIP14 increased ⁶⁵Zn uptake ~4-fold; L441R showed "no sign of ⁶⁵Zn uptake from the extracellular space" - L441R produced a significantly "stronger (p<0.001) increase in intracellular Zn accumulation" than WT - L441R "is not present on the plasma membrane, but appears to be trapped in the cytoplasm" - cAMP-CREB: "significant (p = 0.004) 5-fold increase"; NFAT signalling doubled

Tissue-level pathology (human bone histology)

From the HCI patient specimen (PMID:29621230, full text — re-verify): - "patient interna is wider and characterized by a great and dense amount of well-organized bone, suggesting an increased bone formation or decreased bone resorption" - "number of Haversian channels and osteocytes are significantly lower in the patient interna"

And from the linkage paper:

"Histomorphological investigations showed increased bone formation with a normal tissue structure. Biochemical parameters were normal." — PMID:23640157

Note the tension between "well-organized bone / normal tissue structure" and the CT finding that the deposited bone is less dense than normal cortex:

"The attenuation of the deposited hyperostotic bone was lower than normal cortical bone." — PMID:22194361

This is a real, curatable nuance: HCI bone is abundant but hypomineralized relative to normal cortex — it is a quantity, not a quality, lesion.

Metabolic, immune, biochemical

  • Metabolic changes: none demonstrated in bone. Systemic biochemistry is normal (PMID:23640157). ZIP14 has metabolic roles elsewhere (hepatic gluconeogenesis, insulin signalling) that are not reported as abnormal in HCI patients.
  • Immune involvement: none. No autoimmunity, immunodeficiency, or inflammation reported.
  • Serum Zn / Mn / Fe in HCI patients: not measured/not reported. A conspicuous gap — the paralogous recessive disease is defined by hypermanganesaemia, and nobody has published metal levels in HCI carriers. High-value proposed_experiment.

Molecular profiling and advanced technologies

None available for HCI. No transcriptomics, proteomics, metabolomics, lipidomics, single-cell, spatial, multi-omics, or CRISPR/RNAi screen has been performed on HCI tissue. There is no GEO/ArrayExpress dataset for this disease. Do not manufacture datasets: records; gene-only searches on SLC39A14 will surface manganese-neurotoxicity and hepatology datasets that are GENE_ONLY/CONFLICT for this entry.

Suggested ontology bindings (labels verified against OLS4/local caches unless flagged)

Biological processes (GO): | CURIE | Canonical label | Suggested modifier | |---|---|---| | GO:0071578 | zinc ion import across plasma membrane | DECREASED | | GO:0006882 | intracellular zinc ion homeostasis | ALTERED state → use INCREASED for labile Zn accumulation | | GO:0072659 | protein localization to plasma membrane | DECREASED | | GO:0007189 | adenylate cyclase-activating G protein-coupled receptor signaling pathway | GAIN_OF_FUNCTION (qualitative — signalling escapes normal PDE restraint) | | GO:0033173 | calcineurin-NFAT signaling cascade | INCREASED | | GO:0001649 | osteoblast differentiation | INCREASED | | GO:0030282 | bone mineralization | INCREASED | | GO:0001957 | intramembranous ossification | INCREASED | | GO:0045453 | bone resorption | consider DECREASED — hypothesis only, the histology says "increased bone formation or decreased bone resorption" |

⚠️ GO:0019933 ("cAMP-mediated signaling") is OBSOLETE in GO — do not bind it. Use GO:0007189 (verified in the local cache/go/terms.csv).

Molecular functions (GO): GO:0005385 zinc ion transmembrane transporter activity (verified, in local cache); GO:0005384 manganese ion transmembrane transporter activity (from UniProt annotation, verify with OAK before binding).

Cell types (CL): CL:0000062 osteoblast; CL:0000092 osteoclast; CL:0000137 osteocyte; CL:0007010 preosteoblast (all verified in cache/cl/terms.csv).

Chemical entities (CHEBI): zinc(2+), manganese(2+), iron(2+), cAMP — resolve CURIEs with OAK before binding; not verified here.

7. Anatomical Structures Affected

Organ level

  • Primary: the skull — specifically the inner table (lamina interna) of the calvaria and the skull base. Frontal, parietal, temporal and occipital regions are all involved; the sphenoid bone and clivus show the highest metabolic activity.
  • Secondary: cranial nerves I, II, V, VII, VIII; the orbit (ocular hypertension, proptosis, epiphora); the intracranial compartment (reduced volume, raised ICP, and in one case a Chiari type I malformation, HP:0007099, 1/13).
  • Explicitly spared: the appendicular skeleton, vertebral column, and the cochlea. Mandibular involvement is present but lesser (PMID:22194361).
  • Body systems: skeletal (primary); nervous — cranial nerves (secondary); special senses (olfactory, visual, auditory, vestibular).

