Goltz–Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap

Abstract

Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.

Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation

“…Indeed, mosaicism for mutations causing autosomal or X-linked dominant disorders may result in segmental presentation of some clinical features (as described above), typical but milder findings, a classical phenotype, or even no apparent phenotype [Gripp et al, 2006;Harmsen et al, 2009]. The two reported individuals and our patient with somatic mosaicism for the HRAS alteration highlight the different phenotypic outcomes in these cases and illustrate the importance of genetic testing in patients with an atypical phenotype.…”

Co‐occurrence of severe Goltz–Gorlin syndrome and pentalogy of Cantrell – Case report and review of the literature

“…Grzeschlik et al [2007] described a patient with classical Goltz-Gorlin syndrome, manifestations being linear skin lesion, syndactyly, asymmetric bone defects and dental defects. The phenotype in the patient with the R243X mutation described by Harmsen et al [2009] had a severe, lethal phenotype: linear skin lesion, syndactyly of both hands and feet, malformed ears, iris coloboma, omphalocele, and hypoplastic left heart. The present patient has classical, severe Goltz-Gorlin syndrome and in addition four main signs of Cantrell (-Haller-Ravitsch) syndrome, which were absent in the earlier reported patients with the same mutation.…”

“…The c.727C>T (R243X) mutation has been reported twice before [Grzeschlik et al, 2007;Harmsen et al, 2009]. Grzeschlik et al [2007] described a patient with classical Goltz-Gorlin syndrome, manifestations being linear skin lesion, syndactyly, asymmetric bone defects and dental defects.…”

“…PORCN was investigated by sequence analysis as described before [Maas et al, 2009], and disclosed the mutation c.727C>T. This single nucleotide substitution introduces a premature translation stop at amino acid Arginine 243 (p.Arg243X). The c.727C>T allele is predicted to produce a truncated protein and has been described twice before [Grzeschlik et al, 2007;Harmsen et al, 2009;Lombardi et al, submitted for publication].…”

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

“…Pathogenic PORCN variants have previously been reported that affect the same transmembrane domain, which further supports the pathogenicity of the p.(Gly157Asp) variant. 5,[19][20][21] Variants in PORCN were first reported as a cause of FDH in 2007. 19, 22 Froyen et al later identified PORCN variants and gene deletions in a cohort of patients with a clinical diagnosis of FDH.…”