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Home , CHILD syndrome, Epidermolysis bullosa, Erythrokeratodermia, Ichthyosis, Ichthyosis vulgaris, Keratoderma

Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 Acta Derm Derm Acta Venereol 34–47 213: 83Suppl 2003; three into fied groups: main thepatients were and criteria, typic genotypic classi- hood or adulthood. Applying ofpheno- acombination child- in examined 127 cases ofcongenital genodermatosiscentre, anational in ence we describe andthis development, on ourown ofexperi- 5years that tools aretic continuously updated. being Based on new diagnos- toseveral ofichthyosis haveled advances ourunderstandingcent in ofthemolecular correct diagnosis already infancy. in Fortunately, re- tant, but tomakea painstakingly sometimes difficult, expressed It lesions. obviously is impor- hyperkeratotic bullous focally only or or ichthyosis tomild lamellar problems later from mayrange life in asevere pending on which causes gene thedisease, the erythroderma, with or De- . without superficial dion phenotype or degrees as variable ofichthyosiform diseases that present monogenetic ly as atbirth acollo- arare ichthyosisCongenital comprises group ofusual- of Departments Derm Acta Venereol 34–47 213: 2003,Suppl. ANDERS VAHLQUIST of 127Cases The ClinicalSpectrumofCongenitalIchthyosisinSweden: A Review hyperkertosis, EKV:hyperkertosis, electron EM: variabilis, EHK: epidermolytic gene, Cx: scaling, or focal fine with ichthyosis CIFS: congenital defects, limb with ichthyosis lateral hemi- CHILD: congenital ichthyosis, congenital CI: Abbreviations: [email protected] Sweden. E-mail: 85Uppsala, SE-751 Hospital, versity Anders Vahlquist, ofDermatology, Department Uni- Uppsala due to mutationsdue tokeratin ( )and related(epidermolytic disorders mainly due totransglutaminasemainly 1mutations ( erythrodermathyosiform and eases due tomany different causes ( Syndromic dis- (multi-organ) systemic ichthyosis, i.e. congenita; Netherton’scongenita; syndrome. neurocutaneouskeratoderma; syndromes; pachonychia DNA erythro- test; microscopy; electron connexin; transglutaminase; keratin; ; thyosis; ich- lamellar hyperkeratosis; epidermolytic baby; dion ichthyosis. for usefulness procedures diagnostic ofvarious the clinical relationin torecent data theliterature in emphasizing othervarious techniques. Our findings are discussed analysis,tation electron microscopy and ofepidermis befurthercould 4–11 into stratified using mu- entities 1 , Dermatology, Key words: congenital ichthyosis; collo- ichthyosis; words:Key congenital 1 , AGNETAGÅNEMO 2 Clinical Genetics and and Genetics Clinical n =21); =21); 1)

2) Bullous ichthyosis n

=26). Eachgroup=26). Non-bullous ich- 3 Pathology, University Hospital, Uppsala, Sweden Uppsala, Hospital, University Pathology, 1 , MARITTA PIGG n =80); =80); 3) onstrated. dem- be mutation gene causative a can Onlyrarely tient. pa- work-up ofthe laboratory at and examination clinical history, family the in findings oftypical combination at emerge. ona contingent of CIis diagnosis a Meanwhile, soon DNA will simple tests and classification ology-based new aeti- ofCI,a genetics molecular the progress in cent different used in minology Hopefully, textbooks. re- with ter- conflicting sometimes the CIis when diagnosing tion specialist. bya when judged even ful complica- Another help- always not and expensive time-consuming, is (EM)ofepi- microscopy electron For example, diagnosis. quick fora cumbersome too or are missing either are tests observations. diagnostic sophisticated more often, too All onclinical based diagnosis a preclude may features ping is. of CIit overlap- many the and diseases ofthe rarity The difficult be may type which decide to specialist fora even birth. at appear donot they because simply here cluded Darier’s and vulgaris ichthyosis nant in- not are disease, such as autosomal-domi- ofkeratinization, disorders netic . with associated is Other, monoge- common more Netherton’s and disease, roectodermal which syndrome, neu- a is (SLS), which syndrome Sjögren-Larsson example for symptoms, non-cutaneous major with associated also ofCIare forms Some (LI). ichthyosis lamellar and (CIE) erythroderma ichthyosiform congenital inherited sively reces- autosomal ofmostly sis forms (EHK), various to hyperkerato- orepidermolytic ichthyosis such as bullous diseases, fragility skin inherited dominantly spans from erosions. skin and derma ofCI spectrum the Thus defined, erythro- with associated sometimes and integument, the of scaling and hyperkeratosis as widespread birth at ing present- ofkeratinization disorders monogenetic mostly large a (CI)encompasses ichthyosis Congenital groupof INTRODUCTION ichthyosis. recessive XRI:X-linked 1protein, 1 –transglutaminase syndrome, Sjögren-Larsson SLS: , and congenita Tgase ichthyosis linearis, KLICK: K:keratin, sis deafness, and ichthyo- KID: , erythroderma, ichthyosiform or congenital and/ ichthyosis lamellar LI/CIE: , 1gene transglutaminase with ichthyosis lamellar LI-TGM: photofobia, and alopecia microscopy, IFAP: ichthyosis, HI:Harlequin follicularis, ichthyosis When confronted with a case of neonatal ichthyosis it ichthyosis ofneonatal case a with confronted When 2 , MARIE VIRTANEN 1