"There was significant thickening of the skull in the frontal, parietal, temporal, and occipital regions, which was mainly due to thickening of the inner table of the skull." — PMID:22194361

"…which is confined to the skull, especially the calvarium and the skull base. The rest of the skeleton is not affected." — PMID:23640157

Metabolic topography

"(18)F-Fluoride uptake is statistically significantly higher in the sphenoid bone and clivus regions of affected family members." — Waterval JJ, Van Dongen TM, Stokroos RJ, Teule JG, Kemerink GJ, Brans B, Nieman FH, Manni JJ. Eur J Nucl Med Mol Imaging. 2011;38(5):884–893. PMID:21079950, DOI:10.1007/s00259-010-1655-2

Tissue / cell level

  • Tissue: compact/cortical bone of the calvarial inner table; endosteal surface.
  • Cells: osteoblast (CL:0000062) — driver; osteocyte (CL:0000137) — reduced density in affected bone; osteoclast (CL:0000092) — expresses ZIP14 but is not the HCI effector cell.

Subcellular level (GO Cellular Component)

  • Normal ZIP14: GO:0005886 plasma membrane, GO:0016323 basolateral plasma membrane, GO:0016324 apical plasma membrane.
  • Mutant ZIP14: retained in early endosome membrane and late endosome membrane (UniProt-annotated native locations; the mutant fails to progress beyond them). Resolve GO:0031901/GO:0031902 (early/late endosome membrane) with OAK before binding — not verified here.

Localization and lateralization

Bilateral and strikingly symmetric. This is not incidental — it is what degrades the diagnostic yield of side-to-side electrophysiological comparison:

"Due to the symmetrical bilateral nature of this disease, the sensitivity of visual evoked potentials (VEPs), masseter reflex and blink reflex is decreased (25-37.5%), therefore reducing the value of single registration." — PMID:23622937

Suggested UBERON bindings (verified via OLS4): | CURIE | Canonical label | |---|---| | UBERON:0004339 | vault of skull | | UBERON:0002517 | basicranium | | UBERON:0017692 | internal surface of cranial base | | UBERON:0011859 | internal acoustic meatus | | UBERON:0005745 | optic foramen | | UBERON:0018413 | facial nerve canal |

Cribriform plate and foramen ovale/rotundum terms should be resolved with OAK before binding.

8. Temporal Development

Onset. Insidious, chronic. HPO records both HP:0003621 juvenile onset and HP:0011462 young adult onset. Typically second decade; headache and anosmia are annotated with young-adult onset; documented paediatric onset at age 8 with bilateral facial palsy (PMID:19371457).

Stages (proposed for progression:):

Phase Description
Presymptomatic At-risk carrier; radiological hyperostosis already detectable on CT before symptoms. This is the window in which prophylactic decompression has been argued for.
Early symptomatic Recurrent facial palsy; hyposmia; subclinical BERA I–V interpeak prolongation
Established Fixed facial paresis; progressive SNHL; vestibular hypofunction to areflexia; anosmia; visual decline
Late (post-4th decade) Radiological progression minimal; deficits fixed; in severe cases, reduced intracranial volume with raised ICP — potentially fatal

Progression rate. Slow and progressive over decades, with a plateau after the fourth decade (Orphanet/OMIM summary). Deficits already established do not remit.

Course pattern. Progressive overall; the facial nerve component is characteristically recurrent/episodic early on before becoming fixed — a RECURRENT temporality qualifier is appropriate for the facial-palsy phenotype.

Duration. Chronic, lifelong.

Remission. No spontaneous remission of the bone disease. Treatment-induced functional recovery is documented after surgical decompression (House-Brackmann I and II at one year — PMID:19371457) but the underlying hyperostosis is unaffected.

Critical period / intervention window. Explicit in the literature, and the single most actionable clinical statement in the entry:

"Surgical decompression of the accessible impaired cranial nerves is advised in the early symptomatic period or even in the presymptomatic period in high-risk individuals." — PMID:20140965

9. Inheritance and Population

Epidemiology

  • Prevalence: not documented. Orphanet (ORPHA:443098) does not publish a prevalence class for this disease, and no registry exists. The honest structured record is a CASES_IN_LITERATURE measure, not a rate.
  • Incidence: not available.
  • Case count: the disease has been reported in one Dutch kindred, comprising three related families with common progenitors, 32 individuals over five generations.

"Until today the disease has been described in only three related Dutch families with common progenitors and which consist of 32 individuals over five generations. HCI was observed in 12 family members over four generations." — PMID:23640157

⚠️ Numeric discrepancy to record explicitly: Borra 2013 states 12 affected over four generations; Waterval 2010 analyses 13 affected individuals of three related families (32 individuals); the HPO frequency denominators are /13. Curate 13 (with the /13 denominators) and note the 12-vs-13 discrepancy in notes: rather than silently picking one.

