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  • Review article

    Ichthyoses:Differential diagnosis and molecular genetics

    Vinzenz OJIHeiko TRAUPE

    Department of Dermatology,University Hospital, Von-Esmarch-Str. 58,48149 Mnster, Germany

    Reprints: V. OjiFax: +49 (0) 251 83 56 945

    Article accepted on 11/1/2006

    Ichthyoses are a heterogeneous group of cornification disorders charac-terized by a generalized scaling of the skin. Common types such asichthyosis vulgaris and X-linked recessive ichthyosis manifest afterbirth. In contrast, rare congenital ichthyoses are inherited diseases,which at birth typically present collodion membranes or ichthyosiformerythroderma. Syndromic ichthyoses display a variety of outstandingassociated non-cutaneous symptoms. Because of their rarity these dis-orders often pose a diagnostic challenge for the clinician. This reviewdiscusses a broad spectrum of 13 isolated types of ichthyoses, 11different syndromes with associated ichthyosis and four related cornifi-cation disorders. The clinical, ultrastructural and biochemical character-istics are described along with the different molecular causes of ichthyo-sis. Special attention is given to lamellar ichthyosis and non-bullouscongenital ichthyosiform erythroderma. The different pathomechanismscausing ichthyosis provide a fascinating insight into the role of variousproteins, enzymes, lipids and metabolic pathways involved in terminalepidermal differentiation/keratinisation.

    Key words: congenital ichthyosis, cornification disorders, genetics,molecular pathology, NIRK, vulgar ichthyoses

    I chthyoses form a clinically and etiologically heteroge-neous group of cornification disorders characterizedby a generalized scaling of the skin. The large group ofcongenital ichthyoses (CI), which at birth typically presentwith collodion membrane or ichthyosiform erythroderma,encompasses an apparently confusing number of very rarediseases and often poses a diagnostic challenge for theclinician confronted with ichthyotic symptoms. First of all,it is necessary to distinguish congenital ichthyosis fromcommon ichthyosis vulgaris (IV) and X-linked recessiveichthyosis (XLRI), which both manifest after birth. It isthen recommended to look for outstanding associated non-cutaneous symptoms, which may give a useful diagnostichint for recognising a special syndrome with associatedvulgar or congenital ichthyosis [1]. The precise patient andfamily history, the dermatological features, coupled withthe histological and ultrastructural analysis of the skin andin some cases additional biochemical analyses, will help toestablish the correct diagnosis necessary for prognosis,therapy and genetic counselling. If possible diagnosisshould be confirmed by genetic analysis/mutation screen-ing.The advances in molecular biology have provided a batteryof new diagnostic means and are beginning to allow arefined classification of ichthyoses and other cornificationdisorders such as erythrokeratoderma and palmoplantarkeratoderma [2]. This review describes their differentialdiagnosis and molecular pathology according to the abovementioned clinical criteria. Isolated ichthyoses are summa-rized in table 1, ichthyotic syndromes in table 2.

    Vulgar ichthyoses

    Ichthyosis vulgaris (IV) versus X-linked recessiveichthyosis (XLRI)

    Clinically, it is often difficult to make a clear distinctionbetween these two common ichthyoses (prevalence 1:250-1,000 and 1:2,000-1:6,000, respectively), even though theyshow a different mode of inheritance. Autosomal dominantichthyosis vulgaris is characterised by follicular keratosisand light grey scales, which normally spare the flexures.Accentuated palmoplantar markings, the hallmark of ich-thyosis vulgaris, are not always evident [3]. The clinicalseverity of ichthyosis vulgaris correlates with the ultra-structural reduction of keratohyalin granules, which re-flects a defective epidermal synthesis of filaggrin [4]. Fil-aggrin aggregates keratin intermediate filaments in thelower stratum corneum and is subsequently proteolysed toform free amino acids critical as water-binding compoundsof the stratum corneum, such as urocanic or pyrrolidonecarboxylic acid. Absence of the granular layer observed bylight microscopy is a prominent feature of ichthyosis vul-garis [5]. However, this varies among individuals and is notreliable [6]. In our experience, there can be intra-individualvariation of the granular layer in ichthyosis vulgaris. There-fore, to fully appreciate this histologic feature, a biopsyshould be taken from a site of maximal scaling.In contrast, X-linked recessive ichthyosis caused by muta-tions in the steroid sulfatase gene (STS) can be unequivo-cally diagnosed by steroid sulfatase (~ Arylsulfatase C)testing [7]. The disorder sometimes presents with fine peel-

    Eur J Dermatol 2006; 16 (4): 349-59

    EJD, vol. 16, n 4, July-August 2006 349

  • ing of the entire integument at the age of 1-3 weeks andshows fine scaling in early life. Later on, affected individu-als typically develop polygonal dark scales (figure 1A).Flexures are also involved, but often to a minimal extentmimicking ichthyosis vulgaris. Lipoproteinelectrophoresisshowing an increased mobility of beta-lipoprotein is aconvenient way to screen for steroid sulfatase deficiency [8](figure 1B). The pathogenesis of XLRI has been a subject ofconsiderable research; the development of ichthyosis isusually attributed to the perturbed epidermal cholesterolsulfate cycle and the accumulation of cholesterol sulfate. Inparticular, increased amounts of cholesterol sulphate in-hibit epidermal serine proteases such as kallikreins [9].This results in retained corneodesmosomes and conse-quently decreased desquamation of corneocytes.

