Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia

Abstract

Variants in PORCN are a cause of Goltz-Gorlin syndrome or Focal Dermal Hypoplasia, an X-linked dominant disorder affecting heterozygous females and until now considered to be embryonic lethal in males. Exome sequencing was performed in a family in which two male siblings were characterized by microphthalmia and additional congenital anomalies including diaphragmatic hernia, spina bifida and cardiac defects. Surprisingly, we identified a maternally inherited variant in PORCN present in both males as well as in two female siblings. This represents the first finding of a PORCN variant in non-mosaic males affected with Goltz-Gorlin syndrome. The apparently asymptomatic mother showed extreme skewing of X-inactivation (90%), an asymptomatic female sibling showed skewing of 88%, and the second female sibling affected with cutis aplasia of the scalp showed X-inactivation considered within the normal range.

Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature

“…Of the 24 reported male patients, 19 are mosaics, one patient has Klinefelter syndrome, and four patients from two different families are non‐mosaics (Table 1). Interestingly, all four patients with non‐mosaic PORCN mutations lacked skin manifestations but had other severe symptoms compatible with GS 20, 21. In addition, diaphragm abnormalities were detected in two patients, resembling previously reported cases with pentalogy of Cantrell 18, 22…”

A non-mosaic PORCN mutation in a male with severe congenital anomalies overlapping focal dermal hypoplasia

“…A recently published whole-exome sequencing study has also reported two non-mosaic males with clinical symptoms overlapping FDH with an inherited mutation in the PORCN gene [31]. Both male patients in this study had a c.407G > A mutation change resulting in a Glycine to Aspartate amino acid change in the protein which is different from the variant and amino acid change that we report here.…”

A Novel <b><i>PORCN </i></b>Frameshift Mutation Leading to Focal Dermal Hypoplasia: A Case Report

“…There have been 3 clinical reports of male patients who are nonmosaic for PORCN mutations [Brady et al, 2015;Madan et al, 2017]. Two of these patients, who deceased in their neonatal periods, had a single base pair alteration resulting in a missense mutation.…”

“…Two of these patients, who deceased in their neonatal periods, had a single base pair alteration resulting in a missense mutation. Interestingly, their mother and 2 female siblings also had the same mutation without clinical symptoms of FDH as a result of skewed X inactivation [Brady et al, 2015]. The third patient had a missense mutation in PORCN and died at the age of 8 years.…”

“…About 90% of individuals with FDH are females, and 95% of affected females have a de novo pathogenic PORCN variant. All male patients, with the exception of 3 nonmosaic cases reported in the literature, are mosaic for PORCN mutation, because heterozygous nonmosaic mutations are generally lethal in males [Brady et al, 2015;Madan et al, 2017]. The phenotypes are highly variable due to tissue mosaicism.…”