Review article

Ichthyoses:Differential diagnosis and molecular genetics

Vinzenz OJIHeiko TRAUPE

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

Reprints: V. OjiFax: +49 (0) 251 83 56 945<ojiv@uni-muenster.de>

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 of

congenital 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

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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 phytanic acid by PhyH is dependenton the Pex7p protein, which is an important peroxisomalreceptor. Mutations in the PEX7 gene cause the severeperoxisome biogenesis disorder rhizomelic chondrodys-plasia punctata type 1 (RCDP1), which may also beaccompanied by mild ichthyosis [13]. Interestingly, specialvariants of PEX7 can also cause Refsum disease [14].Multiple sulfatase deficiency is a rare neuropediatric disor-der, which combines the enzyme deficiency and clinicalfeatures of diseases such as metachromatic leukodystrophy,

Table 2. Syndromes with associated ichthyosis. These diseases are clinically distinguished by the age of onset of the ichthyosis.Affected individuals may show dermatological features similar to vulgar ichthyoses or may be born with collodion membrane orichthyosiform erythroderma, as is the case with congenital ichthyoses

Disease Mode ofinheritance

Gene / Locus OMIM Molecular pathology

Syndromes with vulgar ichthyosis

Refsumdisease(HMSN4)

autosomalrecessive

PHYH10pter-p11.2PEX76q22-q24

266500 - Special variant of peroxisomal disorder- Disrupted oxidation of phytanic acid- Accumulation of phytanic acid in tissues

Multiple sulfatasedeficiency(MSD)

SUMF13p26

607939272200

- Lysosomal storage disorder- Deficient posttranslational modification of sulfatasesincluding the steroid sulfatase

Syndromes with congenital ichthyosis

DorfmanChanarin syndrome(DCS)

autosomalrecessive

congenitalichthyosis

(ARCI

(syndromic type)

CGI583p21

604780275630

- Multisystem triglyceride storage disease- Impaired function of a novel esterase/lipase/thioesterase, which is responsible for the long-chain fatty acid oxidation

Gauchersyndrome type 2(GD2)

GBA1q21

606463230900

- Lysosomal storage disease due to a loss of theglucocerebrosidase activity- Accumulation of glucocerebrosides in peripheralleukocytes and body tissues including the central nervoussystem

Sjögren Larssonsyndrome(SLS)

ALDH3A217p11.2

270200 - Impaired oxidation of aliphatic aldehydes due to adefect of the microsomal fatty aldehyde dehydrogenase- Abnormal metabolism of lipids in the skin and phospho-or sphingolipids in the brain

Comèl-Nethertonsyndrome(NTS)

SPINK5 (5q32) 256500 - Deficiency of the serine protease inhibitor LEKTI,which is normally expressed in the upper epidermal layercontrolling proteases involved in desquamation andinflammation

Trichothio-dystrophy(TTD)- Tay syndrome(IBIDS / PIBIDS)

ERCC2 / XPD19q13.2-q13.3ERCC3 / XPB 2q21TTD-A

278730126340601675133510

-

- Impaired DNA transcription and repair- Allelic variants cause Xeroderma Pigmentosa andCockayne syndrome- The molecular cause of TTD without photosensitivity(IBIDS) is unknown

Ichthyosisprematurity syndrome(IPS)

9q33-34 608649 unknown

Conradi-Hünermann-Happle syndrome(CDPX2)

X-linkeddominant

EBPXp11.23-p11.22

300205302960

- Impaired cholesterol synthesis due to mutations in thesterol isomerase (EBP), which is the key enzyme in thefinal step of cholesterol biosynthesis- Interference with “sonic hedgehog”

CHILD syndrome X-linkeddominant

NSDHLXq28

300275308050

- Blockade of cholesterol biosynthesis pathway prior tothe sterol isomerase- Defect of the embryogenesis of the bilateral bodysymmetry

IFAP syndrome (X-linkedrecessive)

unknown 308205 - Unknown- Genetic heterogeneity or a different mode of inheritanceis possible

EJD, vol. 16, n° 4, July-August 2006 351

TGase-1 assay

a c d control

3 months1 week

e f g h

i j k l

(1) patient(2) normal

b 1 2

m n o p IRS

NTS patient healthy skin

SG

Figure 1. Children with ichthyosis and examples of laboratory analyses: (A) 14-year old boy with X-linked recessive ichthyosis(XLRI), (B) increased mobility of beta-lipoprotein in comparison with a normal control, indicating sulfatase deficiency in (XLRI),(C) non-bullous congenital ichthyosiform erythroderma (NCIE) in a newborn with pronounced scaling and minimal ectropion,(D) screening assay for transglutaminase-1 deficiency, which indicates a lack of transglutaminase activity in the epidermis of achild with lamellar icthhyosis (LI), (E) generalised dark, large scaling in LI, (F) Self-healing collodion baby (SHCB) after 1 weekand (G) 3 months, (H) Harlequin ichthyosis (HI) with constriction of the fingers, (I) exfoliative hyperkeratosis and erythema inbullous ichthyosiform erythroderma (BIE) of Brocq, (J) “moulting phenomenon” in ichthyosis bullosa of Siemens (IBS), (K) malebaby with IFAP syndrome, (L) marked, brown lichenification in Sjögren Larsson syndrome (SLS), (M) neonate with Nethertonsyndrome (NTS) showing congenital ichthyosiform erythroderma, (N) trichorrhexis invaginata, (O) immunochemical lack ofLEKTI in NTS epidermis, (P) compared with healthy skin. Abbreviations are also given in tables 1 and 2. (Photograves:Department of Dermatology, University Hospital Münster, Germany).

EJD, vol. 16, n° 4, July-August 2006352

mucopolysaccharidoses and steroid sulfatase deficiency.Affected infants suffer from progressive psychomotor dete-rioration and have a very poor prognosis. This “lysosomalstorage disorder” is caused by recessive mutations inSUMF1, which encodes the FGly generating enzyme(FGE) [15]. This enzyme catalyses the posttranslationalformation of FGly residues, which are functionally impor-tant catalytic residues in the active site of eukaryotic sulfa-tases. Hence, a lack of FGE leads to an impaired function ofall sulfatases including steroid sulfatase, the defective en-zyme in XLRI. Multiple sulfatase deficiency patients showan ichthyosis, which is similar to but usually milder than inXLRI. Therefore, ichthyosis in a child with unexplainedneurological symptoms should prompt measurement ofsteroid sulfatase [16]. There are other syndromes apartfrom multiple sulfatase deficiency, which are associatedwith XLRI and are due to a contiguous gene deletion,affecting neighbouring genes of the steroid sulfatase gene[17]. This mechanism can be observed in Kallman syn-drome, hypertropic pyloric stenosis, unilateral renal apla-sia, mental retardation or hypergonadotropic hypogo-nadism [1].

Isolated congenital ichthyoses

Isolated congenital ichthyosis encompasses a group ofmostly monogenic disorders presenting at birth with gen-eralized hyperkeratosis and scaling (e.g. collodion mem-brane), often with erythroderma. Neonates with bulloustypes of congenital ichthyosis typically show skin erosionsand blistering. Associated clinical symptoms are neonataldehydration, skin infections, ectropion, eclabium, hypo-hidrosis or severe heat intolerance.

Lamellar ichthyosis (LI)/non-bullous congenitalichthyosiform erythroderma (NCIE)

This subgroup of different types of non-syndromic autoso-mal recessive congenital ichthyoses (ARCI) is character-ised by non-bullous hyperkeratosis.The more severe pheno-type, lamellar ichthyosis (LI) has an estimated prevalenceof 1:200,000-300,000. Most patients (~90%) are born en-cased in a tight shiny covering, described as collodionmembrane, and often show erythroderma. During the firstweeks of life, the membrane is gradually replaced, andpatients develop large, dark or plate-like scales (figure 1E),sometimes with marked palmoplantar hyperkeratosis. Incontrast, individuals with non-bullous congenital ichthy-osiform erythroderma (NCIE) show a more pronouncederythroderma with fine, white scaling [18] (figure 1C).Non-erythrodermic, non-lamellar ARCI is regarded as avery mild intermediate phenotype within the spectrum oflamellar ichthyosis (LI) situated at one end of the pole andnon-bullous congenital ichthyosiform erythroderma(NCIE) at the other [19, 20].To date, six genes for lamellar ichthyosis/non-bullous con-genital ichthyosiform erythroderma (LI/NCIE) (type1-6)[19, 21-23] have been localised and five of them identified[24-27] (table 1). In about 35-40% LI/NCIE is caused byhomozygous or compound heterozygous mutations inTGM1 (LI/NCIE type 1), which lead to a deficiency ofkeratinocyte transglutaminase. Transglutaminases areCa2+-dependent enzymes involved in the assembly of thecornified cell envelope. This resilient sheath of e-(c-

glutamyl)lysine cross-linked proteins is deposited subja-cent to the plasma membrane in terminally differentiatingkeratinocytes. The covalent c-amide bonds between vari-ous proteins or peptides are formed by transglutaminase-1,-3 and -5. An important specific function oftransglutaminase-1 is the cross-linking ofx-hydroxyceramides to the cornified cell envelope [28](figure 2). The LI/NCIE locus on chromosome 17p13,which is more often associated with the NCIE phenotype,revealed missense mutations or deletions in ALOXE3 orALOX12B [26]. These genes encode epidermallipoxygenase-3 (eLOX3) and 12R-lipoxygenase (12R-LOX). Lipoxygenases are iron-containing dioxygenases,which metabolise essential fatty acids, phospholipids ortriglycerids. In the epidermis, eLOX3 and 12R-LOX par-ticipate in the same metabolic pathway, which convertsarachidonic acid into specific epoxyalcohol products. Lossof function in one of these enzymes probably impairs theepidermal lipid formation [29, 30]. Lefèvre et al. (2004)reported about a new gene on chromosome 5q33 (LI/NCIEtype 6), mutations of which cause a NCIE-like phenotype,which was always accompanied by palmoplantar kerato-derma [27]. 60% of the patients were born with a collodionmembrane. They showed that the causative gene ichthyinencodes a putative transmembrane protein and speculatedthat it could be a receptor for products of theepoxyalcohol/lipoxygenase pathway [27, 29]. Patients withIL/NCIE type 2 (2q34) were all born with a collodionmembrane and presented a generalised pure lamellar ich-thyosis with palmoplantar keratoderma [21]. This pheno-type was associated with missense mutations in theABCA12 gene [25], the same gene, in which large intra-genic deletions and frameshift deletions cause Harlequinichthyosis [31]. The exact molecular cause of LI/NCIE type3 and 4 remains to be established. Attempts to refine theclassification of LI and NCIE phenotypes by the use ofclinical, biochemical and ultrastructural observations haveso far failed to yield a consistent scheme. This difficulty isillustrated by the fact that the same TGM1 mutation cangive rise to either LI or NCIE [32].The distinct phenotype self-healing collodion baby(SHCB) can be due to a particular mutation in TGM1,which leads to an impaired transglutaminase-1 functionunder intrauterine water pressure [33]. Approximately 10%of all collodion babies heal completely within the firstweeks of life (figure 1F and 1G). The molecular basis ofbathing suit ichthyosis (BSI), which is a variant of lamellarichthyosis sparing the extremities and the face, is unknownso far.

Harlequin ichthyosis (HI)

The newborn who suffers from this most severe ichthyosisis encased in a thick collodion membrane, showing crack-ing with deep fissures, pronounced ectropion/eclabium andoften impaired mobility of the thorax and limbs. The prog-nosis is poor because of secondary complications, but somepatients can be rescued with an early treatment of retinoidsand intensive care (figure 1H). Lawlor (1988) suggestedthat Harlequin ichthyosis may be a severe form of lamellarichthyosis/non-bullous congenital ichthyosiform erythro-derma [34] and was proven right 17 years later, when it wasdemonstrated, that at the one hand missense mutations inABCA12 can cause classic lamellar ichthyosis [25],whereas deletions in this gene predicting a severely trun-

EJD, vol. 16, n° 4, July-August 2006 353

cated protein are the molecular cause of Harlequin ichthyo-sis [31]. The ATP-binding cassette (ABC) transporter fam-ily encompasses a variety of membrane proteins involved inthe energy-dependent transport across membranes. In theepidermis, ABCA12 could have an important function forthe lamellar granules, which through exocytosis traffic lip-ids, proteases, etc. across the apical keratinocyte mem-brane. The ultrastructural key feature of HI is the abnormalformation of lamellar granules [35].