Suggested prevalence record shape:

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Reported in a single extended Dutch kindred. Waterval 2010 analyses 13 affected
    individuals among three related families totalling 32 individuals; Borra 2013
    reports 12 affected over four generations across five generations of pedigree.
    No prevalence rate has been published; Orphanet ORPHA:443098 records no
    prevalence class.

Genetic epidemiology

  • Inheritance pattern: Autosomal dominant (HPO annotation for OMIM:144755; stated in every primary source). Bind HP:0000006 (Autosomal dominant inheritance) — resolve label with OAK before binding.
  • Penetrance: appears high/complete for the radiological phenotype — calvarial hyperostosis and skull-base osteosclerosis are annotated at 13/13. Clinical penetrance of individual nerve deficits is incomplete and age-dependent (facial palsy 9/13; anosmia 6/13). No formal penetrance estimate has been published.
  • Expressivity: variable — "Patients are mildly to severely affected" (PMID:23640157).
  • Anticipation: not reported; not expected (not a repeat-expansion disorder).
  • Germline mosaicism: not reported.
  • Founder effect: the variant is, in effect, a private founder allele of one Dutch kindred with common progenitors. It is not a population founder variant in the usual sense — do not describe it as a Dutch population founder mutation.
  • Consanguinity: not relevant (dominant).
  • Carrier frequency: not applicable (dominant); the allele is absent from population databases.

Demographics

  • Affected populations: Dutch (single kindred). No other ethnicity reported. The apparent Dutch specificity is an ascertainment artefact of a single pedigree, not established population biology.
  • Geographic distribution: the Netherlands (Nijmegen/Maastricht ascertainment).
  • Sex ratio: not reported as skewed; no sex bias described in the pedigree. Autosomal dominant transmission with male-to-male transmission implied by the pedigree structure. Record as unknown rather than 1:1.
  • Age distribution: affected individuals span childhood to old age within the kindred; symptomatic ascertainment concentrates in the second-to-fourth decades.

10. Diagnostics

Imaging — the diagnostic mainstay

CT (high-resolution, bone algorithm) is the primary diagnostic test. From PMID:22194361: - Linear measurement of inner table, medulla (diploë) and outer table at defined skull locations - Attenuation (HU) measurement of the same regions - Neuroforamina width measurement - Findings: significant thickening in frontal, parietal, temporal and occipital regions, predominantly of the inner table; hyperostotic bone attenuation lower than normal cortical bone

"The observed radiologic abnormalities explain the possible impairment of the olfactory, optic, trigeminal, facial, and vestibulocochlear nerves." — PMID:22194361

MRI — complementary, for nerve/soft-tissue assessment and to exclude mimics.

¹⁸F-fluoride (NaF) PET/CT — a quantitative bone-metabolism test with a demonstrated role here:

"(18)F-Fluoride PET/CT is useful in quantifying the metabolic activity in HCI and provides information about the process of disturbed bone metabolism in this specific disorder." — PMID:21079950

Study design for reference: "Nine affected family members, seven non-affected family members and nine non-HCI non-family members underwent (18)F-fluoride PET/CT scans. SUVs were systematically measured in the different regions of interest: frontal bone, sphenoid bone, petrous bone and clivus." (PMID:21079950)

Note that ¹⁸F-NaF PET quantification methodology has since been systematically reviewed across 29 bone conditions including HCI (de Ruiter RD et al., Ann Nucl Med. 2025; PMID:39729191, DOI:10.1007/s12149-024-01991-9).

Functional / electrophysiological testing (the recommended monitoring panel)

Per PMID:23622937, the evidence-based recommendation is explicit about what to use and what to drop:

"In patients with HCI and similar craniofacial sclerosing bone dysplasias we advise monitoring of vestibulocochlear nerve function with tone and speech audiometry, BERA and vestibular tests. VEPs are important to monitor optic nerve function in combination with radiological and ophthalmologic examination. We do not advise the routine use of blink and masseter reflex."

Recommended: pure-tone and speech audiometry; BERA — the I–V interpeak latency specifically ("has the ability to determine nerve encroachment reliably"); vestibular testing (electronystagmography); VEPs for CN II in combination with imaging and ophthalmology. Not recommended for routine use: blink reflex, masseter reflex (sensitivity 25–37.5% owing to bilateral symmetry). Also tested and informative as a negative: otoacoustic emissions are preserved — their preservation is the evidence that the cochlea is spared and the lesion is retrocochlear.

Additional: olfactory testing (for CN I), ophthalmological examination including intraocular pressure (HP:0007906 ocular hypertension, 1/13), visual acuity and fundoscopy for optic atrophy.