AND PER WESTERMARK 3 Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 drome, the patients were provisionally classified into three into classified provisionally were patients the drome, syn- described previously a with orassociated blistering was ichthyosis the ornot onwhether based Methods) and study. and Material (see investigations thorough After the in included 1996–2002,were period the byus in tered CIencoun- with of Swedish patients number cumulative the representing patients, One-hundred-and-twenty-seven RESULTSDISCUSSION AND ticipation. University. par- to consent informed gave (orparents) patients All drome. V SLS, offorexample assess possibility to the specialists other by examined also were problems, ear CNS, and i.e. eye findings, Netherton’sindicating extracutaneous with (7).Patients syndrome shafts, hair the in invaginata oftichorrexis presence forthe scopically micro- examined growthwere hair abnormal with those (7); disease Chanarin-Dorfman indicating leukocytes in droplets oflipid ence pres- forthe examined were to prone (6).Patients ciency defi- sulphatase detect to electrophoresis rum-lipoprotein (XRI) se- using ichthyosis recessive ofx-linked possibility for the (1,3–5). outlined as previously considered were patients male All K1, K6a, K10 the and in for mutations TGM1 was genes performed at –70 at stored and was collected ) cases some in (and (2). Blood described as previously EManalysis, and forhistology taken tinely rou- were skin examination, clinical thorough a and history patient’s the consulting first after sometimes file. full a from Apart symptoms, skin neonatal the about patients oradult parents viewing affected the byexamining either orbyinter- birth soon baby after tests. propriate A was ascertained disease ofthe onset congenital byap- excluded were deficiencies or nutritional infections to due erythroderma and bullosa disorderssuch as epidermolysis Blistering former orthe countries Eastern Middle from mainly Yugoslavia. immigrants previously were some but Swedish were citizens, tients country. the around orpaediatricians dermatologists with gether pa- All to- seen were patients these ourdepartment, to (AG). referred Ifnot Society,thyosis organization patient a authors ofthe byone chaired Swedish Ich- the via identified also were patients Some dermatoses. has official geno- fordiagnosing centre national 1999)as a (since status which Hospital, University ofUppsala ofDermatology Department the to (AV authors 1997–98bytwo ofthe in formed and AG) referred orwere per- survey onichthyosis national a via identified were patients The MATERIALMETHODS AND (1,2). time a ofCIat subtype on one focusing reports multinational in appeared already have results ofthe forCI.Some tools diagnostic the and gies survey, national recent a from aetiolo- discuss we the also onourexperience Sweden. Based like country mogeneous ho- fairly ethnically an ofCIin prevalence and variability ohwinkel’s (KID) syn- orKeratitis-Ichthyosis-Deafness syndrome The study was approved by the local ethics committee ofUppsala committee ethics local bythe was study approved The The inclusion criteria for CI are described in the Introduction. the in described forCIare criteria inclusion The phenotypic the illustrate to is article purpose ofthis The o C pending DNAC pending extraction. screening a appropriate, When (Fig. 1g) is almost invariably almost 1g)is (Fig. keratoderma palmoplantar that fact bythe obtained be can guidance clinical However some K1 orK10, mutated. , is keratin ofthe which about information any yield will techniques ofthese Of none 6a). course (Fig. keratinocytes suprabasal in nuclei around oftonofilaments sis shows clumping EM analy- if obtained be proofcan Further nosis 5a). (Fig. EHK diag- the confirm will epidermolysis suprabasal and layer granular the in degeneration opsy showing prominent adulthood. in also patients formany problem A bi- skin big a is that malodour the causing and blisters to dency ten- the EHK, increasing complicate frequently infections 1). Incidentally, (Fig. syndrome skin scalded lococci skin staphy- and deficiency orbiotin zinc , alized gener- bullosa, forepidermolysis mistaken be readily can when symptoms skin neonates, in is it than few months a of age the above children and patients EHK adult in alized affectedverely ago. 30–50years to compared today babies ofse- rate survival higher bya explained be also might ofEHK incidence increasing an decennium, last the over Sweden has increased in mutations keratin spontaneous of15(1). age of number the that indicate might this While the below children were EHK ourstudy with in patients EHK. Interestingly, as generalized generation ofthe most affected also are next the to transmitted be can trait this cells ofgonadal number substantial a provided but event, spontaneous EHK a always is nevoid causing mosaicism genetic Of ourstudy). a EHK course, in cases eralized gen- 80%ofthe (representing common are ous mutations spontane- but trait, autosomal-dominant an via inherited or post-conceptionally). are mutations keratin As rule, a (via inheritance or via a a orvia inheritance (via has originated mutation onhow and the resides, mutation K6a, K10, K16 orK17) affected, is the gene the in where (K1, genes K2e, keratin ofthe bywhich determined mainly is keratinopathies so-called ofthe heterogeneity clinical (8). mutations keratin negative bydominant caused The hyperkeratosis) invariably almost is congenita, EHK pachonychia and epidermolytic nevoid included ourstudy in which groupofdisorders, This (syn. ichthyosis Bullous in phenotypes and the usefulness of various diagnostic tests. diagnostic usefulness ofvarious the and phenotypes in below,rately variations onwithin-group emphasis an with 4). (Fig. ology discussed sepa- groups are main three The known aeti- orwithout with syndromes various with tients carried TGM1 mutations. group(n=26)was pa- third The large 3),a (Figs 2and types ofwhom (47%) proportion LI/CIE ofthe ichthyosis non-bullous with patients prised 1). Fig. in tures largest and second The group(n=80)com- pic- (clinical mutations keratin to due description) logic patho- a orEHK is (which ichthyosis bullous with patients groups (Tablemain I). group(n=21)comprised first The It is usually easier to make a clinical diagnosis ofgener- diagnosis clinical a make to easier usually is It de novo de