Autosomal dominant lamellar ichthyosis (ADLI)

Autosomal dominant lamellar ichthyosis is characterisedby a generalised dark-grey scaling with palmoplantar kera-toderma [36]. Its genetic cause is not known so far. Thisdisorder appears to be genetically and clinically heteroge-neous and of variable penetrance. Ultrastructurally aprominent transforming zone between the stratum granulo-sum and corneum can be observed [37]. An importantdifferential diagnosis is loricrin keratoderma (see below).

Bullous ichthyosiform erythroderma (BIE)and ichthyosis bullosa of Siemens (IBS)

The term epidermolytic hyperkeratosis derives from thecharacteristic light microscopic observation intracellular

vacuolisation, clumping of tonofilaments and formation ofsmall intraepidermal blisters. It is typically present inbullous ichthyosiform erythroderma of Brocq (BIE), whichis also referred to in the American literature as epider-molytic hyperkeratosis (EHK), in ichthyosis bullosa ofSiemens (IBS) and in palmoplantar keratoderma of Vo-erner (EPPK).Keratins comprise a large family of > 20 proteins, whichare expressed in pairs of acidic (type I) and basic (type II)keratins (encoded on chromosome 17q12-21 and 12q11-13, respectively). Keratin monomers form obligate het-erodimers, which assemble into keratin intermediate fila-ments building a cytoskeleton for the structural stabilityand flexibility of epidermal cells. In the skin, basal kerati-nocytes predominantly express keratin 5 and 14, whilesuprabasal cells switch to the expression of keratin 1 and10. Cells of the granular layer also synthesize keratin 2e.Like other keratinopathies, bullous ichthyosiform erythro-derma (BIE) is inherited by an autosomal dominant trait.Individuals affected at birth show a generalised erythro-derma, often with widespread blistering or erosions. Thehyperkeratosis begins later and persists throughout the restof life (figure 1I). The disorder is caused by heterozygousmutations of KRT1 (keratin 1) and KRT10 (keratin 10) [38,

Glucose ϖ-OH-Ceramide Linoleic acid

OH

NH

O

O

O

O

OH

NH

O

O

O

O

LI type 1 Transglutaminase 1

Ceramidase

Linoleic acid

protein of the

cornified envelope

protein of the

cornified envelope

protein of the

cornified envelope

GD type 2 β-glucocerebrosidase Glucose

OH

NH

OH

O

O

O

Sphingosine

HO

O

O

O

Figure 2. Formation of the cornified cell envelope by transglutaminase-1 and glucocerebrosidase. Transglutaminase-1 attachesceramides to the cornified cell envelope proteins such as involucrin. Transglutaminase-1 activity is reduced or absent in lamellarichthyosis type 1. Glucocerebrosidase, which is impaired in Gaucher syndrome type 2, removes the glucose from the glucocer-ebroside [81].

EJD, vol. 16, n° 4, July-August 2006354

39]. More than half of all cases are due to a de novomutation and occur sporadically. Patients with bullous ich-thyosiform erythroderma and KRT1 mutations often de-velop palmoplantar keratoderma, because keratin 1 is themain expression partner of keratin 9 in palmoplantar skin.Linear epidermolytic epidermal nevi (along the lines ofBlaschko) indicate a somatic and maybe gonadal mosa-icism, which can result in generalised full-blown BIE in theoffspring generation [40]. The diagnostic ultra structuralfinding of BIE is the cytoplasmatic clumping of tonofila-ments in the suprabasal or spinous layer [41].Clinically, ichthyosis bullosa of Siemens (IBS) has a milderphenotype than bullous ichthyosiform erythroderma andcan be distinguished by the lack of erythroderma and by acharacteristic “moulting” of the upper epidermal layers(figure 1J). Lichenified hyperkeratosis develops with apredilection to flexures, over joints and on dorsa of handsand feet [42]. The disorder is caused by heterozygousmutations in the gene of keratin 2e [43, 44]. Light micros-copy reveals a superficial acanthokeratolysis in the granu-lar layer (versus spinous layer in BIE), which correlateswith the distinct expression pattern of keratin 2e.

