Surviving males with PORCN variants: expanding the clinical, molecular, and mechanistic spectrum.

Pathogenic PORCN variants cause an X-linked dominant disorder historically considered lethal in males; residual protein function and mosaic status would account for clinical variability and male survival.

Pathogenic PORCN variants cause focal dermal hypoplasia, or Goltz syndrome, an X-linked dominant disorder historically considered lethal in males, with milder presentations now grouped under the PORCN non-Goltz spectrum (PONGOS). The authors report three male patients identified by exome sequencing: one with a mosaic de novo variant (c.727C>T; p.Arg243Ter) showing features of focal dermal hypoplasia, and two brothers with an inherited non-mosaic variant (c.1315T>G; p.Trp439Gly) transmitted by 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. The authors highlight the role of residual protein function in clinical variability and the implications for diagnosis, genetic counselling and management in families with apparently unaffected carrier mothers.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The operational message fits in one sentence: do not rule out PORCN in a male patient on the grounds of male lethality, including when no mosaicism is detectable. The most delicate point for the clinic is the unaffected carrier mother who transmitted a non-mosaic variant to two sons: recurrence risk is no longer theoretical and maternal status becomes a parameter to document before any pregnancy plan. The series remains limited to three patients with no measurement of residual activity: the hypothesis of preserved protein function is plausible but not demonstrated here.

Analysis by Dr Thibaut Benquey