title: Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism.
abstract: Identification of the underlying genetic, cellular, and biochemical basis of lipid metabolic disorders provides an opportunity to deploy corrective, mechanism-targeted, topical therapy. We assessed this therapeutic approach in two patients with Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) syndrome, an X-linked dominant disorder of distal cholesterol metabolism. On the basis of the putative pathogenic role of both pathway-product deficiency of cholesterol and accumulation of toxic metabolic intermediates, we assessed the efficacy of combined therapy with lovastatin and cholesterol. We also evaluated the basis for the poorly understood, unique lateralization of the cutaneous and bone malformations of CHILD syndrome by analyzing gene activation in abnormal and unaffected skin. Ultrastructural analysis of affected skin showed evidence of both cholesterol depletion and toxic metabolic accumulation. Topical treatment with lovastatin/cholesterol (but not cholesterol alone) virtually cleared skin lesions by 3 months, accompanied by histological and ultrastructural normalization of epidermal structure and lipid secretion. The unusual lateralization of abnormalities in CHILD syndrome reflects selective clearance of keratinocytes and fibroblasts that express the mutant allele from the unaffected side. These findings validate pathogenesis-based therapy that provides the deficient end product and prevents accumulation of toxic metabolites, an approach of potential utility for other syndromic lipid metabolic disorders.
authors.affiliation: Department of Dermatology and Pediatrics, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. apaller@northwestern.edu
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Marina
authors.initials: M
authors.lastname: Rodriguez-Martín
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sorrell
authors.forename: Candrice
authors.initials: C
authors.lastname: Heath
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.forename: Antonio Noda
authors.initials: AN
authors.lastname: Cabrera
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
mesh_terms: D000287:Administration, Topical; D000293:Adolescent; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000235:genetics*; D050356:Lipid Metabolism / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D008659:Metabolic Diseases / Q000235:genetics*; D010641:Phenotype; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012868:Skin Abnormalities / Q000188:drug therapy* / Q000473:pathology; D013577:Syndrome; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D002784:Cholesterol; D008148:Lovastatin