Ichthyosis hystrix Curth Macklin (IHCM)

“Ichthyosis hystrix” is a descriptive name for cornificationdisorders with massive and spiky hyperkeratosis. The pro-totype is ichthyosis hystrix Curth Macklin, which is char-acterised by extensive keratoderma and verrucous hyper-keratosis over joints and flexures [45]. The autosomaldominant disorder sometimes resembles bullous ichthyosi-form erythroderma, but there is no clinical or histologicalevidence for blister formation or epidermolysis. The promi-nent ultrastructural observations in ichthyosis hystrix CurthMacklin are abnormal cytoplasmic aggregates of tonofila-ments, perinuclear vacuolisation and binucleated cells. TheIHCM specific pathology is due to particular heterozygousmutation in KRT1 [46].

Peeling skin syndrome (PSS)

The peeling skin syndrome is characterized by a spontane-ous, lifelong peeling of the stratum corneum without bleed-ing or pain [47]. Ultrastructural analyses reveal an intrac-ellular splitting within the stratum corneum. Peeling skinsyndrome type A is the non-inflammatory variant present-ing at birth or during childhood; peeling skin syndrometype B seems to be identical with Netherton syndrome [48].Another acral localised variant of PSS has been described[49]. A recent study identified a homozygous missensemutation in the gene of transglutaminase-5 (TGM5) in twounrelated families with acral peeling skin syndrome [50].

Syndromes with congenital ichthyoses

Dorfman Chanarin Syndrome (DCS)

The multisystem triglyceride storage disease with impairedlong-chain fatty acid oxidation is a rare form of syndromicnon-bullous congenital ichthyosiform erythroderma [51]and is caused by recessive mutations in the CGI58 gene[52]. At birth individuals suffering from Dorfman Cha-narin Syndrome present with generalised white scaling anda variable degree of erythema. The skin shows a character-istic ultrastructure [53]. The widespread non-lysosomal

tissue deposition of neutral lipids results in a variableexpression of associated symptoms such as cataract,hepatosplenomegaly, neurosensorial deafness, myopathyor developmental delay. Numerous lipid-containing vacu-oles in circulating leukocytes are diagnostic for the disor-der. Prognosis depends on the course of the liver disease,which may be positively influenced by a diet of medium-chain triglyceride [54].

Gaucher syndrome type 2 (GD2)

Gaucher disease refers to a cluster of disorders resultingfrom recessive mutations in the GBA gene encoding gluco-cerebrosidase, an enzyme that normally cleaves the glucoseresidue from ceramides (figure 2). As a result, glucocer-ebrosides accumulate in the phagocytic cells or centralnervous system. Three clinical subtypes have been distin-guished. Type 2, the infantile cerebral type, is characterisedby an almost complete loss of glucocerebrosidase activity,hepatosplenomegaly and dominating progressive neuro-logic signs such as opisthotonus, choking spell and dysph-agia, leading to death usually before the age of 1 year [55].Some but not all patients are born as collodion babies.Therefore, Gaucher syndrome type 2 is a differential diag-nosis for other types of congenital ichthyosis [56]. Diagno-sis can be made by measurement of glucocerebrosidaseactivity in peripheral blood leukocytes or in extracts ofcultured skin fibroblasts.

Sjögren Larsson syndrome (SLS)

Sjögren Larsson syndrome is a recessive neurocutaneousdisorder caused by a deficiency of the mircrosomal enzymefatty aldehyde dehydrogenase (FALDH) [57], which forexample is involved in the leukotriene B4 (LTB4) metabo-lism. The diagnosis of SLS should be especially consideredin preterm babies with congenital ichthyosis [58]. SjögrenLarsson syndrome skin is characterised by a remarkable,cobblestone-like lichenification (figure 1L). Severe dis-abling pruritus, crystalline deposits in the retina appearingas glistening white dots and photophobia are very charac-teristic non-cutaneous symptoms. During infancy andchildhood SLS patients develop severe body spasticity,leading to contractures and, in most patients, to wheelchairdependency. Non-progressive, mild to moderate mentalretardation is a coexisting neurological feature. The patho-logic level of free fatty alcohols in cultured fibroblasts, thedirect testing of the FALDH activity, or the abnormal pres-ence of LTB4 metabolites in urine [58], can provide abiochemical screening or confirmation of the clinical diag-nosis, prior to molecular mutation analysis of the FALDHgene.