Laboratory tests and biomarkers

None diagnostic. Routine bone biochemistry is normal:

"Biochemical parameters were normal." — PMID:23640157

There is no validated biomarker for HCI. Serum/plasma zinc and manganese have not been reported in HCI patients — a testable gap given the allelic recessive disease is defined by hypermanganesaemia. LOINC-coded reference ranges are therefore not applicable to this entry.

Biopsy / histopathology

Rarely indicated diagnostically, but reported: increased bone formation with normal tissue architecture (PMID:23640157); wider, dense, well-organized inner table with reduced Haversian channels and osteocytes (PMID:29621230).

Genetic testing

  • Recommended first-line in a known family: targeted single-variant testing for SLC39A14 c.1322T>G (p.Leu441Arg) — this is cascade testing within the kindred and is the only high-yield test outside it.
  • Single-gene sequencing of SLC39A14: appropriate for a sporadic case with a compatible CT phenotype.
  • Gene panels: sclerosing bone dysplasia / high-bone-mass panels. SLC39A14 is not universally included — verify panel content in GTR before ordering.
  • WES: how the gene was found (one proband); reasonable for an undiagnosed craniofacial sclerosing dysplasia.
  • WGS: no established incremental utility over WES here.
  • CMA / karyotype / FISH: not indicated — HCI is not a structural/CNV disorder.
  • mtDNA testing, repeat-expansion testing: not applicable.
  • Omics-based diagnostics (RNA-seq, proteomics, metabolomics, epigenomics, liquid biopsy): none validated or reported for HCI.

Clinical criteria

There are no formal published diagnostic criteria, no society guideline, and no DSM/ICD-based algorithm. The operational diagnosis is: characteristic CT pattern (inner-table–predominant calvarial + skull-base hyperostosis with normal appendicular skeleton) + cranial neuropathy in ≥1 of CN I/II/V/VII/VIII + autosomal dominant family history and/or SLC39A14 p.L441R.

The clinical trigger for suspicion, per the authors of the phenotype study, is adult- or childhood-onset facial or vestibulocochlear nerve impairment in the right radiological context.

Differential diagnosis

Other sclerosing bone dysplasias with craniofacial involvement — the discriminator is whether the long bones are involved:

"Besides HCI, several bone dysplasias with hyperostosis and sclerosis of the craniofacial bones are known. Examples are Van Buchem disease, sclerosteosis, craniometaphyseal dysplasia, and Camurati-Engelmann disease. However, in these cases the long bones are affected as well." — PMID:23640157

Condition Distinguishing feature vs HCI
Van Buchem disease (SOST) Generalized endosteal hyperostosis including long bones, mandible enlargement
Sclerosteosis (SOST) Gigantism, syndactyly, long-bone involvement
Craniometaphyseal dysplasia (ANKH, GJA1) Metaphyseal flaring of long bones
Camurati-Engelmann disease (TGFB1) Diaphyseal sclerosis, limb pain, waddling gait
Hyperostosis frontalis interna (HFI) Frontal-only, common, non-Mendelian, strongly female/postmenopausal, usually asymptomatic; the most important mimic
Morgagni-Stewart-Morel syndrome HFI + obesity + virilism + neuropsychiatric features
Fibrous dysplasia / Paget disease of bone Focal/mosaic, distinct radiology, abnormal ALP
IAC exostoses / osteomas Focal, unilateral, non-familial (see PMID:32499994)
Osteopetrosis, pycnodysostosis Generalized skeletal sclerosis, marrow failure, fractures

The definitive review for this differential — with a large CT/MRI image collection and craniofacial embryology — is:

"In this review we provide a complete overview of the existing sclerosing bone dysplasias with craniofacial involvement. Clinical presentation, disease course, the craniofacial symptoms, genetic transmission pattern and pathophysiology are discussed. There is an emphasis on radiologic features with a large collection of CT and MRI images. In previous reviews the craniofacial area of the sclerosing bone dysplasias was underexposed. However, craniofacial symptoms are often the first symptoms to address a physician." — Waterval JJ, Borra VM, Van Hul W, Stokroos RJ, Manni JJ. Bone. 2014;60:48–67. PMID:24325978, DOI:10.1016/j.bone.2013.12.003

Also in the differential of the presenting complaint: multiple cranial-nerve palsies of any cause (see PMID:2300109, "Multiple cranial-nerve palsies: a diagnostic challenge", published alongside the original 1990 description).

Screening

  • Newborn screening: not applicable, none exists.
  • Carrier screening: not applicable (dominant).
  • Cascade screening: this is the operative screening modality. At-risk relatives in the kindred should undergo targeted variant testing, and gene-positive individuals should enter radiological (CT) and functional (audiometry/BERA/vestibular/VEP/olfaction/IOP) surveillance — the whole rationale being to identify the presymptomatic window for decompression.

11. Outcome / Prognosis

Survival and mortality

  • No survival data, no life-expectancy figure, no mortality rate has been published. There is no registry and the total literature cohort is ~13 people.
  • Severe disease is described as potentially fatal via reduced intracranial volume (per the OMIM/Orphanet disease summaries: decreased intracranial volume can lead to death in severe cases). Treat this as an authoritative-summary claim without a primary case-level citation attached in the sources retrieved here — verify against the OMIM entry text or Manni 1990 before curating it as a mortality claim.
  • Disease-specific mortality: unquantified.

Morbidity and function

The morbidity burden is sensory-neurological rather than skeletal: bilateral sensorineural deafness, bilateral vestibular areflexia (with the balance disability that implies), facial paralysis (functional and social/aesthetic), anosmia, and visual loss. Several of these are individually disabling and they co-occur.

No ICF coding, no disability registry data, no QoL instrument (EQ-5D/SF-36/PROMIS) has ever been applied to HCI. Record as a knowledge gap.

Complications

  • Raised intracranial pressure; headache (HP:0002315, 5/10)
  • Ocular hypertension (HP:0007906, 1/13); proptosis; epiphora; ocular pain
  • Chiari type I malformation (HP:0007099, 1/13) — presumably secondary to posterior fossa volume reduction
  • Mastoiditis (HP:0000265, very rare)
  • Surgical complication: cerebral vasospasm after auditory brainstem implantation — Waterval JJ, Stokroos RJ, Dings J, Van Overbeeke JJ, Manni JJ. Clin Neurol Neurosurg. 2011;113(8):693–697. PMID:21665359, DOI:10.1016/j.clineuro.2011.05.005 (no abstract available in Europe PMC; obtain full text before citing specifics)

Recovery potential

Established nerve deficits do not spontaneously recover. Timely decompression can restore function — the strongest positive outcome datum in the literature is a single paediatric case:

"Using a middle fossa craniotomy approach, both internal auditory canals were unroofed and cranial nerves VII and VIII were decompressed, with a one-year interval between sides. The mimic function recovered. One year post-operatively, the right and left facial sides had been restored to House-Brackmann grades I and II, respectively." — Waterval JJ, Stokroos RJ, De Bondt RB, Manni JJ. J Laryngol Otol. 2009;123(9):1058–1062. PMID:19371457, DOI:10.1017/S0022215109005349

Prognostic factors

No validated model. Clinically implied factors: age at intervention (earlier = better, hence the presymptomatic-surgery argument); degree of foraminal stenosis on CT; BERA I–V interpeak latency as a marker of nerve encroachment; the post-fourth-decade radiological plateau as a favourable natural-history feature. Prognostic biomarkers: none.

12. Treatment

There is no disease-modifying therapy. Management is symptomatic and surgical.

"The treatment is symptomatic." — PMID:23640157

Surgical / interventional (the principal modality)

Treatment Detail NCIT suggestion
Surgical decompression of cranial nerves Middle-fossa craniotomy with unroofing of the internal auditory canal, decompressing CN VII and VIII; performed bilaterally with a staged interval NCIT:C15329 Surgical Procedure (verify a more specific neurosurgical/decompression term with OAK)
Optic nerve decompression Advised for CN II involvement in the early symptomatic/presymptomatic period (PMID:20140965) NCIT:C15329 Surgical Procedure
Auditory brainstem implantation (ABI) Used for hearing rehabilitation when the cochlear nerve is non-functional; carries documented risk of cerebral vasospasm in HCI (PMID:21665359) DEVICE modality; NCIT term to be resolved with OAK
Prophylactic decompression Explicitly proposed: "Surgical decompression of the internal auditory canal is recommended therapeutically, but may also be performed prophylactically in younger patients with hyperostosis cranialis interna." (PMID:19371457) —

Evidence base and quality: this is level-4/5 evidence — case reports and a single-family case series. There is no comparative study, no RCT, no consensus guideline. Curate the surgical recommendations as expert-opinion-grade with evidence_source: HUMAN_CLINICAL and be explicit in explanation that they rest on individual cases.

therapeutic_modality assignments: SURGERY for the decompressions; DEVICE for ABI/hearing devices.

Pharmacotherapy

No pharmacological treatment exists. Notably: - Bisphosphonates and other antiresorptives are not established for HCI and are mechanistically questionable — the lesion is excess formation, not deficient resorption. Do not curate speculative antiresorptive use. - Chelation therapy (disodium calcium edetate) is effective in the allelic recessive disease (hypermanganesemia with dystonia 2, PMID:27231142) and has no evidence or rationale in HCI, whose mechanism is intracellular zinc accumulation from a mistrafficked transporter, not systemic manganese excess. This is a trap — do not transfer the treatment across the allelic boundary. - Pharmacogenomics: not applicable.