    In ichthyosis vulgaris as well as in X-linked recessiveichthyosis the clinician should ask for non-cutaneoussymptoms. Ichthyosis vulgaris is often associated withatopic diathesis. XLRI possibly includes birth complica-tions, cryptorchidism and corneal opacities [1, 3].

    Syndromes with associated vulgarichthyosis

    Some rare syndromes are associated with vulgar ichthy-oses. This group comprises multiple sulfatase deficiency(MSD) and Refsum disease (RD).Clinical symptoms of Refsum disease, also referred to ashereditary motor and sensory neuropathy type 4 (HMSN4),

    Table 1. The term isolated ichthyosis refers to ichthyoses which are not part of a disease syndrome. They are clinicallydistinguished in two subclasses: common ichthyoses with an age of onset after birth (vulgar ichthyoses) and rare ichthyosespresenting at birth (congenital ichthyoses)

    Disease Mode ofinheritance

    Gene/Locus OMIM Molecular pathology

    Isolated vulgar ichthyoses

    Ichthyosis vulgaris (IV) Autosomaldominant

    FGL1q21-22

    146700 - Genetical heterogeneous / polygeneous- Abnormalities of profilaggrin expression

    Recessive X-linkedichthyosis(RXLI)

    X-linkedrecessive

    STSXp22.3

    308100 - Absence of steroid sulfatase activity- Accumulation of cholesterol sulphate- Inhibition of tryptic enzymes

    Isolated congenital ichthyoses

    Lamellar ichthyosis /non-bullous congenitalichthyosiformerythroderma(LI/NCIE)- LIphenotype- NCIEphenotype- intermediatephenotype

    AutosomalRecessiveCongenitalIchthyoses

    (ARCI)

    (non-syndromictype)

    LI type 1-6:1. TGM114 q112. ABCA122q343. 19p12-q124. 19p135. ALOXE3ALOX12B17p136. ichthyin5q33

    190195242300607800601277604777604781607206603741606545609383

    (1) transglutaminase-1 deficiency, impaired cross-linkingof proteins and lipids to the cornified cell envelope(2) disrupted ATP-binding cassette of the ABC membraneprotein, altered lipid trafficking of lamellar bodies(5) loss of function of the lipoxygenases eLOX or 12R-LOX, disrupted trans-formation process of arachidonicacid(6) disruption of ichthyin, which is a transmembraneprotein of unknown function so far

    Self-healingcollodion baby(SHCB)

    TGM114q11 242300

    - Particular missense mutations in tranglutaminase-1rendering the protein susceptible to water pressure

    Bathing suit ichthyosis(BSI)

    ? Unknown

    Harlequin ichthyosis(HI)

    ABCA122q34

    607800242500

    - Loss of function of the ABC transporter protein A12 anddisrupted function of the lamellar bodies

    Autos. dominantlamellar ichthyosis(ADLI)

    Autosomaldominant

    ? 146750 Unknown

    Bullous ichthyosiformerythroderma(BIE)

    Autosomaldominant

    KRT1KRT1017q21-q22 & 12q13

    139350148080113800

    - Dominant mutations in keratin 1 or keratin 10 leading toa fragmenting and perinuclear clumping of tonofilamentsin the stratum spinosum

    Ichthyosis bullosaof Siemens(IBS)

    KRT2A(~KRT2E)12q11-q13

    600194

    146800

    - Dominant mutations in keratin 2e, leading to a clumpingof tonofilaments restricted to the upper stratum spinosumand stratum granulosum

    Ichthyosis hystrix CurthMacklin (IHCM)

    KRT112q13

    139350146590

    - Keratin disorder due to a specific mutation in thevariable tail domain V2 of keratin 1

    Peeling skin syndrome(PSS)

    Autosomalrecessive

    TGM515q15

    270300 - Homozygous missense mutations in transglutaminase-5leading to a complete loss of enzyme activity in acral PSS

    EJD, vol. 16, n 4, July-August 2006350

  • include night blindness (retinitis pigmentosa), anosmia,progressive deafness, peripheral neuropathy and cerebellarataxia. The age of onset varies from early childhood to theage of ~50 [10]. Many patients develop ichthyotic skinreminiscent of ichthyosis vulgaris. The disease is caused bymutations in PHYH, the gene encoding phytanoyl-CoAhydroxylase (PhyH) [11]. The impaired function of PhyHresults in a pathologic plasma and tissue accumulation ofphytanic acid. Early diagnosis and treatment with a diet lowin phytanic acid can prevent the fatal course of the disease

    [12]. The oxidation of p