Netherton syndrome (NTS)

This rare autosomal recessive ichthyotic syndrome is char-acterised by the triad of congenital ichthyosiform erythro-derma, hair shaft anomalies and severe atopic diathesiswith high IgE blood levels and eosinophilia. Normallycongenital ichthyosiform erythroderma (figure 1M) gradu-ally evolves into the milder ichthyosis linearis circumflexa,which typically shows polycyclic migrating plaques withdouble edged scales. Trichorrhexis invaginata is thepathognomonic microscopic hair shaft anomaly of Nether-ton syndrome (figure 1N). Many NTS patients suffer fromlife threatening neonatal dehydration, failure to thrive and

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recurrent skin infections often caused by staphylococcusaureus [59]. This disorder is caused by recessive mutationsin the SPINK5 gene, which encodes the novel multi-domainserine protease inhibitor LEKTI [60, 61]. Full-length LE-KTI is proteolytically processed in the upper epidermallayer, forming small biological active peptides, which in-hibit a variety of serine proteases such as stratum corneumtrypsin or chymotrypsin enzyme (SCTE/SCCE) or mastcell tryptase. The ichthyotic and inflammatory skin pheno-type, which is associated with an extremely impaired epi-dermal barrier, is explained by the lack of LEKTI, whichconsequently leads to hyperactivity of the proteases in-volved in the desquamation process or inflammatory re-sponse (kallikreins). Thus, from a pathophysiologic pointof view, Netherton syndrome represents the opposite poleof X-linked recessive ichthyosis, which is characterised bya reduced serine protease activity in the epidermis [9]. Thelack of LEKTI antigen in the epidermis provides a strongimmunochemical evidence for the NTS diagnosis (figure1O and 1P) [62].

Ichthyosis prematurity syndrome (IPS)

Ichthyosis prematurity syndrome is often reported in theScandinavian population, but can also be found in Germanpatients (our experience). Pregnancies with an affectedfoetus are complicated by polyhydramnion; delivery usu-ally takes place in the 30th-32nd gestational week. Neo-nates may suffer from transient asphyxia. The ichthyosisoften improves within a few weeks. The skin shows acharacteristic ultrastructure, which has lead to the designa-tion ichthyosis congenita type 4. A novel locus for theichthyosis prematurity syndrome was assigned for chromo-some 9q33-34 [63].

Conradi-Hünermann-Happle syndrome (CDPX2)

X-linked dominant chondrodysplasia punctata type 2(CDPX2), also known as Conradi-Hünermann-Happle syn-drome, is lethal in the majority of male embryos and con-sequently only seen in female patients [64, 65]. Due to theindividual differences in X-inactivation, expression of thedisease is rather variable even within families. Femalesaffected at birth often present with severe ichthyosiformerythroderma, which in infancy later evolves into striatedhyperkeratosis following the lines of Blaschko (ichthyosislinearis). After infancy patients mainly suffer from scaringalopecia, cataracts and the skeletal dysplasia, which leadsto asymmetric shortening of the long bones or severe ky-phoscoliosis, necessitating early orthopaedic interventions.Some individuals only show minor symptoms such as loca-lised hypo-/hyperpigmentations or short stature. Follicularatrophoderma, i.e. large skin pores, or sectorial cataractsare pathognomonic for Conradi-Hünermann-Happle syn-drome. Biochemical analyses via gas chromatography-mass spectrometry reveal increased plasma level of8-dehydrocholesterol and 8(9)-cholesterol, which is due toa block of a key enzyme in the sterol metabolism, namelythe 8-7 sterol isomerase [66]. This enzyme is encoded bythe EBP gene, which shows heterozygous mutations inCDPX2 patients. Direct sequencing of EBP should confirmthe diagnosis of CDPX2. The mechanism behind the intrau-terine loss of affected males and the dermatoskeletal dys-plasia is unclear and may include the accumulation of toxicsterol intermediates and the deficiency of products distal inthe cholesterol biosynthesis pathway.

