SNOMEDCT: 1217210001; ORPHA: 443098;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p21.3 | ?Hyperostosis cranalis interna | 144755 | Autosomal dominant | 3 | SLC39A14 | 608736 |
A number sign (#) is used with this entry because of evidence that hyperostosis cranialis interna (HCIN) is caused by heterozygous mutation in the SLC39A14 gene (608736) on chromosome 8p21. One such family has been reported.
Hyperostosis cranialis interna (HCIN) is a bone disorder characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base. The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII (Waterval et al., 2010).
Manni et al. (1990) described a bone disorder, which they called hyperostosis cranialis interna, in a Dutch kindred. The main radiologic features were intracranial hyperostosis and osteosclerosis of the calvaria and the base of the skull; the mandible and the skeleton were normal. Recurrent facial palsy was the primary clinical sign, and there was a variable simultaneous impairment of the senses of smell, taste, and vision as well as of cochleovestibular function. In all, 9 individuals in 4 sibships and 3 generations were affected. Serum alkaline phosphatase values were normal in all affected family members. Urinary hydroxyproline levels, measured in 4 affected members, were normal as well. The disorder most closely resembled sclerosteosis (269500) and van Buchem disease (239100) as far as the involvement of the skull is concerned; however, the disorder was clearly different by reason of the absence of involvement of sites other than the skull, by the normal serum alkaline phosphatase, and by the suspected autosomal dominant pattern of inheritance.
Waterval et al. (2010) provided follow-up on the Dutch kindred reported by Manni et al. (1990). Five males and 9 females were affected. Patients generally became symptomatic in their early second and third decade; facial nerve involvement was the most frequent first symptom, occurring mainly in adolescence, and was followed by sensorineural hearing loss.
Hendrickx et al. (2018) studied patient skull and first cervical vertebra biopsy specimens from an affected member of the Dutch kindred originally reported by Manni et al. (1990). Compared to control skull biopsy, the patient specimen showed severe involvement of the internal cortex, which was wider than that of the control and characterized by a great and dense amount of well-organized bone, suggesting increased bone formation or decreased bone resorption. The number of Haversian channels and number of osteocytes were significantly lower in the patient internal cortex compared to patient external cortex and cervical vertebra cortex, or control internal cortex. In addition, osteocytes in the patient internal cortex were grouped around the Haversian channels, and some osteocyte lacunae appeared empty, suggesting osteocyte apoptosis; these features were not seen in the patient external cortex or vertebral tissue or in the control skull specimen.
Waterval et al. (2010) suggested that hyperostosis cranialis interna should be suspected in cases of adult or childhood onset of facial nerve or vestibulocochlear nerve impairment. Initial diagnostic investigation is done by audiometry or a lateral skull radiograph. To confirm the diagnosis, a CT scan is performed.
Waterval et al. (2010) suggested that early decompressive operations of the optic, facial, and vestibulocochlear nerves are advised in the early symptomatic period or even in the presymptomatic period in high-risk individuals.
The pedigree pattern in the Dutch kindred reported by Manni et al. (1990) was consistent with autosomal dominant inheritance, but there was no male-to-male transmission.
In a Dutch pedigree with HCIN that was originally reported by Manni et al. (1990), Borra et al. (2013) analyzed 404 genomewide polymorphic microsatellite markers and obtained a maximum multipoint lod score of 3.72 on chromosome 8p, between markers ATAA018 and D8S1477. Saturating the region with additional markers confirmed linkage with a maximum lod score of 4.09, and recombination events delineated the region to 8.3 cM (4.35 Mb) between markers D8S282 and D8S382.
In 1 affected individual from a Dutch pedigree with HCIN mapping to chromosome 8p, originally reported by Manni et al. (1990), Hendrickx et al. (2018) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the SLC39A14 gene (L441R; 608736.0006). The mutation segregated fully with disease in the family and was not found in 100 ethnically matched controls or in public variant databases.
Exclusion Studies
In a Dutch pedigree with HCIN mapping to chromosome 8p, originally reported by Manni et al. (1990), Borra et al. (2013) sequenced 3 candidate genes, BMP1 (112264), ADAM28 (606188), and LOXL2 (606663), but did not detect any mutations.
Borra, V. M., Waterval, J. J., Stokroos, R. J., Manni, J. J., Van Hul, W. Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes. Calcif. Tissue Int. 93: 93-100, 2013. [PubMed: 23640157] [Full Text: https://doi.org/10.1007/s00223-013-9732-8]
Hendrickx, G., Borra, V. M., Steenackers, E., Yorgan, T. A., Hermans, C., Boudin, E., Waterval, J. J., Jansen, I. D. C., Aydemir, T. B., Kamerling, N., Behets, G. J., Plumeyer, C., and 10 others. Conditional mouse models support the role of SLC39A14 (ZIP14) in hyperostosis cranialis interna and in bone homeostasis. PLoS Genet. 14: e1007321, 2018. Note: Electronic Article. [PubMed: 29621230] [Full Text: https://doi.org/10.1371/journal.pgen.1007321]
Manni, J. J., Scaf, J. J., Huygen, P. L. M., Cruysberg, J. R. M., Verhagen, W. I. M. Hyperostosis cranialis interna.: a new hereditary syndrome with cranial-nerve entrapment. New Eng. J. Med. 322: 450-454, 1990. [PubMed: 2300107] [Full Text: https://doi.org/10.1056/NEJM199002153220707]
Waterval, J. J., Stokroos, R. J., Bauer, N. J. C., De Bondt, R. B. J., Manni, J. J. Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base. Am. J. Med. Genet. 152A: 547-555, 2010. [PubMed: 20140965] [Full Text: https://doi.org/10.1002/ajmg.a.33205]