title: Morphological alterations in two siblings with autosomal recessive congenital ichthyosis associated with CYP4F22 mutations.
abstract: Autosomal recessive congenital ichthyosis (ARCI) caused by mutations in CYP4F22 is very rare. CyP4F22, a protein of the cytochrome-P450 family 4, encodes an epidermal ω-hydroxylase decisive in the formation of acylceramides, which is hypothesized to be crucial for skin-barrier function. We report a girl with consanguineous parents presenting as collodion baby with contractures of the great joints and palmoplantar hyperlinearity. In the course of the disease she developed fine scaling of the skin with erythroderma, the latter disappearing until the age of 6 months. Her sister showed a generalized fine-scaling phenotype, and, interestingly, was born without a collodion membrane. The analysis of all known candidate genes for ARCI in parallel with a next-generation sequencing approach using a newly designed dermatogenetics gene panel revealed a previously unknown homozygous splice-site mutation c.549+5G>C in CYP4F22 in both girls, confirming the diagnosis of ARCI. Ultrastructural analysis by transmission electron microscopy in both patients showed epidermal hyperplasia, orthohyperkeratosis with persistence of corneodesmosomes into the outer stratum corneum layers, fragmented and disorganized lamellar lipid bilayers, which could be ascribed to inhomogeneous lamellar body secretion, as well as lamellar body and lipid entombment in the corneocytes. These findings correlated with increased transepidermal water loss on the functional level. For the first time, we report a collodion baby phenotype and epidermal barrier impairment in CyP4F22-deficient epidermis at both the ultrastructural and functional level, and corroborate the importance of CyP4F22 for epidermal maturation and barrier function.
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.|Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Gruber
authors.affiliation: Department of Dermatology, Donauspital Vienna, Vienna, Austria.|Karl Landsteiner Institute for Pediatric Dermatology, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Rainer
authors.affiliation: Department of Paediatrics, Wilhelminen Hospital, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Department of Dermatology, Donauspital Vienna, Vienna, Austria.|Department of Paediatrics, Wilhelminen Hospital, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Udvardi
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: K M
authors.initials: KM
authors.lastname: Eckl
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Schupart
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Zschocke
authors.affiliation: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Schmuth
authors.affiliation: Department of Dermatology, Donauspital Vienna, Vienna, Austria.|Karl Landsteiner Institute for Pediatric Dermatology, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Volc-Platzer
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.|Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.|Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Department of Biological Sciences, University of Huddersfield, Huddersfield, U.K.
authors.forename: H C
authors.initials: HC
authors.lastname: Hennies
mesh_terms: D003241:Consanguinity; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004274:DNA, Recombinant / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000235:genetics* / Q000473:pathology; D007231:Infant, Newborn; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D035781:Siblings
chemical_list: D004274:DNA, Recombinant; D003577:Cytochrome P-450 Enzyme System; C559989:CYP4F22 protein, human