Alternative titles; symbols
ORPHA: 1522; DO: 0080801;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.2 | Craniometaphyseal dysplasia | 123000 | Autosomal dominant | 3 | ANKH | 605145 |
A number sign (#) is used with this entry because of evidence that autosomal dominant craniometaphyseal dysplasia (CMDD) is caused by heterozygous mutation in the ANKH gene (605145) on chromosome 5p15.
Craniometaphyseal dysplasia is an osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, which may finally result in hearing loss and facial palsy (summary by Nurnberg et al., 1997).
The delineation of separate autosomal dominant and autosomal recessive (CMDR; 218400) forms of CMD by Gorlin et al. (1969) was confirmed by reports that made it evident that the dominant form is relatively mild and comparatively common, while the recessive form is rare, severe, and possibly heterogeneous.
Beighton (1995) pointed out that Peter Jackson, an English physician on the staff of Groote Schuur Hospital, University of Cape Town, collaborated with Fuller Albright at the Massachusetts General Hospital, Boston, in the disorders of osseous modeling (Jackson et al., 1954) and identified a specific syndrome that comprised dysplasia of the metaphyses, sclerosis of the base of the skull, and overgrowth of the craniofacial bones. They culled 5 previously reported cases and added 2 of their own, and they termed the condition craniometaphyseal dysplasia.
Podlaha and Kratochvil (1963) and Lejeune et al. (1966) observed that craniometaphyseal dysplasia differs from Pyle disease (metaphyseal dysplasia; 265900) in the presence of conspicuous involvement of the craniofacial bones. Widening of the bridge of the nose develops and eventually leonine facies. Pressure on cranial nerves is responsible for a considerable part of the disability (facial palsy and mixed hearing loss). The cases in the family reported by Rimoin et al. (1969) and those reported by Spranger et al. (1965) should be considered dominant craniometaphyseal dysplasia, reserving the term Pyle disease for the recessive disorder which is more nearly a 'pure' metaphyseal dysplasia with little or no craniofacial involvement. Spranger (1970) reviewed the skull x-ray of Pyle's original case and failed to find the intense increase in bone density characteristic of craniometaphyseal dysplasia. Furthermore the metaphyseal flare is notably abrupt in Pyle disease, producing the 'Erlenmeyer flask' deformity, and is milder ('club-like') in craniometaphyseal dysplasia. The same family was reported by Rimoin et al. (1969) and by Gladney and Monteleone (1970).
Stool and Caruso (1973) observed affected father and 15-month-old daughter. Both had peripheral facial palsy and the father was profoundly deaf.
Taylor and Sprague (1989) described an Australian kindred with 9 affected persons in 4 generations.
Kornak et al. (2010) reported 3 unrelated patients with craniometaphyseal dysplasia and no family history of the disorder. All had typical features of the disorder, with macrocephaly, hypertelorism, skull hyperostosis, paranasal bossing, teeth crowding, and metaphyseal flaring. The first patient, who was the most severely affected, was a French boy who developed hearing loss and bilateral facial palsy soon after birth. He had severe sclerosis of the skull base, orbits, maxilla, and mandible, with almost complete obstruction of the sinuses. There was rapid worsening of the bone phenotype in the first years of life. The second patient was a 24-year-old man from the Netherlands who presented with progressive conductive and sensorineural hearing loss and was found to have typical features of the disorder, with unilateral facial palsy apparent in infancy, macrocephaly, and teeth crowding. The third patient was a 43-year-old Italian man with typical manifestations of CMD, including sclerosis of the skull base and maxilla, hyperostotic but not sclerotic mandible, and partially obstructed sinuses, but without cranial nerve compression. He also had narrowing of the middle ear cavities with bilateral fixation of the body of the incus to the lateral attic, resulting in conductive deafness and tinnitus. These middle ear manifestations were similar to those observed in postinflammatory ossicular fixation secondary to acute or chronic otitis media.
The transmission pattern of CMDD in the families reported by Nurnberg et al. (2001) was consistent with autosomal dominant inheritance.
The heterozygous mutations in the ANKH gene that were identified by Reichenberger et al. (2001) in 2 patients with CMDD occurred de novo.
Using osteoclast-like cells formed from a 3-year-old patient's bone marrow cells in culture, Yamamoto et al. (1993) investigated the pathophysiology of craniometaphyseal dysplasia. The quantitative formation of osteoclast-like cells, as identified by the presence of vitronectin beta-receptors, was only 40% of normal. Studies using a monoclonal antibody, E11, demonstrated that these cells from the patient lacked the osteoclast-reactive vacuolar proton pump. Kurihara et al. (1990) had found that this osteoclast-reactive vacuolar proton pump is expressed in osteoclasts during differentiation. Soriano et al. (1991) found that disruption of the SRC gene in transgenic mice resulted in osteopetrosis; see 190090. Yamamoto et al. (1993) found, however, that SRC expression in the platelets of their patient was comparable to that in the normal control.