mutation in gonadal cells gonadal in mutation Ichthyosis in Sweden Sweden in Ichthyosis 35 Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 36 Fig. 1 Fig. man with severe EHK, especially in the flexures, flexures, the in EHK, especially severe with man blisters due to a K6a mutation, and and K6a mutation, a to due blisters K10 mutation, K10 mutation, to a K10 mutation showing generalized involvement of the trunk, velveted hyperkeratosis around the neck (close up), and int up),and (close neck the around hyperkeratosis velveted trunk, ofthe involvement showing generalized K10 a mutation to hyperkeratosis around the knees, knees, the around hyperkeratosis A. Vahlquist et al. et Vahlquist A. . Clinical spectrum of various keratinopathies: keratinopathies: ofvarious spectrum . Clinical (b)

the same patient a few months later, few months a patient same the (g) (k)

epidermolytic plantar keratoderma in a patient with generalized EHK due to a K1 mutation, K1 a mutation, EHK to due generalized with patient a in keratoderma plantar epidermolytic a close-up view of the finger nails in another boy with the same disease. same the boy with another in nails finger ofthe view close-up a (i)

a boy with suspected nevoid EHK, nevoid suspected boywith a (a) (c)

a newborn girl with epidermolytic hyperkeratosis (EHK, syn. bullous ichthyosis) due to a to due (EHK, ichthyosis) syn. bullous hyperkeratosis epidermolytic with newborn girl a

another case of neonatal EHK due to a K10 mutation, K10 a mutation, EHK to due ofneonatal case another (j)

an adolescent boy with and foot and congenita pachyonychia boywith adolescent an (d–f)

a 9-year-olda EHK due boywith ense (h)

and erythema a 30-year old 30-year a Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 with fine or focal scaling (CIFS) phenotype (i.e. ‘self-healing collodion baby’), baby’), collodion ‘self-healing (i.e. (CIFS) phenotype scaling orfocal fine with a 4-year-olda to due LI with girl II), and (EM type TGM1 mutation 2 Fig. (CIE) (EM type I and no Iand (EMtype (CIE) 6and Fig. see TGM1 mutations’– Table Iforexplanation), II). month-old baby with clumped fingers and toes (harlequin-like EM picture), EM picture), (harlequin-like toes and fingers clumped with baby month-old month-old baby with lamellar ichthyosis (LI) due to to due (LI) ichthyosis lamellar with baby month-old II), (EMtype TGM1 mutations . ichthyosis non-syndromic of non-bullous, spectrum childhood The (i)

a 10-year-olda boywith type (EM ofLI appearance focal a and TGM1 mutation (g) (a)

a 2-month-old baby with LI due to to due LI with baby 2-month-old a II), type (EM TGM1 mutations

a collodion baby who later developed a mild congenital ichthyosis congenital mild a developed who baby later collodion a (b)

(e) a newborn baby with congenital ichthyosiform erythroderma ichthyosiform congenital with newborn baby a (c)

a prematurely born baby with CIFS (EM type IV), CIFS with (EMtype bornbaby prematurely a

a case of harlequin ichthyosis 5 days after birth, birth, 5daysafter ichthyosis ofharlequin case a Ichthyosis in Sweden Sweden in Ichthyosis (d) (f)

a 6- a a 7- a (h) 37 Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 yeo ctyssdansi fpt aiismda alpalmoplantar Presence of & Hair median families Age (yr) No. of ofpat. Total no. diagnostic Additional Bullous type ofichthyosis main Clinicogenetic T EHK (Table ofnevoid case one in I)(1).So we have far EHK and generalized with patients all in identified were K1 orK10 mutations disease-causing (5). Inourmaterial, found be can mutation a before sequenced be to have genes frequently, Quite skin. lesional from tracted however, both DNA or, EHK, onRNA ofnevoid case the in orDNA ex- onblood mapping enzyme byrestriction accomplished K10 recommended. is genes easily relatively be can This K1 and the in mutations forhotspot screening a diagnosis, exact (1).For more a K10 mutations have usually therapy goodresponse to a with patients 9), whereas (see K1 with mutations associated Table refs. 1and Iand 38 Non-bullous Syndromes T photofobia, EKV:photofobia, sulfatase. SS: steroid variabilis; erythrokeratodermia ichthyosi KID: keratitis, defects, limb with ichthyosis hemilateral CHILD: congenital congenit ichthyosis linearis, KLICK: keratosis scaling, orfocal fine with ichthyosis congenital e ichthyosiform congenital and/or ichthyosis lamellar LI/CIE: hyperkeratosis, EHK: epidermolytic otal able I. able FPX neiac 0 0 1 2 1 1 2 0 1 0 0 2 0 1 30,50 0 7 0 15,40 9 3 39(1-49) 0 2 16 10(1-50) 7(3-30) 1 2 4 7 32,34 4 14 2 2(1) 1 1(0) 2(2) acid/s Phytanic 4 (3) 32 Typical histology 2 7(3) 22(1-79) 0 3(0) 4 3(1-33) 6 XR inheritance 1(1) analysis Linkage Cx26mutation 17 4 2(1) Refsum 14 3 Trichorrexis SS-deficiency Typical histology Sjögren-Larsson 30(2-81) 0 EKV 8 V 18(10) IFAP 19(1-71) 17 0 KID 3(2) Abnormal Netherton 9(8-20) Type 26(10-50) IV Iand CHILD 31 XRI 19(13) 16(12-32) Harlequin-like 6 3 38(21) KLICK 4 Type III Iand CIFS 8(3) 3(2) Type II Iand causes) (other LI/CIE 4(0) TGM1 mutations) to (due LI/CIE 6a ” 10 ” cong. Pachonychia 1 Keratin EHK Nevoid Generalized ocpn a yia itlg 0 211 1 72 1 1 (0) Typical histology Man Porcupine Tay A. Vahlquist et al. et Vahlquist A. hiklC 6mtto 0 001 0 60 1 1(0) Cx26mutation ohwinkel ( n Classification of 127 patients with congenital ichthyosis (incl. data from refs. 1, 2, 29 and 32) and 29 2, 1, refs. from data (incl. ichthyosis congenital with patients 127 of Classification =21) (n=26) ( n =80) idns(eae) rne eet keratoderma defects (range) (females) findings 06()41 1-4 0 0 keratohyaline 16(10-74) 4 6(4) 10 ” V findings: EM in: Mutations xldanss3()25(-)31 3 5(1-6) 2 3(0) Excl.diagnosis

aria:  2 6)1118 478 44 1-81 111 127 (67) 1 0-- - 60 1 1 (1) al., unpublished observation), whereas the other patients other the whereas observation), unpublished al., (P. K6a mutation a was carry study foundto Bowden et our in patients Swedish group(12).One ofthe another by childhood in reported been also have patients of the (11). cysts sebaceous multiple and abnormalities brane Two mem- mucous to association described frequently the had patient one and abnormalities, hair and ichthyosis cular folli- showed ourstudy in widespread patients ofeight out five Furthermore, 1j). (Fig. simplex bullosa epidermolysis of reminiscent blistering with soles, and palms ofthe tosis hyperkera- focal with present often 1k)and (Fig. changes (10). K2e mutations to EHK due knownbe to ficial Siemen’s the with found noSwedish patient ofsuper- type Patients with pachyonychia congenita have typical nail typical have congenita pachyonychia with Patients s and deafness, IFAP:s deafness, and follicularis, ichthyosis, and alopecia a and keratoderma, XRI:x-linked keratoderma, and a ichthyosis, recessive rythroderma, rythroderma, transglutaminaseTGM1: 1,CIFS: Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 amples of the EM findings in our study; the results in this in results the ourstudy; in EM findings of the amples orCIFS. ex- CIE 6 gives Fig. LI, into distinction clinical a with harmonize partially only foursubtypes which into ofCI classification proposed a (23–26)have al. et Niemi onEManalysis, Based tion). (22) and Anton-Lamprecht communica- (Dr personal K.-M. Niemi, oftreatment dent indepen- be to seem which findings ofepidermis, layers horny and granular the foundin be often can abnormalities Ultrastructurally,dermatotherapy). however, diagnostic and factors ofclimatic impact the when disregarding (even time over patients many in seen phenotype in variations marked bythe and genes candidate ofsuitable lack by a without tients 5e–h). (Fig. TGM1 mutations pa- in expression up-regulated oreven normal the with with patients 1in Tgase contrasts which TGM1 mutations, of expression decreased dramatically a reveals sis usually analy- immunohistochemical few patients, a byus in firmed 5b–d). However, shown con- (21)and byothers as already without and with patients between (Fig. TGM1 mutations noclear-cut are there histology skin on routine differences forpossible babies dion since especially TGM1 mutations, 5). refs. 1and collo- ofall screening early foran calls This (see ourmaterial in ofLI/CIE cause common Table Iand the in for –encoding TGM1 gene most the 1–were Tgase mutations heterozygous orcompound homozygous fact, (3,19,20).In envelopes cell ofcornified formation for the essential enzyme cross-linking 1),a 1 (Tgase glutaminase (2). common sis are hypohidro- and alopecia partial keratoderma, palmoplantar , with problems permanent orless more and (2,18) birth at baby-appearance ofcollodion history CI, a ofnon-bullous forms (2).Inall scaling) orfocal fine with 17) or, ichthyosis CIFS (congenital it, call to as we prefer (16, non-LI/non-CIE as: described ofCIbest forms mild very are there Inaddition, ichthyosis). lamellar recessive autosomal non-erythematous and NEARLI (erythematous and EARLI twoextremes: these call authors 3). Some (Fig. adulthood in 2)and (Fig. childhood during CIE and (2, 15). pattern inheritance dominant pseudo- a explaining thus allele, disease one carry found to was later children ofthe father (14),the byCIE fected af- twodaughters her and mother a with Swedish family a case, reported previously (13). Ina described been also has ofLI form dominant rare a forLI/CIE, rule the is ance defined. netically inherit- recessive autosomal Although ichthyosis) ge- be to remain ofwhich most entities, ofmany consists lamellar (e.g. ichthyosis groupofnon-syndromic heterogeneous This ichthyosis Non-bullous have not yet been studied in this respect. this in studied been yet not have The further subtyping of non-bullous CI is complicated CIis ofnon-bullous subtyping further The oftrans- deficiency is ofLI/CIE cause A major LI between presentations ofclinical spectrum a is There (Fig. 2c) previously described in detail (28), detail in described previously 2c) (Fig. (HI) ichthyosis Harlequin with girl a in bodies lamellar low). SLSbe- (see as having diagnosed she was later findings; EM nocharacteristic but 4a) (Fig. IV ichthyosis type with compatible who ourstudy symptoms skin had in babies premature ofthe byone illustrated ofCIis forms other from condition this forseparating ofEManalysis fulness (25). 2e) (Fig. asphyxia neonatal exhibiting and use- The born4–6weeks prematurely eyebrows ofinfants and scalp onthe especially material, bymasses ofkeratotic terized childhood. in later charac- is ofichthyosis type latter The symptoms ofskin improvement marked a and ichthyosis” “prematurity with patients IV two male was in type seen EM and picture), 3fforclinical Fig. (see unknown cause of LI with patients IIIwas three foundin EMtype study: our in encountered rarely only were EMtypes maining carrying patients to confined TGM1 mutations. re- The exclusively was hand, almost other II,onthe CI. EMtype ofnon-bullous subtypes clinicogenetic all virtually in seen abnormality, common most the is I,which EM type was in summarized are studies previous and Table I(2,27,29). Syndromes with congenital ichthyosis T congenital with Syndromes tion of otherwise normal corneocytes (Figs 5 and 6),an (Figs 5and corneocytes normal ofotherwise tion reten- opacities, (34),corneal ofcholesterol levels tissue decreased in as reflected sulphate, ofcholesterol mulation accu- to leads (33).It sulphatase ofcholesterol ficiency de- to due disease systemic a is males) 1:5000 prevalence XRI (usual siblings. were ofwhom two patients, male three in was identified symptoms ofskin onset congenital rare (Table very (XRI)a with ichthyosis recessive I).X-linked diagnosed were inheritance, ofMendelian fourmodes all organ different Eleven disease. syndromes, representing multi- underlying an suggesting symptoms extracutaneous ofKLICK unknown. is pathogenesis the in ofthis role exact the (32),but granules keratohyaline large show abnormally patients On EM,the volvement. unknown aetiology, in- has extracutaneous noobvious but of (31)is disease inherited recessively presumably This group. this within fit also 3j), (Fig. flexures the in striae typical exhibiting always keratoderma), and congenita (30). baby’ collodion ‘self-healing entitled phenomenon a 2a), (Fig. birth at phenotype transient but severe a group had CIFSwith (2). latter the in two children and adults Three patients in reported previously EMabnormalities agnostic scribed previously (29), and (29),and previously scribed de- 3g)also (Figs 2fand toes and fingers claw-like and CIE severe with 3patients in abnormalities ultrastructural wenty percent of the patients in our study had associated had ourstudy in patients ofthe percent wenty Additional EM findings were: were: EMfindings Additional Patients with KLICK (keratosis linearis, ichthyosis linearis, KLICK with (keratosis Patients (iii) several forms ofnon-di- forms several (i) Ichthyosis in Sweden Sweden in Ichthyosis

abnormalities ofthe abnormalities (ii) HI-like 39 Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 40 Fig. 3 Fig. type III), type treated lamellar ichthyosis (LI), (LI), ichthyosis lamellar treated flexures with mild LI, and and LI, mild with adolescent girl, girl, adolescent A. Vahlquist et al. et Vahlquist A. . Examples ichthyosis. non-syndromic ofnon-bullous, spectrum adult The (g) a man with severe CIE, note abnormal fingers (harlequin-like EM picture), EM picture), (harlequin-like fingers abnormal note CIE, severe with man a (d)

keratoderma in association with LI (EM type II), (EMtype LI with association in keratoderma (j)

a man with KLICK syndrome (keratosis linearis, ichthyosis congenita and keratoderma) and striate hyperke striate and keratoderma) and congenita ichthyosis linearis, KLICK (keratosis with syndrome man a (b)

a woman with a LI-congenital ichthyosiform erythroderma (CIE) overlap (EM type II), type (EM overlap (CIE) erythroderma ichthyosiform LI-congenital a with woman a (e)

women with severe LI and total alopecia (EM type I), type (EM alopecia total and LI severe with women a–e

are cases due to to due cases are TGM1 mutations: (h) a woman with moderate CIE (EM type I), (EMtype CIE moderate with woman a (a)

a man with severe, non- severe, with man a (f)

female with LI (EM LI with female (c)

a mild LI in an in LI mild a ratosis in the in ratosis (i) a woman a Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 mutilating keratoderma and constriction bands (pseudoainhum) around the finger. the around bands (pseudoainhum) constriction and keratoderma mutilating a 10-day-old baby with the same syndrome; note severe erythroderma of the arms, arms, ofthe erythroderma severe note syndrome; same the with baby 10-day-old a 4 Fig. 8 years later,8 years byDr Bergfelt, L. (picture face Hospital), Borås County typical ichthyotic plaques on the cheek, cheek, onthe plaques ichthyotic typical . Clinical spectrum of syndromic ichthyosis: ichthyosis: ofsyndromic spectrum . Clinical (h)

right thigh of a girl with erythrokeratodermia variables, and and variables, erythrokeratodermia with girl ofa thigh right (f)

the neck of an adult woman with suspected KID suspected syndrome, with woman adult ofan neck the (a) a newborn girl with Sjögren-Larsson syndrome (SLS); note the thick scales on the scalp and scalp onthe scales thick the note (SLS); syndrome Sjögren-Larsson with newborn girl a (b)

right flank of an adult male with SLS, with male adult ofan flank right (i–j)

the feet and fingers of a man with with man ofa fingers and feet the Vohwinkel’s showing syndrome (e)

girl with keratitis-ichthyosis-deafness (KID) and syndrome keratitis-ichthyosis-deafness with girl (c)

a newborn boy with Netherton’s newborn boywith a syndrome, (g)

the face of the same boy as in boyas in same ofthe face the Ichthyosis in Sweden Sweden in Ichthyosis (c) , although (d) 41 Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 related disease, hystrix-like ichthyosis with deafness syn- deafness with -like disease, related closely ofa hallmarks ofthe one is keratohyaline abnormal forKID (45), ultrastructurally syndrome pathognomonic 6h). (Fig. other the not is finding latter this Although in showed keratohyaline dispersed EManalysis vation); (Bondeson and our patients Vahlquist, obser- unpublished of one in identified was recently 26mutation cx causative (43,44). junctions gap the constitute 26,which cx teins, A pro- connexin ofthe one in mutations to due is 4e–f), (Fig. Sweden bornin women twounrelated in was identified 4g). (Fig. simpler diagnosis makes signs atopy and ever, skin and hair oftypical combination a life in later (42).How- 4c–d) (Fig. symptoms prevailing the are thrive to failure and infections life-threatening hypernatraemia, erythroderma, and missing often is abnormality hair when the period, neonatal the in especially erythroderma, Netherton’s and CIE ofsevere types other from syndrome difficult very be can It invaginata. chorrhexis separate to tri- demonstrating microscopy byhair confirmed be ally eventu- could diagnosis the ourpatients, in investigated (41). meostasis SPINK5 in not were mutations Although ho- barrier forskin important anti-protease foran codes en- SPINK5, in that gene a mutations to due is syndrome byus). Netherton’s examined (not birth weeks after several affected also lings just who died but disease, same bythe (40). childhood in reported Two sib- had patients ofthe been has previously patients adult One ofthe of 6months. age the at ofwhomdied one 7patients, in was identified (7), abnormalities shaft hair and erythroderma circumflexa, linearis byichthyosis characterized genodermatosis patient. this in investigated be to mains areas. skin of major (39)re- mutation gene causative The surgery excision repeated after transplantations skin and improved and oral to responsive She was partially shown). not (results cells foam typical and hyperkeratosis showed massive epithelium gastric and skin sies ofher biop- and involvement gastrointestinal had Shealso stan. from girl a in (38)was fetuses) diagnosed male to Afghani- (lethal trait dominant x-linked ofan mosaicism genetic to due defects) limb and ichthyosiform with dysplasia study, hemi- ofCHILD (congenital syndrome case a but our in encountered were (37).No such patients stature) short and ichthyosis linear punctata, (chondrodysplasia disease Conradi-Hunermann and agenesis) renal lateral Kallman’s uni- and stippled (ichthyosis, syndrome (36). arise sometimes can dromes Two are examples syn- gene contiguous so-called XRI gene, the including (7). carriers male fe- in malfunctioning placental and maldescence testicular to leading metabolism, hormone steroid the in turbances dis- (35),and hornylayer the over pH-gradient abnormal 42 KID (keratitis, ichthyosis and deafness) syndrome, which syndrome, deafness) and ichthyosis KID (keratitis, Netherton’s recessive autosomal an is which syndrome, oflarge deletions Owing variable to ofXp22.3, parts A. Vahlquist et al. et Vahlquist A. decreased fertility and short stature) (7,11), stature) short and fertility decreased was tentatively hair, brittle IBIDS (ichthyosis, impairment, intellectual (55). tissues and blood in acid ofphytanic levels of toxic accumulation an to (54)leading CoA hydroxylase Refsum’stoms. ofphytanoyl- deficiency to due is disease diffusemild, symp- neurological predominantly CIand who a one, had investigated Sweden we only in disease known ofRefsum’s cases Of several communication). sonal per- Sweden (Dr S. northern Jagell, in living are patients SLS handicapped neurologically and 20mentally other known not (53).Reportedly, is dehydrogenase hyde an- alde- offatty deficiency a to related SLS are in symptoms skin how the exactly (52).But analysis coupling genetic 6g). (Fig. patients the by was diagnosis confirmed The of ofsome corneum stratum the was in spaces seen lular intercel- ofthe On widening 4a–b). (Fig. EM,a trunk and neck the around (51),especially skin velveted acteristic (50). patients ofthe one in reported as previously acitretin, 4h). suppressed byoral successfully are symptoms The (Fig. plaques hyperkeratotic erythematous, and confluent bylarge, characterized usually is but phenotype sometimes variable has a it disease, ofthe name the in As reflected byus. was examined not this (43,49),although mutations 30.3 cx 31and cx to linked EKV has been uncertain. is (multi-organ) syndromic the disease this in involvement that fact the group,notwithstanding the in included were derma derma from syndrome Vohwinkel’s kerato- (mutilating disease distinguishes unequivocally which finding a Vohwinkel’s (Bondeson and tient Vahlquist, observation), unpublished pa- this in identified has been 26mutation cx causative retinoids. oral with treatment continuous despite noma A carci- cell squamous and ulcers foot to led ourpatient in which 4i), (Fig. keratoderma mutilating and 4j) (Fig. fingers the around bands (pseudo-) constriction deafness, neurosensoral byichthyosis, characterized is syndrome disease. ofthe history family noprevious with man The 60-year-old a in (43,47),was identified proteins junction photofobia. to leading eventually ofkeratitis onset gradual a and oflife, year first the during alopecia progressive a toses, hyperkera- follicular byspiny characterized is It origin. IFAPtoms. ofunknown disease x-linked an probably is symp- similar with uncle maternal has a whoden reportedly 1-year-old a in identified cently Swe- northern boyfrom (IFAP) photophobia and cia (46). was syndrome re- This alope- with follicularis KID ichthyosis is bling syndrome (44). 26mutations by cx resem- clinically disease Another review). 7fora ref. (see drome caused also is disease This loricrin gene (48). gene loricrin Another neurocutaneous disease, disease, neurocutaneous Another Tay’s or syndrome char- the with all SLS identified, were with Four patients V T wo patients with erythrokeratodermia variabilis (EKV) variabilis erythrokeratodermia with wo patients ohwinkel’s gap byabnormal caused also syndrome, without

