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Keywords:

  • focal dermal hypoplasia;
  • Goltz syndrome;
  • PORCN gene;
  • Wnt signalling;
  • X-linked dominant

Summary

Focal dermal hypoplasia (FDH) is an X-linked dominant disorder featuring developmental abnormalities of ectodermal and mesodermal tissues. Pathogenic mutations in the PORCN gene (locus Xp11.23) were identified in 2007 and thus far 27 different mutations have been reported. PORCN encodes a putative O-acyltransferase which facilitates secretion of Wnt proteins required for ectomesodermal tissue development. We investigated PORCN gene pathology and pattern of X-chromosome inactivation analysis in two unrelated Caucasian female patients who presented with multiple developmental abnormalities consistent with FDH. We also reviewed the clinical and molecular data for all reported PORCN mutations and assessed genotype–phenotype correlation for sporadic and familial cases of FDH. DNA sequencing revealed two new PORCN gene mutations: p.W282X and c.74delG (p.G25fsX51). X-chromosome inactivation analysis revealed a random pattern in one case but was uninformative in the other. Collectively, point/small mutations account for 24 out of the 29 PORCN mutations and are typically seen in sporadic cases; larger deletions are more common in familial cases. Identification of two new PORCN gene mutations confirms the importance of PORCN-associated Wnt signalling in embryogenesis. Both new cases showed Blaschko-linear dermal hypoplasia and extensive ectomesodermal abnormalities, including severe limb developmental anomalies and a giant cell tumour of bone in one patient. Clinical variability can be attributed to the degree of lyonization and postzygotic genomic mosaicism, which are important mechanisms in determining the clinical presentation.