In a large German kindred with CMD, Nurnberg et al. (1997) found tight linkage between the disorder and microsatellite markers on 5p in the region 5p15.2-p14.1. This region overlaps with the mapping interval of the growth hormone receptor gene (GHR; 600946), or at least is in the neighborhood of the GHR gene, the location of which was given by the authors as 5p14-p12. GHR is known to be involved in the mitogenic activation of osteoblasts. Testing GHR as a candidate gene, Nurnberg et al. (1997) found recombination events between CMD and GHR in 2 members of the family, thus excluding GHR as a candidate. In the family studied by Nurnberg et al. (1997), there were 24 affected persons in 6 generations.
Chandler et al. (2001) confirmed the linkage mapping of the CMDJ locus to 5p15.2-p14.1 in a large Australian pedigree and a second German family. Using recombinants, they narrowed the critical region to an interval of approximately 4 cM.
Nurnberg et al. (2001) tested ANKH (605145) as a positional candidate in 9 unrelated families and demonstrated 6 different mutations in 8 of the families (e.g., 605145.0001-605145.0003). In 5 different families and in isolated cases, Reichenberger et al. (2001) described mutations in the ANKH gene.
In 3 unrelated patients with craniometaphyseal dysplasia and no family history of the disorder, Kornak et al. (2010) identified 3 different heterozygous mutations in the ANKH gene (605145.0011-605145.0013).
In a large 4-generation Australian family with craniometaphyseal dysplasia, originally described by Taylor and Sprague (1989) and in which Nurnberg et al. (2001) identified a heterozygous missense mutation in the ANKH gene (G389R; 605145.0002), Baynam et al. (2009) found evidence for chondrocalcinosis segregating with CMDD in affected female family members. Although a chance association of chondrocalcinosis with CMDD could not be excluded, Baynam et al. (2009) suggested that the lack of joint symptoms in affected male family members might be due to involvement of sex-dependent mechanisms or to the fact that only mutation-positive women in the pedigree had reached the age at which the chondrocalcinosis phenotype typically expresses.
Baynam, G., Goldblatt, J., Schofield, L. Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation. (Letter) Am. J. Med. Genet. 149A: 1331-1333, 2009. [PubMed: 19449425] [Full Text: https://doi.org/10.1002/ajmg.a.32875]
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Kornak, U., Brancati, F., Le Merrer, M., Lichtenbelt, K., Hohne, W., Tinschert, S., Garaci, F. G., Dallapiccola, B., Nurnberg, P. Three novel mutations in the ANK membrane protein cause craniometaphyseal dysplasia with variable conductive hearing loss. Am. J. Med. Genet. 152A: 870-874, 2010. [PubMed: 20358596] [Full Text: https://doi.org/10.1002/ajmg.a.33301]
Kurihara, N., Gluck, S., Roodman, G. D. Sequential expression of phenotype markers for osteoclasts during differentiation of precursors for multinucleated cells formed in long-term human marrow cultures. Endocrinology 127: 3215-3221, 1990. [PubMed: 1701138] [Full Text: https://doi.org/10.1210/endo-127-6-3215]
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Nurnberg, P., Thiele, H., Chandler, D., Hohne, W., Cunningham, M. L., Ritter, H., Leschik, G., Uhlmann, K., Mischung, C., Harrop, K., Goldblatt, J., Borochowitz, Z. U., Kotzot, D., Westermann, F., Mundlos, S., Braun, H.-S., Laing, N., Tinschert, S. Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nature Genet. 28: 37-41, 2001. [PubMed: 11326272] [Full Text: https://doi.org/10.1038/ng0501-37]
Nurnberg, P., Tinschert, S., Mrug, M., Hampe, J., Muller, C. R., Fuhrmann, E., Braun, H.-S., Reis, A. The gene for autosomal dominant craniometaphyseal dysplasia maps to chromosome 5q and is distinct from the growth hormone-receptor gene. Am. J. Hum. Genet. 61: 918-923, 1997. [PubMed: 9382103] [Full Text: https://doi.org/10.1086/514880]
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Stool, S. E., Caruso, V. G. Cranial metaphyseal dysplasia. Arch. Otolaryng. 97: 410-412, 1973. [PubMed: 4703537] [Full Text: https://doi.org/10.1001/archotol.1973.00780010422014]
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Yamamoto, T., Kurihara, N., Yamaoka, K., Ozono, K., Okada, M., Yamamoto, K., Matsumoto, S., Michigami, T., Ono, J., Okada, S. Bone marrow-derived osteoclast-like cells from a patient with craniometaphyseal dysplasia lack expression of osteoclast-reactive vacuolar proton pump. J. Clin. Invest. 91: 362-367, 1993. [PubMed: 7678608] [Full Text: https://doi.org/10.1172/JCI116194]