PORCN – Focal Dermal Hypoplasia (Goltz Syndrome)

Focal dermal hypoplasia (FDH; MONDO_0010592) is a rare X-linked dominant ecto-mesodermal dysplasia characterized by patchy dermal hypoplasia, limb malformations, ocular anomalies, and dental defects. Causal variants in PORCN (HGNC:17652), which encodes an O-acyltransferase required for Wnt ligand palmitoylation and secretion, underlie FDH pathogenesis. X-linked dominant inheritance leads to embryonic lethality in hemizygous males, with surviving males typically harboring postzygotic mosaicism.

Genetic evidence for PORCN involvement includes 24 unrelated probands with pathogenic PORCN variants (12 nonsense, 8 missense, 1 splice-site, 3 microdeletions) (PMID:19309688). Recurrent c.129G>A (p.Trp43Ter) is observed in multiple families (PMID:23399492), and diagnostic sequencing in 53 additional FDH cases identified over 16 novel variants (PMID:20854095). Segregation analysis in familial cases, including two affected siblings with germline mosaicism, supports transmission of PORCN variants (PMID:19586929).

Functional assays in mouse and cellular models demonstrate that PORCN loss-of-function impairs Wnt3a secretion and gastrulation. Porcn-deficient mouse embryos fail to generate mesoderm and recapitulate limb and skin abnormalities characteristic of FDH, confirming a haploinsufficiency mechanism (PMID:21768372, PMID:21554866). Structure–function analyses identify active site residues critical for acyltransferase activity and Wnt binding, with FDH-associated mutations reducing protein stability and function (PMID:24798332).

Diagnostic challenges include cases lacking detectable PORCN mutations by standard blood sequencing, highlighting the need for mosaicism assessment in affected tissues (PMID:21332693). Prevalence is estimated at 1.2–1.6 per million (PMID:39256944), underscoring FDH’s rarity and phenotypic variability. Clinical management requires multidisciplinary surveillance, focusing on cutaneous, skeletal, ocular, and neurologic evaluations.

In summary, abundant genetic and functional data establish a definitive association between PORCN and FDH. Molecular diagnosis via targeted sequencing or high-resolution melting analysis guides early intervention, with variant characterization informing genetic counseling and potential therapeutic targeting of Wnt signaling.

Key take-home: PORCN sequencing should be integrated into diagnostic workflows for FDH, and functional assays provide a basis for future Wnt-modulating therapies.

References

• Human mutation • 2009 • PORCN mutations in focal dermal hypoplasia: coping with lethality PMID:19309688
• Human mutation • 2011 • Mutation update for the PORCN gene PMID:21472892
• Proceedings of the National Academy of Sciences • 2011 • Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome PMID:21768372
• The Journal of Biological Chemistry • 2014 • Identification of key residues and regions important for porcupine-mediated Wnt acylation PMID:24798332
• European Journal of Dermatology • 2013 • Novel and recurrent PORCN gene mutations in almost unilateral and typical focal dermal hypoplasia patients PMID:23399492
• Pediatric Dermatology • 2024 • Phenotypes, Genetics, and Estimated Prevalence of Focal Dermal Hypoplasia (Goltz Syndrome): A Single-Center Report PMID:39256944
• The Australasian Journal of Dermatology • 2011 • A case of mosaic Goltz syndrome (focal dermal hypoplasia) in a male patient PMID:21332693
• Developmental Biology • 2011 • Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos PMID:21554866

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