CHILD syndrome

CHILD is an acronym for congenital hemidysplasia withichthyosiform nevus and limb defects [67]. This X-linkeddominant dysplasia is also determined by the phenomenonof X-chromosome inactivation. Like CDPX2, it is lethal inmales and therefore almost exclusively observed in fe-males. The syndrome is caused by mutations in the NSDHLgene encoding the 3b hydroxysteroid dehydrogenase alsoknown as C3 sterol dehydrogenase [68]. This enzyme ofthe cholesterol biosynthesis pathway is located prior to the8-7 sterol isomerase, the enzyme impaired in Conradi-Hünermann-Happle syndrome (CDPX2). The most strik-ing feature in the CHILD syndrome is the inflammatorynevus, which has a highly characteristic ultrastructure andnormally shows a unique lateralisation with strict midlinedemarcation. The ipsilateral hypoplasia of the body may berepresented by a shortening or even complete absence of alimb.

Trichothiodystrophy (TTD)

Trichothiodystrophy refers to a heterogeneous group ofautosomal recessive disorders that share the distinctivefeatures of extremely brittle hair and abnormally low sulfurcontent of the hair shaft (decrease of cysteine). Trichochisisand alternating light and dark banding by polarizing mi-croscopy are typical findings, but they may occasionallyoccur in patients without this disorder as well [69]. Inparticular, zinc deficiency can produce similar clinical hairalterations [70]. At least two TTD subtypes are associatedwith congenital ichthyosis: The acronym IBIDS describesthe distinct “Tay syndrome” and refers to its clinical find-ings ichthyosis (e.g. collodion membrane), brittle hair,intellectual impairment, decreased fertility and short stat-ure. Other features are microcephaly, dysplasia of nails,failure to thrive, “progeria”-like symptoms, cataracts andphotosensitivity (~PIBIDS) [71]. Half of all trichothiodys-trophy patients show an abnormal nucleotide excision re-pair (NER) of UV-damaged DNA, which is caused byrecessive mutations in the XPD gene (in about 95%), in theXPB gene or in the predicted gene “TTD-A”. It is believedthat most individuals with IBIDS/PIBIDS do not have anincreased risk of skin cancers [69], but rare cases with anoverlapping phenotype of trichothiodystrophy and Xero-derma pigmentosum (XP) with skin cancers have beendescribed [72, 73]. Therefore, sun protective measuresshould be recommended for TTD patients.

IFAP syndrome

The acronym IFAP stands for ichthyosis follicularis, atri-chia and photophobia [74]. The congenital and universalatrichia is the most striking clinical feature (figure 1K). Thefollicular keratosis often improves during the first year oflife and should be distinguished from other diseases such askeratosis follicularis spinulosa decalvans of Siemens orsimply ichthyosis vulgaris. The cause of the photophobia isunclear and may be related to follicular keratosis within theeye lids. Some patients also suffer from recurrent respira-tory infections or progressive deteriorating neurologicsymptoms such as generalised seizures and cerebellarsymptoms. The complete IFAP phenotype seems to be onlyobserved in male patients. It is therefore thought to be ofX-linked recessive inheritance. Female carriers maypresent with linear “lesions of Blaschko” showing circum-

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scribed hairless or ichthyotic skin areas [75]. A differentmode of inheritance and genetic heterogeneity was consid-ered by Cambiaghi et al. (2002) [76].

