Lucía Miranda-Alcaraz, Simone Carbonera, Mónica Mora-Gómez, Natalia Gallego-Zazo, Inmaculada Guillén, Elena Padilla, Gaia Visani, Alessia Asaro, Valeria Vásquez-Amell, Mario Cazalla, Manuel Rodríguez-Canó, Cristina Silván, Pedro Arias, Juan Andrés Jiménez-Estrada, Tomás Valle, Alejandro Cruz-Utrilla, Pilar Escribano-Subías, Nuria Ochoa Parra, María Jesús del Cerro Marín, Julián Nevado, Spanish PAH Consortium, Pablo Lapunzina, Fabio Sirchia, Jair Tenorio-Castano
Hospital Universitario La Paz. Instituto de Salud Carlos III. European Reference Network on Rare Malformations Syndromes, Intellectual and Other Neuro-Developmental Disorders. Universidad Autónoma de Madrid. Hospital Universitario Virgen del Rocío. IRCCS Mondino Foundation. Hospital Universitario 12 de Octubre. ERN-LUNG, European Reference Network on Rare Lung Diseases. Hospital Universitario Ramón y Cajal and Instituto de Investigación Biomédica del Hospital Universitario Ramón y Cajal. Centro Universitario HM Hospitales de Ciencias de la Salud (CUHMED) and Universidad Camilo José Cela. Fondazione IRCCS Policlinico San Matteo.
Spain, France, Italy and Germany
Clinical Genetics
Clin Genet 2026;
DOI: 10.1111/cge.70228
Abstract
Pathogenic variants in PORCN cause focal dermal hypoplasia (FDH/Goltz syndrome), an X-linked dominant disorder historically considered lethal in males, with milder presentations now recognized as PORCN non-Goltz spectrum (PONGOS). We report three male patients identified by exome sequencing: one with a mosaic de novo variant (c.727C>T; p.Arg243*) showing FDH features, and two siblings with an inherited non-mosaic variant (c.1315T>G; p.Trp439Gly) from their unaffected carrier mother with a PONGOS phenotype. These cases confirm that male survival is possible with both mosaic and non-mosaic PORCN variants and expand the clinical and molecular spectrum of the disease. Our findings highlight the role of residual protein function in clinical variability and have important implications for diagnosis, genetic counseling, and management in families with apparently unaffected carrier mothers.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes