ANKH – Autosomal Dominant Craniometaphyseal Dysplasia

Autosomal dominant craniometaphyseal dysplasia (AD-CMD) is a rare skeletal disorder marked by progressive cranial hyperostosis and metaphyseal widening of long bones. ANKH is the sole gene implicated in AD-CMD; two unrelated probands have been reported with heterozygous pathogenic ANKH variants (c.1122-4delCTC (p.Ser375del) in a toddler with macrodolichocephaly, irregular dentition and metaphyseal clubbing (PMID:39914871); and a complex exon 7 deletion (c.942_953delTGGTTGACGGAA (p.Trp292_Glu295del)) in a sporadic case (PMID:20186813)). These variants act in a dominant manner with no additional affected relatives identified to date.

Cellular studies demonstrate that craniometaphyseal dysplasia–linked ANKH mutants (including p.Ser375del and p.Trp292_Glu295del) mislocalize to the cytoplasm, fail to reach the plasma membrane and disrupt inorganic pyrophosphate transport, consistent with a dominant-negative mechanism (PMID:32366894). Rescue experiments have not been reported, but concordant functional data support pathogenicity.

Key Take-home: ANKH sequencing is clinically indicated in patients with radiographic features of AD-CMD to guide diagnosis and genetic counseling.

References

• BMJ case reports • 2025 • Highlighting the importance of X-ray diagnostics for targeted molecular genetic analysis in the diagnosis of rare autosomal dominant craniometaphyseal dysplasia. PMID:39914871
• American Journal of Medical Genetics Part A • 2010 • Novel ANKH mutation in a patient with sporadic craniometaphyseal dysplasia. PMID:20186813
• 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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