Related types of cornification disorders

This group refers to erythrokeratoderma and palmoplantarkeratoderma, which have been historically separated fromichthyoses. The following entities may have a considerableclinical or etiological overlap with ichthyoses.Erythrokeratodermia variabilis of Mendel Da Costa(EKV) (OMIM 133200) is due to recessive mutations in thegenes of connexin 31 or 30.3 [77]. Connexins are essentialcomponents of the intercellular gap junction communica-tion, which is crucial for tissue homeostasis, growth con-trol, development and synchronized response of cells tostimuli. EKV is characterised by transient, figurate erythe-mas, which can be easily provoked by external factors, andhyperkeratosis with developing pachydermia. Patients alsosuffer from palmoplantar keratosis and burning sensationsof involved extremities. There is no characteristic ultra-structure in this disorder. The so called keratitis ichthyosisdeafness (KID) syndrome (OMIM 148210) is a rare ecto-dermal dysplasia, which is characterised by corneal epithe-lial defects, sometimes leading to blindness, and a develop-ment of follicular hyperkeratosis with circumscribed,erythematous plaques of thickened skin. The hearing loss isnot always bilateral, nor always complete. In contrast toerythrokeratodermia variabilis of Mendel Da Costa, thedominant inherited KID syndrome is caused by heterozy-gous mutations in CX-26, the gene of connexin 26 [78]. Themajority of all KID syndrome cases seem to occur sporadi-cally. The specific mutation D66H of CX-26 can also causecongenital deafness with mutilating keratoderma (Vo-hwinkel syndrome) (OMIM 124500) [79], which demon-strates the multiplicity of phenotypes in connexin disor-ders. The variant form of Vohwinkel syndrome, referred toas loricrin keratoderma (OMIM 604117), is caused bymutations in the gene for loricrin and, in contrast to eryth-rokeratodermas, shows a characteristic ultrastructure withcompact hyperkeratosis, round retained nuclei and hyper-granulosis [80]. Affected individuals may show congenitalichthyosis prior to the development of palmoplantor kera-toderma with pseudoanihum, illustrating that keratodermahas to be added to the differential diagnosis of collodionbabies and ichthyosis.

Conclusion

Ichthyoses form an extremely heterogeneous group of in-herited diseases; most of them are rare and therefore diffi-cult to diagnose. From the clinical point of view it is usefulto distinguish between vulgar or congenital and isolated orsyndromic ichthyoses. Histological features such as epider-molytic hyperkeratosis (BIE, IBS), ultrastructural findingssuch as cholesterol clefts, lipid vacuoles, malformed corni-fied cell envelope (LI/NCIE) and abnormal lamellar gran-ules (HI), or biochemical results such as the lack of trans-glutaminase activity (LI/NCIE) or of LEKTI (NTS)expression, may be regarded as effective diagnostic orscreening tools. Other diagnostic procedures include

blood/plasma analyses for steroid sulfatase activity (XLRI,MSD), phytanic acid (HMSN4), lipid vacuoles of leuko-cytes (DCS), glucocerebrosidase activity (GD2),8-dehydrocholesterol and 8(9)-cholestenol (CDPX2) oranalyses for the aldehyde dehydrogenase (FALDH) activityin cultured fibroblasts (SLS) or for the amino acid contentof the hair (TTD). Most of these procedures have to becarried out in specialised centres. The transglutaminaseactivity test developed at our Centre in Münster (figure 1D)is performed with unfixed cryosections, which have to besent on dry ice.Further information concerning diagnostic as well as thera-peutic questions can be downloaded from the “Network forIchthyosis and Related Cornification Disorders” NIRK(www.netzwerk-ichthyose.de) or can be given via E-mailfrom the authors. NIRK is closely linked to the German selfsupport group “Selbsthilfe Ichthyose e.V.” (www.ichthy-ose.de) and is open to international collaborators. Furtherresearch is necessary for a better understanding of thepathogenesis of all cornification disorders, which will en-able improved diagnostics and treatment of these diseases.Very recently, two homozygous or compound heterozygousnonsense mutations have been identified in the filaggrin(FGL) in ichthyosis vulgaris patients [82]. These mutationsare also associated with atopic dermatitis [83] j

Acknowledgements. We thank Mrs. Bückmann, Mr. Wisseland Mr. Thomas for the help with the photographs, Mrs.Gamble-Brodte for the revision of the manuscript, and wewould like to dedicate this review to all our patients andtheir families. Special thanks to Stefan and Melody. Ourwork is supported by the Deutsche Forschungsgemein-schaft (Tr 228/6-2) and by the Bundesministerium fürBildung und Forschung as part of the Network for rarediseases NIRK (GFGM01143901)

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