title: Exacerbation of X-linked ichthyosis phenotype in a female by inheritance of filaggrin and steroid sulfatase mutations.
abstract: BACKGROUND
  X-linked ichthyosis (XLI) is a relatively common, recessive condition caused by mutations in the steroid sulfatase (STS) gene. Common loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and predispose individuals to atopic eczema.
  
  
  OBJECTIVE
  To test the hypothesis that co-inheritance of FLG mutations can act as a genetic modifier in XLI.
  
  
  METHODS
  An unusually severe XLI phenotype in addition to eczema and mild childhood asthma was investigated in a female Indian patient by fluorescent in situ hybridization (FISH) for the common STS gene deletion. Direct sequencing of the entire FLG gene was also performed.
  
  
  RESULTS
  FISH analysis revealed that the proband was homozygous for the common STS genomic deletion mutation. Further investigation revealed a frame-shift mutation 3672del4 in the gene encoding filaggrin (FLG), leading to premature termination of profilaggrin translation. Interestingly, her father, who had a very typical mild presentation of XLI, did not carry this FLG mutation in addition to his STS deletion. Her mother was a heterozygous carrier of the FLG mutation and consistent with this, had mild symptoms of ichthyosis vulgaris; she was also a heterozygous carrier of the STS deletion.
  
  
  CONCLUSIONS
  This is the second reported case of the modifying effects of FLG null alleles on XLI and strengthens the hypothesis that filaggrin defects can synergize with STS deficiency to exacerbate the ichthyosis phenotype.
authors.affiliation: Dermatology Department, The Royal Free Hospital, Pond Street, London NW3 2QG, UK.
authors.forename: Raakhee
authors.initials: R
authors.lastname: Ramesh
authors.forename: Huijia
authors.initials: H
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Kukula
authors.forename: Emma L
authors.initials: EL
authors.lastname: Wakeling
authors.forename: Malcolm H A
authors.initials: MH
authors.lastname: Rustin
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
mesh_terms: D000279:Administration, Cutaneous; D002648:Child; D004252:DNA Mutational Analysis; D003879:Dermatologic Agents / Q000008:administration & dosage; D005260:Female; D000091344:Filaggrin Proteins; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016114:Ichthyosis, X-Linked / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017404:In Situ Hybridization, Fluorescence; D007381:Intermediate Filament Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D043266:Steryl-Sulfatase / Q000235:genetics*
chemical_list: D003879:Dermatologic Agents; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D043266:Steryl-Sulfatase