Advanced therapeutics

None. No gene therapy, gene editing, ASO, siRNA, mRNA therapy, cell therapy, targeted therapy or immunotherapy exists or is in development for HCI. There is no therapeutic_agent to curate.

The only forward-looking therapeutic statement in the literature is at the level of target biology, not a candidate drug:

"Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases." — PMID:29621230

Note carefully: that sentence proposes ZIP14 modulation for common bone disease (osteoporosis), not as a treatment for HCI. The paper's framing is that the L438R mouse "mimic[s] the disparate actions of estrogen on cortical and trabecular bone through osteoblasts." Do not curate it as an HCI therapeutic lead.

Supportive / rehabilitative

  • Hearing rehabilitation: hearing aids, bone-conduction devices, cochlear implantation (limited value once the lesion is retrocochlear — preserved OAEs indicate cochlear function is intact but the nerve is the bottleneck), ABI as above.
  • Vestibular rehabilitation for balance dysfunction / areflexia.
  • Ocular surface protection and oculoplastic management for facial palsy (lagophthalmos, epiphora).
  • Facial reanimation / physiotherapy for established facial paresis.
  • Ophthalmological management of raised IOP.
  • NCIT suggestions: NCIT:C15315 Rehabilitation, NCIT:C15747 Supportive Care, NCIT:C15302 Physical Therapy — verify each label with OAK before binding.

Experimental treatments

No clinical trials. A ClinicalTrials.gov search for hyperostosis cranialis interna returns no interventional studies; there are no NCT or ICTRP identifiers to curate for this disease.

Treatment strategy

The one clear, citable algorithm statement:

"Surgical decompression of the accessible impaired cranial nerves is advised in the early symptomatic period or even in the presymptomatic period in high-risk individuals." — PMID:20140965

Combined with the monitoring panel from PMID:23622937, the operational pathway is: genotype → serial CT + audiometry/BERA/vestibular/VEP/olfaction/IOP surveillance → decompress the accessible foramina at the earliest sign of encroachment → rehabilitate residual deficits.

13. Prevention

Primary prevention of the disease itself is impossible — it is a germline dominant mutation with no environmental component. Everything below is secondary or tertiary.

  • Primary prevention: not applicable. No vaccination, no risk-factor modification.
  • Secondary prevention (early detection): the core of management. Cascade genetic testing of at-risk relatives followed by presymptomatic CT and cranial-nerve function surveillance, so that decompression can be offered inside the intervention window.
  • Tertiary prevention (complication avoidance): decompression to prevent irreversible nerve loss; corneal protection in facial palsy; IOP control; vestibular rehabilitation to prevent falls; ICP monitoring in severe disease.
  • Immunization: not applicable.
  • Screening programmes: no population or newborn screening; not appropriate for a single-kindred ultra-rare dominant disorder.
  • Genetic screening / reproductive options: prenatal diagnosis and preimplantation genetic testing are technically available for a known familial SLC39A14 variant. No published case of either in HCI; present them as available options, not as documented practice.
  • Risk stratification: genotype is the stratifier. No clinical risk model exists.
  • Behavioural interventions: none.
  • Genetic counselling: indicated — autosomal dominant, 50% recurrence risk per pregnancy, high radiological penetrance with variable clinical expressivity (a counselling point that should be made explicitly: a gene-positive child cannot be told how severely they will be affected). NCIT suggestion: NCIT:C15240 Genetic Counseling.
  • Public health / environmental interventions: not applicable.
  • Prophylaxis: the only "prophylaxis" in the literature is prophylactic surgical decompression in younger patients (PMID:19371457) — an aggressive recommendation resting on a single case, and worth curating with that caveat visible.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring animal counterpart of HCI has been reported in any species. Human only (NCBITaxon:9606).
  • Breed (VBO): not applicable — no companion-animal breed predisposition described.
  • Orthologous genes: mouse Slc39a14 (the residue equivalent to human L441 is L438 — the mouse knock-in allele is L438R); zebrafish slc39a14 (CRISPR nulls characterized in PMID:27231142 and in a 2020 bioRxiv study of manganese deficiency/hypersensitivity). Resolve NCBI Gene IDs for the orthologues before curating.
  • OMIA: no OMIA entry corresponding to HCI.
  • Veterinary relevance: none.
  • Comparative pathology: the informative comparative finding is a negative one — the calvarial phenotype is not conserved in mouse (Section 15). Cranial vault ossification and the relative contribution of intramembranous ossification differ substantially between human and mouse, which is the leading explanation.
  • Evolutionary conservation: ZIP14's metal-transport and cAMP-regulatory functions are conserved across vertebrates ("SLC39A14 functions as a pivotal manganese transporter in vertebrates" — PMID:27231142); the skeletal site-specificity of the HCI phenotype is not.
  • Zoonotic potential / cross-species transmission: not applicable.

