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Surviving Males With PORCN Variants: Expanding the Clinical, Molecular, and Mechanistic Spectrum
Lucía Miranda-Alcaraz1,2,3,4, Simone Carbonera5, Mónica Mora-Gómez1,2,3,4
1Instituto de Genética Médica y Molecular (INGEMM), Instituto de Investigación del Hospital Universitario La Paz (IdiPaz), Hospital Universitario La Paz, Madrid, Spain.
Clinical Genetics
|August 10, 2026
Summary
Pathogenic variants in PORCN cause focal dermal hypoplasia (FDH) and related disorders. This study shows males can survive with mosaic and non-mosaic PORCN variants, expanding the disease spectrum and informing genetic counseling.
Area of Science:
- Genetics
- Developmental Biology
- Dermatology
Background:
- Pathogenic variants in PORCN cause focal dermal hypoplasia (FDH/Goltz syndrome), an X-linked dominant disorder.
- Historically, FDH was considered lethal in males, but milder presentations, now termed PORCN non-Goltz spectrum (PONGOS), are recognized.
Purpose of the Study:
- To report on male patients with PORCN variants, expanding the understanding of the clinical and molecular spectrum of FDH and PONGOS.
- To investigate the implications of mosaic and non-mosaic PORCN variants on male survival and clinical presentation.
Main Methods:
- Exome sequencing was used to identify pathogenic variants in three male patients.
- Clinical features of patients with de novo mosaic and inherited non-mosaic PORCN variants were analyzed.
Main Results:
- One male patient with a mosaic de novo PORCN variant (c.727C>T; p.Arg243*) presented with FDH features.
- Two siblings with an inherited non-mosaic PORCN variant (c.1315T>G; p.Trp439Gly) from a carrier mother with PONGOS phenotype were identified.
- These cases demonstrate male survival is possible with both mosaic and non-mosaic PORCN variants.
Conclusions:
- Male survival with mosaic and non-mosaic PORCN variants is confirmed, broadening the disease spectrum.
- Residual protein function significantly influences clinical variability in PORCN-related disorders.
- Findings have implications for diagnosis, genetic counseling, and management of families with PORCN variants, including those with apparently unaffected carrier mothers.