hearing problems) due to mutations in the in mutations to due problems) hearing Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 to bacterial infections. However, infections. bacterial to was al- disease latter the proneness and byCI,myopathi (59), characterized disease Chanarin-Dorfman cause found to been have 58 mutations CGI- (58)and CIE with patients North-African found in and been 17have chromosome to ALOX12B linked genes emerged. recently have the in Thus mutations ALOXE3 genes candidate few interesting a 40%ofcases, maining Sweden (see in observed CIcases all Table re- I).For the for15%of known with aetiology syndromes various and 15%, forabout account tations for30% TGM1 mutations ofCI. causes established ready mu- keratin Thus classified, ofal- analysis an with combined are findings structural ultra- and clinical if obtained be can classification useful a that subgroup one ofCI,we believe within even siderable communication). personal (Dr Scandinavia foundoutside scarcely T. Jr, Gedde-Dahl IV) is (EMtype ichthyosis’ ‘prematurity Sweden (51)and northern to clustering SLS shows genetic For example, ofCI. types ofsome incidence the influence may fects, ef- founder local and Sweden, such as consanguinity in However,ref.7). peculiarities ethno-geographical certain (forreview, countries other formany ures reported see 000. 1/50 at estimated offig- range the within falls This Sweden is ofCIin prevalence the of9million, figure tion amination. Taking popula- a given and account into this forex- available not were other orthe who reason forone We under-represented probably were symptoms, ourstudy. in suffer extracutaneous predominantly syndromeswith from who those and advice, dermatologic seek to CI who fail say, to Needless millennium. ofthe turn mild with patients the Sweden around in living ofCIpatients majority vast the represent here described 127 cases the that believe to country. same the and one ofCIin types We reason have ofvarious frequency and spectrum overall the scribing To CONCLUDING COMMENTS vitamin high-dose A (57). goodresults with therapy courses short of 1980s was he given the in was introduced this before long also but acitretin, oral with ous treatment continu- to well He responded retardation. mental mild a our70-year-old in and radically with was associated patient sata pine Man syndrome ( Man syndrome pine disease. forthis able avail- were tests Sweden (56).No from diagnostic ported month). We re- case additional one least ofat aware are of1 age the at ofwhomdied (one babies born as collodion 5-year-old a in identified twins ofmale couple a in boyand Although the phenotypic and genotypic variability is con- is variability genotypic and phenotypic the Although Lastly, Porcu- rare very the with patient a we identified the best of our knowledge this is the first report de- report first the is this ofourknowledge best the are also aware of some patients with severe ichthyosis severe with patients ofsome aware also are ). spo- occurs ofunknown syndrome aetiology This malformatio ectodermalis generali- ectodermalis malformatio from the E. E. the from Welander Foundations. Finsen and Council. bygrants possible was made report ofthis publication The County Uppsala and Council Research Swedish Medical the from came support Financial analyses. ultrastructural and histologic the in assisted Ms Benita mutations. Pihl-Lundin Inger and Jarild Andersson, Madeleine Dr Bowden, Cardiff, Paul keratin ofthe some identify us to forhelping We Dr T. Jr, Gedde-Dahl, Olso University, acknowledged. gratefully are University, Uppsala Unit, Genetics N. Clinical Bondeson and Dahl, and us. to patients ring Drs discussions with M.-L. genetic valuable The We We ACKNOWLEDGEMENTS (63). diseases ofthese for some forCI. pies promising are therapy forgene prospects The .Virtanen K, Gedde-Dahl M, Smith T, Vahlquist A, Bowden P. 5. JL,Kansky Bowden Haley PE, JA, JonesA, DO, Rothnagel 4. M, Pigg Gedde-Dahl T, CoxD, Hausser I, I, Anton-Lamprecht 3. 2. Virtanen M, Gedde-Dahl T, Mörk I,Bowden P, N-J, Leigh 1. REFERENCES enable: enable: also ofCIwill aetiology ofthe knowledge exact more and neonates. in diagnosis the A accuracy diagnostic higher work to out when trying analysis EM forexample than ity prior- higher a given be can mutations gene ease-causing Consequently, DNA ofblood screening the dis- forvarious effective more ofCIfar genotyping make today. is it than (60–62). forLI/CIE loci more several indicated has already analysis coupling deed, ofCI.In- classification the improving thus identified, be soon will new causes several genetics, of molecular vance (7).Hopefully, inclusions forlipid leukocytes ad- the with blood their examining after ourpatients in excluded ready information, and and information, The development of new microarray techniques will soon will techniques ofnew microarray development The thank all Swedish colleagues who made this study possible byrefer- possible study this who made Swedish colleagues all thank thank Dr K.-M. Niemi, Helsinki, for expert opinions about EM and EM about opinions forexpert Dr Helsinki, K.-M.thank Niemi, Dermatol 2003 (in press). 2003(in Dermatol J Invest hyperkeratosis. epidermolytic with patients navian KRT10)and Scandi- in alterations phenotypic unusual genes: (KRT1 mutations keratin in mutations deletion and site Splice 363–365. 10: 1995; Genet Nat congenita. onychia T 589–596. Norway. from erythroderma 6: 1998; Genetics J Eur Human ichthyosiform congenital and ichthyosis lamellar in tion effect N. founder Dahl Strong 1muta- transglutaminase fora 30. 83patients. in findings tural Derm Acta Venereol 83:24– 2003; ultrastruc- and genetic Clinical, Estonia: Sweden and in thyosis P,Rossman-Ringdahl al. et ich- congenital recessive Autosomal Gånemo A, M, Pigg Virtanen M, Kukk T, H, Raudsepp 170. expression. on keratin Derm Acta Venereol 163– 81: 2001; effects the and hyperkeratosis epidermolytic therapy ofretinoid V urner RJ. Mutation of a type II keratin gene (K6a) in pachy- (K6a) in gene IIkeratin type ofa RJ.urner Mutation ahlquist ahlquist with patients in correlations A. Phenotypic/Genotypic (i)