15. Model Organisms

Mouse — conditional Zip14 L438R knock-in (the HCI model)

Design (Hendrickx 2018, PMID:29621230): conditional knock-in overexpressing the mouse orthologous mutant Zip14 L438R, driven by tissue-specific Cre:

Cre driver Target cell Outcome
Sox2-Cre (ubiquitous) all Perinatal lethality — "ubiquitous expression of mutant Zip14 results in perinatal lethality"
Runx2-Cre osteoblast lineage Severe cortical bone phenotype (below)
CtsK-Cre osteoclast lineage Minimal skeletal effect

Osteoblast-specific (Zip14^L438R Ob-KI) phenotype, male mice, femur:

Parameter Direction p
Cortical thickness (Ct.Th) ↑ 6.0E-6
Cortical porosity (Ct.Po) ↓ 0.0014
Midshaft diameter (Ms.D) ↓ 4.1E-6
Endosteal bone formation rate (BFR/BS) ↑ 0.0012
Trabecular BV/TV ↓ 0.0071
Trabecular number (Tb.N) ↓ 0.033
Trabecular separation (Tb.Sp) ↑ 0.035
Connectivity density (Conn.D) ↓ 0.018

"Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts." — PMID:29621230

⚠️ The model's central limitation — a HUMAN_MODEL_MISMATCH, not a knowledge gap

The mouse reproduces the cellular mechanism (endosteal cortical thickening via osteoblasts) but does NOT reproduce the anatomical hallmark of the human disease (calvarial hyperostosis). The authors say so explicitly. Full-text statements (PMID:29621230 — re-verify as exact substrings before snippet use):

  • "we were surprised to see no calvarial phenotype as this is truly opposite of what we see in HCI patients"
  • "loss of endogenous Zip14 did not affect the calvariae, even though the appendicular skeleton and vertebral column were osteoporotic"
  • "aberrations in Zn homeostasis by Zip14 do not seem to affect calvariae of mice, even though the rest of the skeleton is affected"
  • "Although calvarial porosity appears lower in these mice there were no significant differences in calvarial parameters"

This maps directly onto a dismech discussions entry with kind: HUMAN_MODEL_MISMATCH, and onto modeled_mechanisms links with split relationships on the same model:

animal_models:
- name: Osteoblast-specific Zip14 L438R conditional knock-in mouse (Runx2-Cre)
  species: Mouse
  genotype: Zip14^fl(L438R); Runx2-Cre
  publication: PMID:29621230
  modeled_mechanisms:
  - target: Increased Endosteal Bone Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
  - target: Calvarial and Skull Base Hyperostosis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    limitations: >-
      No significant calvarial thickness or porosity difference was observed in
      Runx2-Cre L438R knock-in mice, and loss of endogenous Zip14 likewise left
      the calvariae unaffected while the appendicular skeleton and vertebral
      column were osteoporotic. The craniofacial restriction that defines HCI in
      humans is absent from the mouse.
    evidence:   # required for FAILS_TO_RECAPITULATE
    - reference: PMID:29621230
      ...

Additional limitations to record: the knock-in is an overexpression construct (supraphysiological, unlike the human heterozygous single-copy allele); ubiquitous expression is perinatally lethal, so no whole-organism model of the human genotype exists; skull-base foramina and cranial-nerve entrapment cannot be modelled at all in mouse.

Mouse — constitutive Slc39a14 knockout (mechanism-supporting, not disease-modelling)

Two independent KO characterizations, both showing the opposite bone phenotype, which is what establishes that HCI is not a loss-of-function disease:

"Mice lacking Slc39a14 (Slc39a14-KO mice) exhibit growth retardation and impaired gluconeogenesis, which are attributable to disrupted GPCR signaling in the growth plate, pituitary gland, and liver. The decreased signaling is a consequence of the reduced basal level of cyclic adenosine monophosphate (cAMP) caused by increased phosphodiesterase (PDE) activity in Slc39a14-KO cells. We conclude that SLC39A14 facilitates GPCR-mediated cAMP-CREB signaling by suppressing the basal PDE activity…" — Hojyo et al., PMID:21445361

"In this study, we thoroughly investigated the bone phenotypes of Zip14-KO mice, demonstrating that the KO mice exhibited osteopenia in both trabecular and cortical bones. In Zip14-KO mice, bone resorption was increased, whereas the bone formation rate was unchanged. Zip14 mRNA was expressed in normal osteoclasts both in vivo and in vitro, but receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis was not impaired in bone marrow-derived macrophages prepared from Zip14-KO mice." — Sasaki S, Tsukamoto M, Saito M, Hojyo S, Fukada T, Takami M, Furuichi T. FEBS Open Bio. 2018;8(4):655–663. PMID:29632817, DOI:10.1002/2211-5463.12399

(The Sasaki abstract as retrieved contains an apparent typographical artefact — "inhibiting bore resorption" — in its concluding sentence. Avoid quoting that sentence; the two sentences quoted above are clean.)

