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:

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

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.

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

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

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:

The allelic-disease contrast (important for the entry)

SLC39A14 produces two clinically unrelated diseases by two different mechanisms:

"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:):

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

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)

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:

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

"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

• OMIM #144755 — HYPEROSTOSIS CRANIALIS INTERNA; HCIN
• OMIM #617013 — HYPERMANGANESEMIA WITH DYSTONIA 2
• Orphanet: Hyperostosis cranialis interna (ORPHA:443098) · Orphanet-derived record, ORPHA:443098
• Manni JJ et al. Hyperostosis cranialis interna. A new hereditary syndrome with cranial-nerve entrapment. NEJM 1990 — PMID:2300107
• Manni JJ et al. Eighth cranial nerve dysfunction in hyperostosis cranialis interna. Acta Otolaryngol 1992 — PMID:1575042
• Waterval JJ et al. Phenotypic manifestations and management of HCI. Am J Med Genet A 2010 — PMID:20140965
• Waterval JJ et al. Facial nerve decompression via middle fossa approach for HCI. J Laryngol Otol 2009 — PMID:19371457
• Waterval JJ et al. Bone metabolic activity in HCI measured with 18F-fluoride PET. Eur J Nucl Med Mol Imaging 2011 — PMID:21079950
• Waterval JJ et al. Cerebral vasospasm after auditory brainstem implantation in HCI. Clin Neurol Neurosurg 2011 — PMID:21665359
• Waterval JJ et al. Imaging features and progression of HCI. AJNR 2012 — PMID:22194361
• Waterval JJ et al. Neurophysiologic, audiometric and vestibular function tests in HCI. Clin Neurol Neurosurg 2013 — PMID:23622937
• Borra VM et al. Localization of the gene for HCI to chromosome 8p21. Calcif Tissue Int 2013 — PMID:23640157
• Waterval JJ et al. Sclerosing bone dysplasias with involvement of the craniofacial skeleton. Bone 2014 — PMID:24325978
• Hendrickx G et al. Conditional mouse models support the role of SLC39A14 (ZIP14) in HCI and in bone homeostasis. PLoS Genet 2018 — PMID:29621230 · PMC5903675
• Hojyo S et al. SLC39A14/ZIP14 controls GPCR-mediated signaling required for systemic growth. PLoS One 2011 — PMID:21445361
• Sasaki S et al. Disruption of mouse Slc39a14 is associated with decreased bone mass. FEBS Open Bio 2018 — PMID:29632817
• Tuschl K et al. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Commun 2016 — PMID:27231142 · SLC39A14 Deficiency, GeneReviews
• Goodarzi A et al. Internal Acoustic Canal Stenosis Due to Hyperostosis. J Neurol Surg B 2020 — PMID:32499994
• Alsaleh AS et al. HCI Presenting With Cerebrospinal Fluid Leak. Cureus 2025 — PMID:40091967
• Otken E et al. Hyperostosis Fronto-Parieto-Occipitalis: A Cadaveric Case Report. Cureus 2023 — PMID:37546094
• Bergen DJM et al. High Bone Mass Disorders. JBMR 2023 — PMID:36161343
• Huang T et al. Zinc Homeostasis in Bone: Zinc Transporters and Bone Diseases. IJMS 2020 — PMID:32059605
• de Ruiter RD et al. Validation of quantitative [18F]NaF PET uptake parameters in bone diseases. Ann Nucl Med 2025 — PMID:39729191
• ClinVar VCV000523143 — SLC39A14 c.1322T>G (p.Leu441Arg) · NIH GTR: Hyperostosis cranialis interna (C1840404)
• HGNC:20858 SLC39A14 · UniProt Q15043 (ZIP14) · HPO annotations for OMIM:144755 · MONDO:0007765 via OLS4

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.

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.

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.