improved genetic counselling, counselling, genetic improved (iii)

development of more specific thera- specific ofmore development Ichthyosis in Sweden Sweden in Ichthyosis (ii)

better patient better 43 Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 antibodies against transglutaminase 1 (Tgase1)). 1(Tgase1)). transglutaminase against antibodies 44 Fig. 5 Fig. LI without without LI and TGM1 1mutations, with hyperkeratosis, acanthosis and dermal , inflammation, dermal and acanthosis hyperkeratosis, with massive hyperkeratosis, hyperkeratosis, massive in severe LI due to homozygous homozygous to due LI severe in TGM1 mutations, A. Vahlquist et al. et Vahlquist A. . Histopathologic abnormalities in various types of congenital ichthyosis ( ichthyosis ofcongenital types various in abnormalities . Histopathologic (b)

lamellar ichthyosis (LI) showing mild hyperkeratosis and acanthosis, acanthosis, and hyperkeratosis showing (LI) mild ichthyosis lamellar (h) overexpression of overexpression without CIE 1in Tgase TGM1 mutations. (a) (f)

Epidermolytic hyperkeratosis (bullous ichthyosis) showing acanthosis, suprabasal cytolysis and cytolysis suprabasal showing acanthosis, ichthyosis) (bullous hyperkeratosis Epidermolytic

weak expression in a milder type of LI also due to to due also of LI type milder a in expression weak TGM1 mutations, (d)

x-linked recessive ichthyosis with mild orthohyperkeratosis, orthohyperkeratosis, mild with ichthyosis recessive x-linked a–d:

van Gieson staining; Gieson staining; van (c)

congenital ichthyosiform erythroderma (CIE) erythroderma ichthyosiform congenital e–h:

immunoperoxidase staining using staining immunoperoxidase (e) (g)

no Tgase1 expression no Tgase1

normal expression in expression normal Downloaded By: [Akademiska Sjukhuset] At: 12:48 5 October 2007 with membrane inclusions (arrowheads) in “prematurity ichthyosis” (EM type IV), (EMtype ichthyosis” “prematurity in (arrowheads) inclusions membrane with around the nuclei in bullous ichthyosis (epidermolytic hyperkeratosis), hyperkeratosis), (epidermolytic ichthyosis bullous in nuclei the around dispersed keratohyaline in KID syndrome, previously reported also in hystrix-like ichthyosis with deafness (7). deafness with ichthyosis hystrix-like in also reported KID in previously syndrome, keratohyaline dispersed 6 Fig. type II), type erythroderma (CIE) of unknown cause (EM type I), type (EM ofunknown (CIE) cause erythroderma (arrows) in x-linked ichthyosis, ichthyosis, (arrows) x-linked in . Electron microscopy (EM) analysis of superficial epidermis in various types of congenital ichthyosis s ichthyosis ofcongenital types various in epidermis ofsuperficial (EM) analysis microscopy . Electron (d)

elongated intra-corneocyte membranes (arrowheads) in LI of unknown cause (EM type III), (EM type ofunknown LI cause in (arrowheads) membranes intra-corneocyte elongated (g)

abnormally wide intercorneocyte spaces (x) in Sjögren-Larsson syndrome (picture by Dr H. Nordlinder), and byDr and H. Nordlinder), (picture syndrome Sjögren-Larsson (x)in spaces intercorneocyte wide abnormally (c)

aggregates of “ clefts” in lamellar ichthyosis (LI) due to to due (LI) ichthyosis lamellar in clefts” of“cholesterol aggregates (EM TGM1 mutations (b)

numerous intra-corneocyte droplets in congenital ichthyosisform congenital in droplets intra-corneocyte numerous (f)

densely packed corneocytes with well-developed cell envelopes cell well-developed with corneocytes packed densely (e)

lentiform areas in filled corneum stratum in areas lentiform howing: howing: (a) Ichthyosis in Sweden Sweden in Ichthyosis

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