ANKH – Craniometaphyseal Dysplasia

Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder characterized by progressive hyperostosis of craniofacial bones and metaphyseal flaring of long bones. Heterozygous mutations in ANKH, encoding a pyrophosphate transporter, underlie the autosomal dominant form of CMD, disrupting cranial bone remodeling and causing cranial nerve compression with hearing loss, facial palsy, and malocclusion ([PMID:19426903]).

Autosomal dominant inheritance predominates, with at least seven unrelated probands reported across six studies carrying pathogenic ANKH variants ([PMID:19426903], [PMID:20186813], [PMID:27594963], [PMID:26820766], [PMID:37654679], [PMID:20358596], [PMID:21806345]). Segregation has been confirmed in multiplex families, and no unaffected carriers have been described. Variant classes include single amino-acid substitutions (missense) and small in-frame deletions affecting conserved residues within transmembrane domains.

The mutational spectrum comprises recurrent residues such as p.Cys339Arg, p.Leu334Arg, p.Leu391Pro, and in-frame deletions like c.1124_1126del (p.Ser375del) ([PMID:37654679]). These alterations cluster in exons 7–9 and correlate with phenotypic severity: larger deletions often manifest with early-onset, severe cranial hyperostosis, while missense changes yield variable conductive hearing loss and cranial nerve involvement.

Functional assays in transfected COS-7, CH-8 chondrocytes, and HEK293 cells demonstrate that CMD-linked ANKH mutants are mislocalized to the cytoplasm, fail to reach the plasma membrane, and exhibit impaired inorganic pyrophosphate export ([PMID:20186813], [PMID:32366894]). Concordant increases in extracellular matrix mineralization and altered ENPP1/TNAP activity replicate human bone pathology.

Animal models and rescue experiments remain scarce, but in vitro studies provide moderate experimental support for a loss-of-function mechanism leading to impaired pyrophosphate homeostasis. These data align with the skeletal hyperostosis seen in patients and reinforce ANKH’s role in bone mineral regulation.

Integrated evidence supports a strong clinical validity for ANKH in autosomal dominant CMD, with consistent genotype–phenotype correlations, segregation in families, and mechanistic functional data. Early molecular diagnosis can guide craniofacial management, anticipate nerve compression complications, and inform genetic counseling.

Key Take-home: ANKH mutation screening is clinically actionable for definitive diagnosis and management of autosomal dominant craniometaphyseal dysplasia.

References

• Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics • 2009 • Craniometaphyseal dysplasia: a case report. PMID:19426903
• American journal of medical genetics. Part A • 2010 • Novel ANKH mutation in a patient with sporadic craniometaphyseal dysplasia. PMID:20186813
• Radiology case reports • 2016 • Craniometaphyseal dysplasia in a 14-month old: a case report and review of imaging differential diagnosis. PMID:27594963
• Clinica chimica acta • 2016 • Craniometaphyseal dysplasia with obvious biochemical abnormality and rickets-like features. PMID:26820766
• Bone reports • 2023 • Hypophosphatemic rickets: An unexplained early feature of craniometaphyseal dysplasia. PMID:37654679
• American journal of medical genetics. Part A • 2010 • Three novel mutations in the ANK membrane protein cause craniometaphyseal dysplasia with variable conductive hearing loss. PMID:20358596
• Neurosurgical focus • 2011 • Intracranial hypertension in two cases of craniometaphyseal dysplasia: differing surgical options. PMID:21806345
• Scientific reports • 2020 • Differences in intracellular localisation of ANKH mutants that relate to mechanisms of calcium pyrophosphate deposition disease and craniometaphyseal dysplasia. PMID:32366894

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