Curation note: these KO mice are models of SLC39A14 biology, not of HCI. Their modeled_mechanisms links, if curated at all, belong to the mechanism nodes about ZIP14/cAMP-CREB physiology with explicit limitations stating that the null allele produces the inverse skeletal phenotype.

Zebrafish

CRISPR slc39a14 null zebrafish show manganese dyshomeostasis and altered locomotor activity (PMID:27231142). Relevant to the recessive manganese disease, not to HCI. No zebrafish bone phenotype for the L441R-equivalent allele has been reported.

In vitro / cellular models

The functional characterization in PMID:29621230 used transfected cell systems: ⁶⁵Zn uptake assays, FluoZin-3 labile-zinc imaging, subcellular localization with early/late endosome markers, and luciferase reporters for CRE and NFAT response elements. evidence_source: IN_VITRO for all of these.

No iPSC, organoid, or patient-derived osteoblast model of HCI exists. No CRISPR or RNAi functional-genomics screen has been run against this disease. No entry in DepMap, GenomeRNAi, or the Human Cell Atlas is disease-relevant here.

Model resources

MGI (mouse Slc39a14, MGI gene page), IMPC/KOMP (constitutive KO alleles), ZFIN (slc39a14), Alliance of Genome Resources. The L438R conditional knock-in line is a bespoke line from the Van Hul/Schinke laboratories and is not, as far as can be determined, deposited in a public repository (IMSR/EMMA/MMRRC) — availability should be confirmed with the authors rather than assumed.

Summary of high-value knowledge gaps for the KB entry

Ranked by curatable value:

  1. HUMAN_MODEL_MISMATCH — the mouse knock-in reproduces endosteal cortical thickening but explicitly fails to reproduce calvarial hyperostosis, the defining lesion. Authors state they were "surprised." This is the single most important structured claim in the entry.
  2. Why craniofacial-only? No mechanism explains why a ubiquitously expressed transporter produces a skeletal lesion confined to the skull. Intramembranous vs endochondral ossification and neural-crest vs mesoderm skull origin are the obvious hypotheses; neither has been tested.
  3. Serum/tissue zinc, manganese and iron have never been measured in HCI patients — despite the allelic recessive disease being a metal-accumulation disease with a chelation therapy.
  4. Increased formation vs decreased resorption is unresolved — the histology paper says "increased bone formation or decreased bone resorption"; the mouse implicates formation; the null implicates resorption. These are different mechanistic claims.
  5. No QoL, survival, or natural-history quantification exists beyond n≈13 in one family.
  6. The single-family, single-variant evidence base. One WES proband, one family, one ClinVar submission with "no assertion criteria provided" review status. High mechanistic confidence, low genetic-epidemiological confidence — and those should be recorded separately.
  7. The "death from decreased intracranial volume" claim appears in the OMIM/Orphanet disease summaries but was not traced here to a primary case report. Verify before curating it as a mortality claim.

Sources

Next step: if you want this turned into the YAML at kb/disorders/Hyperostosis_Cranialis_Interna.yaml, say the word and I'll run just fetch-reference for each PMID first so every snippet above is verified as an exact substring before it goes into an evidence: block — several of the Hendrickx full-text quotes in Sections 4, 6 and 15 came through a summarizing fetch and must be re-verified against the cache before use.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 39
Resolved 39
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 4
Quoted claims found in source 3
Quoted claims not found in source 1
References weighed for topical relevance 39
On topic 12
Off topic 3

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:794825 (abstract only): "Dominant generalized cortical hyperostosis with multiple cranial nerve involvement"
  • closest text in source: "The authors report an observation of dominant generalized cortical hyperostosis with multiple and unilateral involvement of a certain number of cranial nerves"

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:21445361 (3 mentions) - The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth.
  • shared terms: zip14
  • DOI:10.1038/ncomms11601 (1 mention) - Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia
  • shared terms: patient, manganese
  • DOI:10.1152/ajpgi.00244.2022 (1 mention) - Enterocyte-specific deletion of metal transporter Zip14 (Slc39a14) alters intestinal homeostasis through epigenetic mechanisms
  • shared terms: zip14

Weighed against this report's own most characteristic terms: hci, bone, disease, hyperostosis, zip14, nerve, affected, phenotype, interna, patient, normal, facial, dominant, family, vestibular, cranialis, waterval, manganese, allele, manni.

Term Validation

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

Outcome Count
Terms checked 63
Resolved 59
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 3
Terms whose name was checked 39
Terms named correctly 39
Terms named as a different term 0

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:0019933 (obsolete cAMP-mediated signaling) (1 mention)

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, OMIM.

59 of 63 terms resolved to a current term; the rest could not be looked up either way.